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Sample records for strong genetic risk

  1. Genetic and environmental contributions to cardiovascular disease risk in American Indians: the strong heart family study.

    Science.gov (United States)

    North, Kari E; Howard, Barbara V; Welty, Thomas K; Best, Lyle G; Lee, Elisa T; Yeh, J L; Fabsitz, Richard R; Roman, Mary J; MacCluer, Jean W

    2003-02-15

    The aims of the Strong Heart Family Study are to clarify the genetic determinants of cardiovascular disease (CVD) risk in American Indians and to map and identify genes for CVD susceptibility. The authors describe the design of the Strong Heart Family Study (conducted between 1998 and 1999) and evaluate the heritabilities of CVD risk factors in American Indians from this study. In the first phase of the study, approximately 950 individuals, aged 18 years or more, in 32 extended families, were examined. The examination consisted of a personal interview, physical examination, laboratory tests, and an ultrasound examination of the carotid arteries. The phenotypes measured during the physical examination included anthropometry, lipoproteins, blood pressure, glycemic status, and clotting factors. Heritabilities for CVD risk factor phenotypes were estimated using a variance component approach and the program SOLAR. After accounting for the effects of covariates, the authors detected significant heritabilities for many CVD risk factor phenotypes (e.g., high density lipoprotein cholesterol (heritability = 0.50) and diastolic blood pressure (heritability = 0.34)). These results suggest that heredity explains a substantial proportion of the variability of CVD risk factors and that these heritabilities are large enough to warrant a search for major risk factor genes.

  2. Strongly enhanced colorectal cancer risk stratification by combining family history and genetic risk score

    Directory of Open Access Journals (Sweden)

    Weigl K

    2018-01-01

    Full Text Available Korbinian Weigl,1,2 Jenny Chang-Claude,3,4 Phillip Knebel,5 Li Hsu,6 Michael Hoffmeister,1 Hermann Brenner1,2,7 1Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ, Heidelberg, 2German Cancer Consortium (DKTK, German Cancer Research Center (DKFZ, Heidelberg, 3Unit of Genetic Epidemiology, German Cancer Research Center (DKFZ, Heidelberg, 4University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, 5Department for General, Visceral and Transplantation Surgery, University Heidelberg, Heidelberg, Germany; 6Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 7Division of Preventive Oncology, German Cancer Research Center (DKFZ and National Center for Tumor Diseases (NCT, Heidelberg, Germany Background and aim: Family history (FH and genetic risk scores (GRSs are increasingly used for risk stratification for colorectal cancer (CRC screening. However, they were mostly considered alternatively rather than jointly. The aim of this study was to assess the potential of individual and joint risk stratification for CRC by FH and GRS.Patients and methods: A GRS was built based on the number of risk alleles in 53 previously identified single-nucleotide polymorphisms among 2,363 patients with a first diagnosis of CRC and 2,198 controls in DACHS [colorectal cancer: chances for prevention through screening], a population-based case-control study in Germany. Associations between GRS and FH with CRC risk were quantified by multiple logistic regression.Results: A total of 316 cases (13.4% and 214 controls (9.7% had a first-degree relative (FDR with CRC (adjusted odds ratio [aOR] 1.86, 95% CI 1.52–2.29. A GRS in the highest decile was associated with a 3.0-fold increased risk of CRC (aOR 3.00, 95% CI 2.24–4.02 compared with the lowest decile. This association was tentatively more pronounced in older age groups. FH and GRS were essentially unrelated, and their

  3. Individual genetic variations related to satiety and appetite control increase risk of obesity in preschool-age children in the STRONG kids program.

    Science.gov (United States)

    Wang, Yingying; Wang, Anthony; Donovan, Sharon M; Teran-Garcia, Margarita

    2013-01-01

    The burden of the childhood obesity epidemic is well recognized; nevertheless, the genetic markers and gene-environment interactions associated with the development of common obesity are still unknown. In this study, candidate genes associated to satiety and appetite control pathways with obesity-related traits were tested in Caucasian preschoolers from the STRONG Kids project. Eight genetic variants in genes related to obesity (BDNF, LEPR, FTO, PCSK1, POMC, TUB, LEP, and MC4R) were genotyped in 128 children from the STRONG Kids project (mean age 39.7 months). Data were analyzed for individual associations and to test for genetic predisposition scores (GPSs) with body mass index (BMI) and anthropometric traits (Z-scores, e.g. height-for-age Z-score, HAZ). Covariates included age, sex, and breastfeeding (BF) duration. Obesity and overweight prevalence was 6.3 and 19.5%, respectively, according to age- and sex-specific BMI percentiles. Individual genetic associations of MC4R and LEPR markers with HAZ were strengthened when BF duration was included as a covariate. Our GPSs show that, as the number of risk alleles increased, the risk of higher BMI and HAZ also increased. Overall, the GPSs assembled were able to explain 2-3% of the variability in BMI and HAZ phenotypes. Genetic associations with common obesity-related phenotypes were found in the STRONG Kids project. GPSs assembled for specific candidate genes were associated with BMI and HAZ phenotypes. © 2013 S. Karger AG, Basel.

  4. Assessing the impact of a combined analysis of four common low-risk genetic variants on autism risk

    Directory of Open Access Journals (Sweden)

    Carayol Jerome

    2010-02-01

    Full Text Available Abstract Background Autism is a complex disorder characterized by deficits involving communication, social interaction, and repetitive and restrictive patterns of behavior. Twin studies have shown that autism is strongly heritable, suggesting a strong genetic component. In other disease states with a complex etiology, such as type 2 diabetes, cancer and cardiovascular disease, combined analysis of multiple genetic variants in a genetic score has helped to identify individuals at high risk of disease. Genetic scores are designed to test for association of genetic markers with disease. Method The accumulation of multiple risk alleles markedly increases the risk of being affected, and compared with studying polymorphisms individually, it improves the identification of subgroups of individuals at greater risk. In the present study, we show that this approach can be applied to autism by specifically looking at a high-risk population of children who have siblings with autism. A two-sample study design and the generation of a genetic score using multiple independent genes were used to assess the risk of autism in a high-risk population. Results In both samples, odds ratios (ORs increased significantly as a function of the number of risk alleles, with a genetic score of 8 being associated with an OR of 5.54 (95% confidence interval [CI] 2.45 to 12.49. The sensitivities and specificities for each genetic score were similar in both analyses, and the resultant area under the receiver operating characteristic curves were identical (0.59. Conclusions These results suggest that the accumulation of multiple risk alleles in a genetic score is a useful strategy for assessing the risk of autism in siblings of affected individuals, and may be better than studying single polymorphisms for identifying subgroups of individuals with significantly greater risk.

  5. Genetic, Maternal, and Environmental Risk Factors for Cryptorchidism

    DEFF Research Database (Denmark)

    Barthold, Julia Spencer; Reinhardt, Susanne; Thorup, Jorgen

    2016-01-01

    genetic risk, multiple susceptibility loci, and a role for the maternal environment. Epidemiologic studies have identified low birth weight or intrauterine growth retardation as factors most strongly associated with cryptorchidism, with additional evidence suggesting that maternal smoking and gestational...

  6. Trapped in the extinction vortex? Strong genetic effects in a declining vertebrate population

    Directory of Open Access Journals (Sweden)

    Larsson Mikael

    2010-02-01

    Full Text Available Abstract Background Inbreeding and loss of genetic diversity are expected to increase the extinction risk of small populations, but detailed tests in natural populations are scarce. We combine long-term population and fitness data with those from two types of molecular markers to examine the role of genetic effects in a declining metapopulation of southern dunlins Calidris alpina schinzii, an endangered shorebird. Results The decline is associated with increased pairings between related individuals, including close inbreeding (as revealed by both field observations of parentage and molecular markers. Furthermore, reduced genetic diversity seems to affect individual fitness at several life stages. Higher genetic similarity between mates correlates negatively with the pair's hatching success. Moreover, offspring produced by related parents are more homozygous and suffer from increased mortality during embryonic development and possibly also after hatching. Conclusions Our results demonstrate strong genetic effects in a rapidly declining population, emphasizing the importance of genetic factors for the persistence of small populations.

  7. Strong evidence for a genetic contribution to late-onset Alzheimer's disease mortality: a population-based study.

    Directory of Open Access Journals (Sweden)

    John S K Kauwe

    Full Text Available Alzheimer's disease (AD is an international health concern that has a devastating effect on patients and families. While several genetic risk factors for AD have been identified much of the genetic variance in AD remains unexplained. There are limited published assessments of the familiality of Alzheimer's disease. Here we present the largest genealogy-based analysis of AD to date.We assessed the familiality of AD in The Utah Population Database (UPDB, a population-based resource linking electronic health data repositories for the state with the computerized genealogy of the Utah settlers and their descendants. We searched UPDB for significant familial clustering of AD to evaluate the genetic contribution to disease. We compared the Genealogical Index of Familiality (GIF between AD individuals and randomly selected controls and estimated the Relative Risk (RR for a range of family relationships. Finally, we identified pedigrees with a significant excess of AD deaths.The GIF analysis showed that pairs of individuals dying from AD were significantly more related than expected. This excess of relatedness was observed for both close and distant relationships. RRs for death from AD among relatives of individuals dying from AD were significantly increased for both close and more distant relatives. Multiple pedigrees had a significant excess of AD deaths.These data strongly support a genetic contribution to the observed clustering of individuals dying from AD. This report is the first large population-based assessment of the familiality of AD mortality and provides the only reported estimates of relative risk of AD mortality in extended relatives to date. The high-risk pedigrees identified show a true excess of AD mortality (not just multiple cases and are greater in depth and width than published AD pedigrees. The presence of these high-risk pedigrees strongly supports the possibility of rare predisposition variants not yet identified.

  8. Genetic variants in hormone-related genes and risk of breast cancer.

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    Tess Clendenen

    Full Text Available Sex hormones play a key role in the development of breast cancer. Certain polymorphic variants (SNPs and repeat polymorphisms in hormone-related genes are associated with sex hormone levels. However, the relationship observed between these genetic variants and breast cancer risk has been inconsistent. We conducted a case-control study nested within two prospective cohorts to assess the relationship between specific genetic variants in hormone-related genes and breast cancer risk. In total, 1164 cases and 2111 individually-matched controls were included in the study. We did not observe an association between potential functional genetic polymorphisms in the estrogen pathway, SHBG rs6259, ESR1 rs2234693, CYP19 rs10046 and rs4775936, and UGT1A1 rs8175347, or the progesterone pathway, PGR rs1042838, with the risk of breast cancer. Our results suggest that these genetic variants do not have a strong effect on breast cancer risk.

  9. Genetic risks from radiation

    International Nuclear Information System (INIS)

    Selby, P.B.

    Two widely-recognized committees, UNSCEAR and BEIR, have reevaluated their estimates of genetic risks from radiation. Their estimates for gene mutations are based on two different approaches, one being the doubling-dose approach and the other being a new direct approach based on an empirical determination of the amount of dominant induced damage in the skeletons of mice in the first generation following irradiation. The estimates made by these committees are in reasonably good agreement and suggest that the genetic risks from present exposures resultng from nuclear power production are small. There is room for much improvement in the reliability of the risk estimates. The relatively new approach of measuring the amount of induced damage to the mouse skeleton shows great promise of improving knowledge about how changes in the mutation frequency affect the incidence of genetic disorders. Such findings may have considerable influence on genetic risk estimates for radiation and on the development of risk estimates for other less-well-understood environmental mutagens. (author)

  10. Strong genetic overlap between executive functions and intelligence.

    Science.gov (United States)

    Engelhardt, Laura E; Mann, Frank D; Briley, Daniel A; Church, Jessica A; Harden, K Paige; Tucker-Drob, Elliot M

    2016-09-01

    Executive functions (EFs) are cognitive processes that control, monitor, and coordinate more basic cognitive processes. EFs play instrumental roles in models of complex reasoning, learning, and decision making, and individual differences in EFs have been consistently linked with individual differences in intelligence. By middle childhood, genetic factors account for a moderate proportion of the variance in intelligence, and these effects increase in magnitude through adolescence. Genetic influences on EFs are very high, even in middle childhood, but the extent to which these genetic influences overlap with those on intelligence is unclear. We examined genetic and environmental overlap between EFs and intelligence in a racially and socioeconomically diverse sample of 811 twins ages 7 to 15 years (M = 10.91, SD = 1.74) from the Texas Twin Project. A general EF factor representing variance common to inhibition, switching, working memory, and updating domains accounted for substantial proportions of variance in intelligence, primarily via a genetic pathway. General EF continued to have a strong, genetically mediated association with intelligence even after controlling for processing speed. Residual variation in general intelligence was influenced only by shared and nonshared environmental factors, and there remained no genetic variance in general intelligence that was unique of EF. Genetic variance independent of EF did remain, however, in a more specific perceptual reasoning ability. These results provide evidence that genetic influences on general intelligence are highly overlapping with those on EF. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

  11. Risk perception after genetic counseling in patients with increased risk of cancer

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    Rantala Johanna

    2009-08-01

    Full Text Available Abstract Background Counselees are more aware of genetics and seek information, reassurance, screening and genetic testing. Risk counseling is a key component of genetic counseling process helping patients to achieve a realistic view for their own personal risk and therefore adapt to the medical, psychological and familial implications of disease and to encourage the patient to make informed choices 12. The aim of this study was to conceptualize risk perception and anxiety about cancer in individuals attending to genetic counseling. Methods The questionnaire study measured risk perception and anxiety about cancer at three time points: before and one week after initial genetic counseling and one year after completed genetic investigations. Eligibility criteria were designed to include only index patients without a previous genetic consultation in the family. A total of 215 individuals were included. Data was collected during three years period. Results Before genetic counseling all of the unaffected participants subjectively estimated their risk as higher than their objective risk. Participants with a similar risk as the population overestimated their risk most. All risk groups estimated the risk for children's/siblings to be lower than their own. The benefits of preventive surveillance program were well understood among unaffected participants. The difference in subjective risk perception before and directly after genetic counseling was statistically significantly lower in all risk groups. Difference in risk perception for children as well as for population was also statistically significant. Experienced anxiety about developing cancer in the unaffected subjects was lower after genetic counseling compared to baseline in all groups. Anxiety about cancer had clear correlation to perceived risk of cancer before and one year after genetic investigations. The affected participants overestimated their children's risk as well as risk for anyone in

  12. Lobular breast cancer: incidence and genetic and non-genetic risk factors.

    Science.gov (United States)

    Dossus, Laure; Benusiglio, Patrick R

    2015-03-13

    While most invasive breast cancers consist of carcinomas of the ductal type, about 10% are invasive lobular carcinomas. Invasive lobular and ductal carcinomas differ with respect to risk factors. Invasive lobular carcinoma is more strongly associated with exposure to female hormones, and therefore its incidence is more subject to variation. This is illustrated by US figures during the 1987 to 2004 period: after 12 years of increases, breast cancer incidence declined steadily from 1999 to 2004, reflecting among other causes the decreasing use of menopausal hormone therapy, and these variations were stronger for invasive lobular than for invasive ductal carcinoma. Similarly, invasive lobular carcinoma is more strongly associated with early menarche, late menopause and late age at first birth. As for genetic risk factors, four high-penetrance genes are tested in clinical practice when genetic susceptibility to breast cancer is suspected, BRCA1, BRCA2, TP53 and CDH1. Germline mutations in BRCA1 and TP53 are predominantly associated with invasive ductal carcinoma, while BRCA2 mutations are associated with both ductal and lobular cancers. CDH1, the gene coding for the E-cadherin adhesion protein, is of special interest as mutations are associated with invasive lobular carcinoma, but never with ductal carcinoma. It was initially known as the main susceptibility gene for gastric cancer of the diffuse type, but the excess of breast cancers of the lobular type in CDH1 families led researchers to identify it also as a susceptibility gene for invasive lobular carcinoma. The risk of invasive lobular carcinoma is high in female mutation carriers, as about 50% are expected to develop the disease. Carriers must therefore undergo intensive breast cancer screening, with, for example, yearly magnetic resonance imaging and mammogram starting at age 30 years.

  13. Genetic and environmental influences on risk of death due to infections assessed in Danish twins, 1943-2001

    DEFF Research Database (Denmark)

    Obel, Niels; Christensen, Kaare; Petersen, Inge

    2010-01-01

    Genetic differences have been proposed to play a strong role in risk of death from infectious diseases. The study base of 44,005 included all same-sex twin pairs born in 1870-2001, with both twins alive on January 1, 1943, or those born thereafter. Cause of death was obtained from the Danish Cause...... from infectious diseases could be demonstrated, the absolute effect of the genetic component on mortality was small....... genetic influence on the risk of death...

  14. An animal model of differential genetic risk for methamphetamine intake

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    Tamara ePhillips

    2015-09-01

    Full Text Available The question of whether genetic factors contribute to risk for methamphetamine (MA use and dependence has not been intensively investigated. Compared to human populations, genetic animal models offer the advantages of control over genetic family history and drug exposure. Using selective breeding, we created lines of mice that differ in genetic risk for voluntary MA intake and identified the chromosomal addresses of contributory genes. A quantitative trait locus was identified on chromosome 10 that accounts for more than 50% of the genetic variance in MA intake in the selected mouse lines. In addition, behavioral and physiological screening identified differences corresponding with risk for MA intake that have generated hypotheses that are testable in humans. Heightened sensitivity to aversive and certain physiological effects of MA, such as MA-induced reduction in body temperature, are hallmarks of mice bred for low MA intake. Furthermore, unlike MA-avoiding mice, MA-preferring mice are sensitive to rewarding and reinforcing MA effects, and to MA-induced increases in brain extracellular dopamine levels. Gene expression analyses implicate the importance of a network enriched in transcription factor genes, some of which regulate the mu opioid receptor gene, Oprm1, in risk for MA use. Neuroimmune factors appear to play a role in differential response to MA between the mice bred for high and low intake. In addition, chromosome 10 candidate gene studies provide strong support for a trace amine associated receptor 1 gene, Taar1, polymorphism in risk for MA intake. MA is a trace amine-associated receptor 1 (TAAR1 agonist, and a non-functional Taar1 allele segregates with high MA consumption. Thus, reduced TAAR1 function has the potential to increase risk for MA use. Overall, existing findings support the MA drinking lines as a powerful model for identifying genetic factors involved in determining risk for harmful MA use. Future directions include the

  15. Debunking vaccination myths: strong risk negations can increase perceived vaccination risks.

    Science.gov (United States)

    Betsch, Cornelia; Sachse, Katharina

    2013-02-01

    Information about risks is often contradictory, especially in the health domain. A vast amount of bizarre information on vaccine-adverse events (VAE) can be found on the Internet; most are posted by antivaccination activists. Several actors in the health sector struggle against these statements by negating claimed risks with scientific explanations. The goal of the present work is to find optimal ways of negating risk to decrease risk perceptions. In two online experiments, we varied the extremity of risk negations and their source. Perception of the probability of VAE, their expected severity (both variables serve as indicators of perceived risk), and vaccination intentions. Paradoxically, messages strongly indicating that there is "no risk" led to a higher perceived vaccination risk than weak negations. This finding extends previous work on the negativity bias, which has shown that information stating the presence of risk decreases risk perceptions, while information negating the existence of risk increases such perceptions. Several moderators were also tested; however, the effect occurred independently of the number of negations, recipient involvement, and attitude. Solely the credibility of the information source interacted with the extremity of risk negation: For credible sources (governmental institutions), strong and weak risk negations lead to similar perceived risk, while for less credible sources (pharmaceutical industries) weak negations lead to less perceived risk than strong negations. Optimal risk negation may profit from moderate rather than extreme formulations as a source's trustworthiness can vary.

  16. Fine mapping in the MHC region accounts for 18% additional genetic risk for celiac disease

    NARCIS (Netherlands)

    Gutierrez-Achury, Javier; Zhernakova, Alexandra; Pulit, Sara L.; Trynka, Gosia; Hunt, Karen A.; Romanos, Jihane; Raychaudhuri, Soumya; van Heel, David A.; Wijmenga, Cisca; de Balcker, Paul I. W.

    Although dietary gluten is the trigger for celiac disease, risk is strongly influenced by genetic variation in the major histocompatibility complex (MHC) region. We fine mapped the MHC association signal to identify additional risk factors independent of the HLA-DQA1 and HLA-DQB1 alleles and

  17. White Matter Hyperintensities Are Under Strong Genetic Influence.

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    Sachdev, Perminder S; Thalamuthu, Anbupalam; Mather, Karen A; Ames, David; Wright, Margaret J; Wen, Wei

    2016-06-01

    The genetic basis of white matter hyperintensities (WMH) is still unknown. This study examines the heritability of WMH in both sexes and in different brain regions, and the influence of age. Participants from the Older Australian Twins Study were recruited (n=320; 92 monozygotic and 68 dizygotic pairs) who volunteered for magnetic resonance imaging scans and medical assessments. Heritability, that is, the ratio of the additive genetic variance to the total phenotypic variance, was estimated using the twin design. Heritability was high for total WMH volume (0.76), and for periventricular WMH (0.64) and deep WMH (0.77), and varied from 0.18 for the cerebellum to 0.76 for the occipital lobe. The genetic correlation between deep and periventricular WMH regions was 0.85, with one additive genetics factor accounting for most of the shared variance. Heritability was consistently higher in women in the cerebral regions. Heritability in deep but not periventricular WMH declined with age, in particular after the age of 75. WMH have a strong genetic influence but this is not uniform through the brain, being higher for deep than periventricular WMH and in the cerebral regions. The genetic influence is higher in women, and there is an age-related decline, most markedly for deep WMH. The data suggest some heterogeneity in the pathogenesis of WMH for different brain regions and for men and women. © 2016 American Heart Association, Inc.

  18. Genetic cancer risk assessment in practice

    International Nuclear Information System (INIS)

    Gruber, S.

    2004-01-01

    The advent of genetic testing has made a dramatic impact on the management of individuals with inherited susceptibility to cancer and their relatives. Genetic counsel ing, with or without testing, is warranted when clues to familial cancer are recognized. Today, genetic testing for classic cancer genetic syndromes is now the standard of care, and has been complemented by genetic testing for other situations commonly encountered in clinical practice. Genetic testing for colorectal cancer, breast cancer, kidney cancer, thyroid cancer, melanoma, and pancreatic cancer raise important issues about the parameters for testing. Genetic cancer risk assessment can lead to measurable reductions in morbidity and mortality through strategies that rely on surveillance, chemo prevention, and risk-reducing surgery

  19. Genetic risks of ionizing radiation

    International Nuclear Information System (INIS)

    Sankaranarayanan, K.

    1990-01-01

    Quantitative genetic risk estimation is made using two methods: the direct method, and the doubling dose (DD) method. The doubling dose currently used is 1 Gy for low LET, low dose, low dose rate irradiation, and is based on mouse data. Tables present the 1988 UNSCEAR estimates of genetic risk using both methods. (L.L.) (Tab.)

  20. Adaptive divergence despite strong genetic drift: genomic analysis of the evolutionary mechanisms causing genetic differentiation in the island fox (Urocyon littoralis)

    Science.gov (United States)

    FUNK, W. CHRIS; LOVICH, ROBERT E.; HOHENLOHE, PAUL A.; HOFMAN, COURTNEY A.; MORRISON, SCOTT A.; SILLETT, T. SCOTT; GHALAMBOR, CAMERON K.; MALDONADO, JESUS E.; RICK, TORBEN C.; DAY, MITCH D.; POLATO, NICHOLAS R.; FITZPATRICK, SARAH W.; COONAN, TIMOTHY J.; CROOKS, KEVIN R.; DILLON, ADAM; GARCELON, DAVID K.; KING, JULIE L.; BOSER, CHRISTINA L.; GOULD, NICHOLAS; ANDELT, WILLIAM F.

    2016-01-01

    The evolutionary mechanisms generating the tremendous biodiversity of islands have long fascinated evolutionary biologists. Genetic drift and divergent selection are predicted to be strong on islands and both could drive population divergence and speciation. Alternatively, strong genetic drift may preclude adaptation. We conducted a genomic analysis to test the roles of genetic drift and divergent selection in causing genetic differentiation among populations of the island fox (Urocyon littoralis). This species consists of 6 subspecies, each of which occupies a different California Channel Island. Analysis of 5293 SNP loci generated using Restriction-site Associated DNA (RAD) sequencing found support for genetic drift as the dominant evolutionary mechanism driving population divergence among island fox populations. In particular, populations had exceptionally low genetic variation, small Ne (range = 2.1–89.7; median = 19.4), and significant genetic signatures of bottlenecks. Moreover, islands with the lowest genetic variation (and, by inference, the strongest historical genetic drift) were most genetically differentiated from mainland gray foxes, and vice versa, indicating genetic drift drives genome-wide divergence. Nonetheless, outlier tests identified 3.6–6.6% of loci as high FST outliers, suggesting that despite strong genetic drift, divergent selection contributes to population divergence. Patterns of similarity among populations based on high FST outliers mirrored patterns based on morphology, providing additional evidence that outliers reflect adaptive divergence. Extremely low genetic variation and small Ne in some island fox populations, particularly on San Nicolas Island, suggest that they may be vulnerable to fixation of deleterious alleles, decreased fitness, and reduced adaptive potential. PMID:26992010

  1. Adaptive divergence despite strong genetic drift: genomic analysis of the evolutionary mechanisms causing genetic differentiation in the island fox (Urocyon littoralis).

    Science.gov (United States)

    Funk, W Chris; Lovich, Robert E; Hohenlohe, Paul A; Hofman, Courtney A; Morrison, Scott A; Sillett, T Scott; Ghalambor, Cameron K; Maldonado, Jesus E; Rick, Torben C; Day, Mitch D; Polato, Nicholas R; Fitzpatrick, Sarah W; Coonan, Timothy J; Crooks, Kevin R; Dillon, Adam; Garcelon, David K; King, Julie L; Boser, Christina L; Gould, Nicholas; Andelt, William F

    2016-05-01

    The evolutionary mechanisms generating the tremendous biodiversity of islands have long fascinated evolutionary biologists. Genetic drift and divergent selection are predicted to be strong on islands and both could drive population divergence and speciation. Alternatively, strong genetic drift may preclude adaptation. We conducted a genomic analysis to test the roles of genetic drift and divergent selection in causing genetic differentiation among populations of the island fox (Urocyon littoralis). This species consists of six subspecies, each of which occupies a different California Channel Island. Analysis of 5293 SNP loci generated using Restriction-site Associated DNA (RAD) sequencing found support for genetic drift as the dominant evolutionary mechanism driving population divergence among island fox populations. In particular, populations had exceptionally low genetic variation, small Ne (range = 2.1-89.7; median = 19.4), and significant genetic signatures of bottlenecks. Moreover, islands with the lowest genetic variation (and, by inference, the strongest historical genetic drift) were most genetically differentiated from mainland grey foxes, and vice versa, indicating genetic drift drives genome-wide divergence. Nonetheless, outlier tests identified 3.6-6.6% of loci as high FST outliers, suggesting that despite strong genetic drift, divergent selection contributes to population divergence. Patterns of similarity among populations based on high FST outliers mirrored patterns based on morphology, providing additional evidence that outliers reflect adaptive divergence. Extremely low genetic variation and small Ne in some island fox populations, particularly on San Nicolas Island, suggest that they may be vulnerable to fixation of deleterious alleles, decreased fitness and reduced adaptive potential. © 2016 John Wiley & Sons Ltd.

  2. Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease

    Science.gov (United States)

    The strong observational association between total homocysteine (tHcy) concentrations and risk of coronary artery disease (CAD) and the null associations in the homocysteine-lowering trials have prompted the need to identify genetic variants associated with homocysteine concentrations and risk of CA...

  3. Personalized Genetic Risk Counseling to Motivate Diabetes Prevention

    OpenAIRE

    Grant, Richard W.; O’Brien, Kelsey E.; Waxler, Jessica L.; Vassy, Jason L.; Delahanty, Linda M.; Bissett, Laurie G.; Green, Robert C.; Stember, Katherine G.; Guiducci, Candace; Park, Elyse R.; Florez, Jose C.; Meigs, James B.

    2012-01-01

    OBJECTIVE To examine whether diabetes genetic risk testing and counseling can improve diabetes prevention behaviors. RESEARCH DESIGN AND METHODS We conducted a randomized trial of diabetes genetic risk counseling among overweight patients at increased phenotypic risk for type 2 diabetes. Participants were randomly allocated to genetic testing versus no testing. Genetic risk was calculated by summing 36 single nucleotide polymorphisms associated with type 2 diabetes. Participants in the top an...

  4. Genetic variants and multiple myeloma risk

    DEFF Research Database (Denmark)

    Martino, Alessandro; Campa, Daniele; Jurczyszyn, Artur

    2014-01-01

    BACKGROUND: Genetic background plays a role in multiple myeloma susceptibility. Several single-nucleotide polymorphisms (SNP) associated with genetic susceptibility to multiple myeloma were identified in the last years, but only a few of them were validated in independent studies. METHODS...... with multiple myeloma risk (P value range, 0.055-0.981), possibly with the exception of the SNP rs2227667 (SERPINE1) in women. CONCLUSIONS: We can exclude that the selected polymorphisms are major multiple myeloma risk factors. IMPACT: Independent validation studies are crucial to identify true genetic risk...

  5. Assessing Extinction Risk: Integrating Genetic Information

    Directory of Open Access Journals (Sweden)

    Jason Dunham

    1999-06-01

    Full Text Available Risks of population extinction have been estimated using a variety of methods incorporating information from different spatial and temporal scales. We briefly consider how several broad classes of extinction risk assessments, including population viability analysis, incidence functions, and ranking methods integrate information on different temporal and spatial scales. In many circumstances, data from surveys of neutral genetic variability within, and among, populations can provide information useful for assessing extinction risk. Patterns of genetic variability resulting from past and present ecological and demographic events, can indicate risks of extinction that are otherwise difficult to infer from ecological and demographic analyses alone. We provide examples of how patterns of neutral genetic variability, both within, and among populations, can be used to corroborate and complement extinction risk assessments.

  6. Increased genetic risk for obesity in premature coronary artery disease.

    Science.gov (United States)

    Cole, Christopher B; Nikpay, Majid; Stewart, Alexandre F R; McPherson, Ruth

    2016-04-01

    There is ongoing controversy as to whether obesity confers risk for CAD independently of associated risk factors including diabetes mellitus. We have carried out a Mendelian randomization study using a genetic risk score (GRS) for body mass index (BMI) based on 35 risk alleles to investigate this question in a population of 5831 early onset CAD cases without diabetes mellitus and 3832 elderly healthy control subjects, all of strictly European ancestry, with adjustment for traditional risk factors (TRFs). We then estimated the genetic correlation between these BMI and CAD (rg) by relating the pairwise genetic similarity matrix to a phenotypic covariance matrix between these two traits. GRSBMI significantly (P=2.12 × 10(-12)) associated with CAD status in a multivariate model adjusted for TRFs, with a per allele odds ratio (OR) of 1.06 (95% CI 1.042-1.076). The addition of GRSBMI to TRFs explained 0.75% of CAD variance and yielded a continuous net recombination index of 16.54% (95% CI=11.82-21.26%, P<0.0001). To test whether GRSBMI explained CAD status when adjusted for measured BMI, separate models were constructed in which the score and BMI were either included as covariates or not. The addition of BMI explained ~1.9% of CAD variance and GRSBMI plus BMI explained 2.65% of CAD variance. Finally, using bivariate restricted maximum likelihood analysis, we provide strong evidence of genome-wide pleiotropy between obesity and CAD. This analysis supports the hypothesis that obesity is a causal risk factor for CAD.

  7. Quantifying introgression risk with realistic population genetics.

    Science.gov (United States)

    Ghosh, Atiyo; Meirmans, Patrick G; Haccou, Patsy

    2012-12-07

    Introgression is the permanent incorporation of genes from the genome of one population into another. This can have severe consequences, such as extinction of endemic species, or the spread of transgenes. Quantification of the risk of introgression is an important component of genetically modified crop regulation. Most theoretical introgression studies aimed at such quantification disregard one or more of the most important factors concerning introgression: realistic genetical mechanisms, repeated invasions and stochasticity. In addition, the use of linkage as a risk mitigation strategy has not been studied properly yet with genetic introgression models. Current genetic introgression studies fail to take repeated invasions and demographic stochasticity into account properly, and use incorrect measures of introgression risk that can be manipulated by arbitrary choices. In this study, we present proper methods for risk quantification that overcome these difficulties. We generalize a probabilistic risk measure, the so-called hazard rate of introgression, for application to introgression models with complex genetics and small natural population sizes. We illustrate the method by studying the effects of linkage and recombination on transgene introgression risk at different population sizes.

  8. Defining a Contemporary Ischemic Heart Disease Genetic Risk Profile Using Historical Data.

    Science.gov (United States)

    Mosley, Jonathan D; van Driest, Sara L; Wells, Quinn S; Shaffer, Christian M; Edwards, Todd L; Bastarache, Lisa; McCarty, Catherine A; Thompson, Will; Chute, Christopher G; Jarvik, Gail P; Crosslin, David R; Larson, Eric B; Kullo, Iftikhar J; Pacheco, Jennifer A; Peissig, Peggy L; Brilliant, Murray H; Linneman, James G; Denny, Josh C; Roden, Dan M

    2016-12-01

    Continued reductions in morbidity and mortality attributable to ischemic heart disease (IHD) require an understanding of the changing epidemiology of this disease. We hypothesized that we could use genetic correlations, which quantify the shared genetic architectures of phenotype pairs and extant risk factors from a historical prospective study to define the risk profile of a contemporary IHD phenotype. We used 37 phenotypes measured in the ARIC study (Atherosclerosis Risk in Communities; n=7716, European ancestry subjects) and clinical diagnoses from an electronic health record (EHR) data set (n=19 093). All subjects had genome-wide single-nucleotide polymorphism genotyping. We measured pairwise genetic correlations (rG) between the ARIC and EHR phenotypes using linear mixed models. The genetic correlation estimates between the ARIC risk factors and the EHR IHD were modestly linearly correlated with hazards ratio estimates for incident IHD in ARIC (Pearson correlation [r]=0.62), indicating that the 2 IHD phenotypes had differing risk profiles. For comparison, this correlation was 0.80 when comparing EHR and ARIC type 2 diabetes mellitus phenotypes. The EHR IHD phenotype was most strongly correlated with ARIC metabolic phenotypes, including total:high-density lipoprotein cholesterol ratio (rG=-0.44, P=0.005), high-density lipoprotein (rG=-0.48, P=0.005), systolic blood pressure (rG=0.44, P=0.02), and triglycerides (rG=0.38, P=0.02). EHR phenotypes related to type 2 diabetes mellitus, atherosclerotic, and hypertensive diseases were also genetically correlated with these ARIC risk factors. The EHR IHD risk profile differed from ARIC and indicates that treatment and prevention efforts in this population should target hypertensive and metabolic disease. © 2016 American Heart Association, Inc.

  9. Chymotrypsinogen C Genetic Variants, Including c.180TT, Are Strongly Associated With Chronic Pancreatitis in Pediatric Patients.

    Science.gov (United States)

    Grabarczyk, Alicja Monika; Oracz, Grzegorz; Wertheim-Tysarowska, Katarzyna; Kujko, Aleksandra Anna; Wejnarska, Karolina; Kolodziejczyk, Elwira; Bal, Jerzy; Koziel, Dorota; Kowalik, Artur; Gluszek, Stanislaw; Rygiel, Agnieszka Magdalena

    2017-12-01

    Genetic studies in adults/adolescent patients with chronic pancreatitis (CP) identified chymotrypsinogen C (CTRC) genetic variants but their association with CP risk has been difficult to replicate. To evaluate the risk of CP associated with CTRC variants in CP pediatric patients-control study. The distribution of CTRC variants in CP pediatric cohort (n = 136, median age at CP onset 8 years) with no history of alcohol/smoking abuse was compared with controls (n = 401, median age 45). We showed that p.Arg254Trp (4.6%) and p.Lys247_Arg254del (5.3%) heterozygous mutations are frequent and significantly associated with CP risk in pediatric patients (odds ratio [OR] = 19.1; 95% CI 2.8-160; P = 0.001 and OR = 5.5; 95% CI 1.6-19.4; P = 0.001, respectively). For the first time, we demonstrated that the c.180TT genotype of common p.Gly60Gly variant is strong, an independent CP risk factor (OR = 23; 95% CI 7.7-70; P A variant, both CA and AA genotype, is significantly underrepresented in CP compared with controls (15% vs 35%; OR = 0.33; 95% CI 0.19-0.59; P risk factors. The c.493+51C>A variant may play a protective role against CP development.

  10. Characterizing the genetic influences on risk aversion.

    Science.gov (United States)

    Harrati, Amal

    2014-01-01

    Risk aversion has long been cited as an important factor in retirement decisions, investment behavior, and health. Some of the heterogeneity in individual risk tolerance is well understood, reflecting age gradients, wealth gradients, and similar effects, but much remains unexplained. This study explores genetic contributions to heterogeneity in risk aversion among older Americans. Using over 2 million genetic markers per individual from the U.S. Health and Retirement Study, I report results from a genome-wide association study (GWAS) on risk preferences using a sample of 10,455 adults. None of the single-nucleotide polymorphisms (SNPs) are found to be statistically significant determinants of risk preferences at levels stricter than 5 × 10(-8). These results suggest that risk aversion is a complex trait that is highly polygenic. The analysis leads to upper bounds on the number of genetic effects that could exceed certain thresholds of significance and still remain undetected at the current sample size. The findings suggest that the known heritability in risk aversion is likely to be driven by large numbers of genetic variants, each with a small effect size.

  11. Methods to estimate the genetic risk

    International Nuclear Information System (INIS)

    Ehling, U.H.

    1989-01-01

    The estimation of the radiation-induced genetic risk to human populations is based on the extrapolation of results from animal experiments. Radiation-induced mutations are stochastic events. The probability of the event depends on the dose; the degree of the damage dose not. There are two main approaches in making genetic risk estimates. One of these, termed the direct method, expresses risk in terms of expected frequencies of genetic changes induced per unit dose. The other, referred to as the doubling dose method or the indirect method, expresses risk in relation to the observed incidence of genetic disorders now present in man. The advantage of the indirect method is that not only can Mendelian mutations be quantified, but also other types of genetic disorders. The disadvantages of the method are the uncertainties in determining the current incidence of genetic disorders in human and, in addition, the estimasion of the genetic component of congenital anomalies, anomalies expressed later and constitutional and degenerative diseases. Using the direct method we estimated that 20-50 dominant radiation-induced mutations would be expected in 19 000 offspring born to parents exposed in Hiroshima and Nagasaki, but only a small proportion of these mutants would have been detected with the techniques used for the population study. These methods were used to predict the genetic damage from the fallout of the reactor accident at Chernobyl in the vicinity of Southern Germany. The lack of knowledge for the interaction of chemicals with ionizing radiation and the discrepancy between the high safety standards for radiation protection and the low level of knowledge for the toxicological evaluation of chemical mutagens will be emphasized. (author)

  12. Factors Motivating Individuals to Consider Genetic Testing for Type 2 Diabetes Risk Prediction.

    Directory of Open Access Journals (Sweden)

    Jennifer Wessel

    Full Text Available The purpose of this study was to identify attitudes and perceptions of willingness to participate in genetic testing for type 2 diabetes (T2D risk prediction in the general population. Adults (n = 598 were surveyed on attitudes about utilizing genetic testing to predict future risk of T2D. Participants were recruited from public libraries (53%, online registry (37% and a safety net hospital emergency department (10%. Respondents were 37 ± 11 years old, primarily White (54%, female (69%, college educated (46%, with an annual income ≥$25,000 (56%. Half of participants were interested in genetic testing for T2D (52% and 81% agreed/strongly agreed genetic testing should be available to the public. Only 57% of individuals knew T2D is preventable. A multivariate model to predict interest in genetic testing was adjusted for age, gender, recruitment location and BMI; significant predictors were motivation (high perceived personal risk of T2D [OR = 4.38 (1.76, 10.9]; family history [OR = 2.56 (1.46, 4.48]; desire to know risk prior to disease onset [OR = 3.25 (1.94, 5.42]; and knowing T2D is preventable [OR = 2.11 (1.24, 3.60], intention (if the cost is free [OR = 10.2 (4.27, 24.6]; and learning T2D is preventable [OR = 5.18 (1.95, 13.7] and trust of genetic testing results [OR = 0.03 (0.003, 0.30]. Individuals are interested in genetic testing for T2D risk which offers unique information that is personalized. Financial accessibility, validity of the test and availability of diabetes prevention programs were identified as predictors of interest in T2D testing.

  13. Behavioural Susceptibility Theory: Professor Jane Wardle and the Role of Appetite in Genetic Risk of Obesity.

    Science.gov (United States)

    Llewellyn, Clare H; Fildes, Alison

    2017-03-01

    There is considerable variability in human body weight, despite the ubiquity of the 'obesogenic' environment. Human body weight has a strong genetic basis and it has been hypothesised that genetic susceptibility to the environment explains variation in human body weight, with differences in appetite being implicated as the mediating mechanism; so-called 'behavioural susceptibility theory' (BST), first described by Professor Jane Wardle. This review summarises the evidence for the role of appetite as a mediator of genetic risk of obesity. Variation in appetitive traits is observable from infancy, drives early weight gain and is highly heritable in infancy and childhood. Obesity-related common genetic variants identified through genome-wide association studies show associations with appetitive traits, and appetite mediates part of the observed association between genetic risk and adiposity. Obesity results from an interaction between genetic susceptibility to overeating and exposure to an 'obesogenic' food environment.

  14. Early environmental exposures influence schizophrenia expression even in the presence of strong genetic predisposition.

    Science.gov (United States)

    Husted, Janice A; Ahmed, Rashid; Chow, Eva W C; Brzustowicz, Linda M; Bassett, Anne S

    2012-05-01

    There are few studies of environmental factors in familial forms of schizophrenia. We investigated whether childhood adversity or environmental factors were associated with schizophrenia in a familial sample where schizophrenia is associated with the NOSA1P gene. We found that a cumulative adversity index including childhood illness, family instability and cannabis use was significantly associated with narrow schizophrenia, independent of NOSA1P risk genotype, previously measured childhood trauma, covariates and familial clustering (adjusted odds ratio (95% confidence interval)=1.55 (1.01, 2.38)). The results provide further support that early environmental exposures influence schizophrenia expression even in the presence of strong genetic predisposition. Copyright © 2012 Elsevier B.V. All rights reserved.

  15. Exploration of genetically determined resistance against hepatitis C infection in high-risk injecting drug users.

    Science.gov (United States)

    Sugden, P B; Cameron, B; Luciani, F; Lloyd, A R

    2014-08-01

    Genetic resistance to specific infections is well recognized. In hepatitis C virus (HCV) infection, genetic polymorphisms in IL-28B and the killer cell immunoglobulin-like receptors (KIR) and their HLA class I ligands have been shown to affect clearance of the virus following infection. There are limited data regarding resistance to established HCV infection. Reliable quantification of repeated exposure in high-risk populations, such as injecting drug users (IDU), is a key limitation of previous studies of resistance. Behavioural data and DNA from IDU (n = 210) in the Hepatitis C Incidence and Transmission Study in prisons (HITS-p) cohort were genotyped for polymorphisms in: IL-28B, peptidyl-prolyl isomerase A (PPIA), HLA-C and KIR2. To quantify risk, a composite risk index based on factors predictive of incident HCV infection was derived. Logistic regression analysis revealed the risk index was strongly associated with incident HCV infection (P C1, or their combination. A framework for the investigation of genetic determinants of resistance to HCV infection has been developed. Several candidate gene associations were investigated and excluded. Further investigation of genetic determinants of resistance to HCV infection is warranted. © 2014 John Wiley & Sons Ltd.

  16. Simple, standardized incorporation of genetic risk into non-genetic risk prediction tools for complex traits: coronary heart disease as an example

    Directory of Open Access Journals (Sweden)

    Benjamin A Goldstein

    2014-08-01

    Full Text Available Purpose: Genetic risk assessment is becoming an important component of clinical decision-making. Genetic Risk Scores (GRSs allow the composite assessment of genetic risk in complex traits. A technically and clinically pertinent question is how to most easily and effectively combine a GRS with an assessment of clinical risk derived from established non-genetic risk factors as well as to clearly present this information to patient and health care providers. Materials & Methods: We illustrate a means to combine a GRS with an independent assessment of clinical risk using a log-link function. We apply the method to the prediction of coronary heart disease (CHD in the Atherosclerosis Risk in Communities (ARIC cohort. We evaluate different constructions based on metrics of effect change, discrimination, and calibration.Results: The addition of a GRS to a clinical risk score (CRS improves both discrimination and calibration for CHD in ARIC. Results are similar regardless of whether external vs. internal coefficients are used for the CRS, risk factor SNPs are included in the GRS, or subjects with diabetes at baseline are excluded. We outline how to report the construction and the performance of a GRS using our method and illustrate a means to present genetic risk information to subjects and/or their health care provider. Conclusion: The proposed method facilitates the standardized incorporation of a GRS in risk assessment.

  17. Birth Characteristics and Childhood Leukemia Risk: Correlations With Genetic Markers.

    Science.gov (United States)

    Kennedy, Amy E; Kamdar, Kala Y; Lupo, Philip J; Okcu, Mehmet F; Scheurer, Michael E; Dorak, Mehmet T

    2015-07-01

    Birth characteristics such as birth order, birth weight, birth defects, and Down syndrome showed some of the first risk associations with childhood leukemia. Examinations of correlations between birth characteristics and leukemia risk markers have been limited to birth weight-related genetic polymorphisms. We integrated information on nongenetic and genetic markers by evaluating the relationship of birth characteristics, genetic markers for childhood acute lymphoblastic leukemia (ALL) susceptibility, and ALL risk together. The multiethnic study consisted of cases with childhood ALL (n=161) and healthy controls (n=261). Birth characteristic data were collected through questionnaires, and genotyping was achieved by TaqMan SNP Genotyping Assays. We observed risk associations for birth weight over 4000 g (odds ratios [OR]=1.93; 95% confidence interval [CI], 1.16-3.19), birth length (OR=1.18 per inch; 95% CI, 1.01-1.38), and with gestational age (OR=1.10 per week; 95% CI, 1.00-1.21). Only the HFE tag single-nucleotide polymorphism (SNP) rs9366637 showed an inverse correlation with a birth characteristic, gestational age, with a gene-dosage effect (P=0.005), and in interaction with a transferrin receptor rs3817672 genotype (Pinteraction=0.05). This correlation translated into a strong association for rs9366637 with preterm birth (OR=5.0; 95% CI, 1.19-20.9). Our study provides evidence for the involvement of prenatal events in the development of childhood ALL. The inverse correlation of rs9366637 with gestational age has implications on the design of HFE association studies in birth weight and childhood conditions using full-term newborns as controls.

  18. Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease

    NARCIS (Netherlands)

    Meurs, J.B.J. van; Pare, G.; Schwartz, S.M.; Hazra, A.; Tanaka, T.; Vermeulen, S.; Cotlarciuc, I.; Yuan, X.; Malarstig, A.; Bandinelli, S.; Bis, J.C.; Blom, H.; Brown, M.J.; Chen, C.; Chen, Y.D.; Clarke, R.J.; Dehghan, A.; Erdmann, J.; Ferrucci, L.; Hamsten, A.; Hofman, A.; Hunter, D.J.; Goel, A.; Johnson, A.D.; Kathiresan, S.; Kampman, E.; Kiel, D.P.; Kiemeney, L.A.L.M.; Chambers, J.C.; Kraft, P.; Lindemans, J.; McKnight, B.; Nelson, C.P.; O'Donnell, C.J.; Psaty, B.M.; Ridker, P.M.; Rivadeneira, F.; Rose, L.M.; Seedorf, U.; Siscovick, D.S.; Schunkert, H.; Selhub, J.; Ueland, P.M.; Vollenweider, P.; Waeber, G.; Waterworth, D.M.; Watkins, H.; Witteman, J.C.; Heijer, M. den; Jacques, P.; Uitterlinden, A.G.; Kooner, J.S.; Rader, D.J.; Reilly, M.P.; Mooser, V.; Chasman, D.I.; Samani, N.J.; Ahmadi, K.R.

    2013-01-01

    BACKGROUND: The strong observational association between total homocysteine (tHcy) concentrations and risk of coronary artery disease (CAD) and the null associations in the homocysteine-lowering trials have prompted the need to identify genetic variants associated with homocysteine concentrations

  19. Changes to perceptions of the pros and cons of genetic susceptibility testing after APOE genotyping for Alzheimer disease risk

    Science.gov (United States)

    Christensen, Kurt D.; Roberts, J. Scott; Uhlmann, Wendy R.; Green, Robert C.

    2011-01-01

    Purpose Perceptions about the pros and cons of genetic susceptibility testing are among the best predictors of test utilization. How actual testing changes such perceptions has yet to be examined. Methods In a clinical trial, first-degree relatives of patients with Alzheimer disease received genetic risk assessments for Alzheimer disease including APOE disclosure. Participants rated 11 possible benefits associated with genetic testing (pros) and 10 risks or limitations (cons) before genetic risk disclosure and again 12 months afterward. Results Pros were rated higher than cons at baseline (3.53 vs. 1.83, P cons did not change (1.88 vs. 1.83, P = 0.199) except for a three-item discrimination subscale which increased (2.07 vs. 1.92, P = 0.012). Among specific pros and cons, three items related to prevention and treatment changed the most. Conclusion The process of APOE genetic risk assessment for Alzheimer disease sensitizes some to its limitations and the risks of discrimination; however, 1-year after disclosure, test recipients still consider the pros to strongly outweigh the cons. PMID:21270636

  20. Specificity of genetic and environmental risk factors for symptoms of cannabis, cocaine, alcohol, caffeine, and nicotine dependence.

    Science.gov (United States)

    Kendler, Kenneth S; Myers, John; Prescott, Carol A

    2007-11-01

    Although genetic risk factors have been found to contribute to dependence on both licit and illicit psychoactive substances, we know little of how these risk factors interrelate. To clarify the structure of genetic and environmental risk factors for symptoms of dependence on cannabis, cocaine, alcohol, caffeine, and nicotine in males and females. Lifetime history by structured clinical interview. General community. Four thousand eight hundred sixty-five members of male-male and female-female pairs from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. Main Outcome Measure Lifetime symptoms of abuse of and dependence on cannabis, cocaine, alcohol, caffeine, and nicotine. Controlling for greater symptom prevalence in males, genetic and environmental parameters could be equated across sexes. Two models explained the data well. The best-fit exploratory model contained 2 genetic factors and 1 individual environmental factor contributing to all substances. The first genetic factor loaded strongly on cocaine and cannabis dependence; the second, on alcohol and nicotine dependence. Nicotine and caffeine had high substance-specific genetic effects. A confirmatory model, which also fit well, contained 1 illicit drug genetic factor--loading only on cannabis and cocaine--and 1 licit drug genetic factor loading on alcohol, caffeine, and nicotine. However, these factors were highly intercorrelated (r = + 0.82). Large substance-specific genetic effects remained for nicotine and caffeine. The pattern of genetic and environmental risk factors for psychoactive substance dependence was similar in males and females. Genetic risk factors for dependence on common psychoactive substances cannot be explained by a single factor. Rather, 2 genetic factors-one predisposing largely to illicit drug dependence, the other primarily to licit drug dependence-are needed. Furthermore, a large proportion of the genetic influences on nicotine and particularly caffeine dependence

  1. Arranging marriage; negotiating risk: genetics and society in Qatar.

    Science.gov (United States)

    Kilshaw, Susie; Al Raisi, Tasneem; Alshaban, Fouad

    2015-01-01

    This paper considers how the globalized discourse of genetic risk in cousin marriage is shaped, informed and taken up in local moral worlds within the context of Qatar. This paper investigates the way Qataris are negotiating the discourse on genetics and risk. It is based on data from ongoing ethnographic research in Qatar and contributes to anthropological knowledge about this understudied country. Participants were ambivalent about genetic risks and often pointed to other theories of causation in relation to illness and disability. The discourse on genetic risk associated with marrying in the family was familiar, but for some participants the benefits of close marriage outweighed potential risks. Furthermore, the introduction of mandatory pre-marital screening gave participants confidence that risks were monitored and minimized.

  2. Quantification of the genetic risk of environmental mutagens

    International Nuclear Information System (INIS)

    Ehling, U.H.

    1988-01-01

    Screening methods are used for hazard identification. Assays for heritable mutations in mammals are used for the confirmation of short-term test results and for the quantification of the genetic risk. There are two main approaches in making genetic risk estimates. One of these, termed the direct method, expresses risk in terms of the expected frequency of genetic changes induced per unit. The other, referred to as the doubling dose method or the indirect method, expresses risk in relation to the observed incidence of genetic disorders now present in man. The indirect method uses experimental data only for the calculation of the doubling dose. The quality of the risk estimation depends on the assumption of persistence of the induced mutations and the ability to determine the current incidence of genetic diseases. The difficulties of improving the estimates of current incidences of genetic diseases or the persistence of the genes in the population led them to the development of an alternative method, the direct estimation of the genetic risk. The direct estimation uses experimental data for the induced frequency for dominant mutations in mice. For the verification of these quantifications one can use the data of Hiroshima and Nagasaki. According to the estimation with the direct method, one would expect less than 1 radiation-induced dominant cataract in 19,000 children with one or both parents exposed. The expected overall frequency of dominant mutations in the first generation would be 20-25, based on radiation-induced dominant cataract mutations. It is estimated that 10 times more recessive than dominant mutations are induced. The same approaches can be used to determine the impact of chemical mutagens

  3. Melanoma risk prediction using a multilocus genetic risk score in the Women's Health Initiative cohort.

    Science.gov (United States)

    Cho, Hyunje G; Ransohoff, Katherine J; Yang, Lingyao; Hedlin, Haley; Assimes, Themistocles; Han, Jiali; Stefanick, Marcia; Tang, Jean Y; Sarin, Kavita Y

    2018-07-01

    Single-nucleotide polymorphisms (SNPs) associated with melanoma have been identified though genome-wide association studies. However, the combined impact of these SNPs on melanoma development remains unclear, particularly in postmenopausal women who carry a lower melanoma risk. We examine the contribution of a combined polygenic risk score on melanoma development in postmenopausal women. Genetic risk scores were calculated using 21 genome-wide association study-significant SNPs. Their combined effect on melanoma development was evaluated in 19,102 postmenopausal white women in the clinical trial and observational study arms of the Women's Health Initiative dataset. Compared to the tertile of weighted genetic risk score with the lowest genetic risk, the women in the tertile with the highest genetic risk were 1.9 times more likely to develop melanoma (95% confidence interval 1.50-2.42). The incremental change in c-index from adding genetic risk scores to age were 0.075 (95% confidence interval 0.041-0.109) for incident melanoma. Limitations include a lack of information on nevi count, Fitzpatrick skin type, family history of melanoma, and potential reporting and selection bias in the Women's Health Initiative cohort. Higher genetic risk is associated with increased melanoma prevalence and incidence in postmenopausal women, but current genetic information may have a limited role in risk prediction when phenotypic information is available. Copyright © 2018 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  4. Effects of smoking on the genetic risk of obesity: the population architecture using genomics and epidemiology study

    Directory of Open Access Journals (Sweden)

    Fesinmeyer Megan D

    2013-01-01

    Full Text Available Abstract Background Although smoking behavior is known to affect body mass index (BMI, the potential for smoking to influence genetic associations with BMI is largely unexplored. Methods As part of the ‘Population Architecture using Genomics and Epidemiology (PAGE’ Consortium, we investigated interaction between genetic risk factors associated with BMI and smoking for 10 single nucleotide polymorphisms (SNPs previously identified in genome-wide association studies. We included 6 studies with a total of 56,466 subjects (16,750 African Americans (AA and 39,716 European Americans (EA. We assessed effect modification by testing an interaction term for each SNP and smoking (current vs. former/never in the linear regression and by stratified analyses. Results We did not observe strong evidence for interactions and only observed two interactions with p-values TMEM18, the risk allele (C was associated with BMI only among AA females who were former/never smokers (β = 0.018, p = 0.002, vs. current smokers (β = 0.001, p = 0.95, pinteraction = 0.10. For rs9939609/FTO, the A allele was more strongly associated with BMI among current smoker EA females (β = 0.017, p = 3.5x10-5, vs. former/never smokers (β = 0.006, p = 0.05, pinteraction = 0.08. Conclusions These analyses provide limited evidence that smoking status may modify genetic effects of previously identified genetic risk factors for BMI. Larger studies are needed to follow up our results. Clinical Trial Registration NCT00000611

  5. Genetic Risk Score for Essential Hypertension and Risk of Preeclampsia.

    Science.gov (United States)

    Smith, Caitlin J; Saftlas, Audrey F; Spracklen, Cassandra N; Triche, Elizabeth W; Bjonnes, Andrew; Keating, Brendan; Saxena, Richa; Breheny, Patrick J; Dewan, Andrew T; Robinson, Jennifer G; Hoh, Josephine; Ryckman, Kelli K

    2016-01-01

    Preeclampsia is a hypertensive complication of pregnancy characterized by novel onset of hypertension after 20 weeks gestation, accompanied by proteinuria. Epidemiological evidence suggests that genetic susceptibility exists for preeclampsia; however, whether preeclampsia is the result of underlying genetic risk for essential hypertension has yet to be investigated. Based on the hypertensive state that is characteristic of preeclampsia, we aimed to determine if established genetic risk scores (GRSs) for hypertension and blood pressure are associated with preeclampsia. Subjects consisted of 162 preeclamptic cases and 108 normotensive pregnant controls, all of Iowa residence. Subjects' DNA was extracted from buccal swab samples and genotyped on the Affymetrix Genome-wide Human SNP Array 6.0 (Affymetrix, Santa Clara, CA). Missing genotypes were imputed using MaCH and Minimac software. GRSs were calculated for hypertension, systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) using established genetic risk loci for each outcome. Regression analyses were performed to determine the association between GRS and risk of preeclampsia. These analyses were replicated in an independent US population of 516 cases and 1,097 controls of European ancestry. GRSs for hypertension, SBP, DBP, and MAP were not significantly associated with risk for preeclampsia (P > 0.189). The results of the replication analysis also yielded nonsignificant associations. GRSs for hypertension and blood pressure are not associated with preeclampsia, suggesting that an underlying predisposition to essential hypertension is not on the causal pathway of preeclampsia. © American Journal of Hypertension, Ltd 2015. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  6. Nature, Nurture, and Cancer Risks: Genetic and Nutritional Contributions to Cancer.

    Science.gov (United States)

    Theodoratou, Evropi; Timofeeva, Maria; Li, Xue; Meng, Xiangrui; Ioannidis, John P A

    2017-08-21

    It is speculated that genetic variants are associated with differential responses to nutrients (known as gene-diet interactions) and that these variations may be linked to different cancer risks. In this review, we critically evaluate the evidence across 314 meta-analyses of observational studies and randomized controlled trials of dietary risk factors and the five most common cancers (breast, lung, prostate, colorectal, and stomach). We also critically evaluate the evidence across 13 meta-analyses of observational studies of gene-diet interactions for the same cancers. Convincing evidence for association was found only for the intake of alcohol and whole grains in relation to colorectal cancer risk. Three nutrient associations had highly suggestive evidence and another 15 associations had suggestive evidence. Among the examined gene-diet interactions, only one had moderately strong evidence.

  7. Genetic resources of teak (Tectona grandis Linn. f.)—strong genetic structure among natural populations

    DEFF Research Database (Denmark)

    Hansen, Ole Kim; Changtragoon, Suchitra; Ponoy, Bundit

    2015-01-01

    had the highest genetic diversity while provenances from Laos showed the lowest. In the eastern part of the natural distribution area, comprising Myanmar, Thailand and Laos, there was a strong clinal decrease in genetic diversity the further east the provenance was located. Overall, the pattern......) the Indian provenances from the dry interior and the moist west coast and (3) the provenances from northern Myanmar. The provenances from southern Myanmar were placed close to the root of the tree together with the three provenances from the semi-moist east coast of India. A Bayesian cluster analysis using...

  8. Population genetics inference for longitudinally-sampled mutants under strong selection.

    Science.gov (United States)

    Lacerda, Miguel; Seoighe, Cathal

    2014-11-01

    Longitudinal allele frequency data are becoming increasingly prevalent. Such samples permit statistical inference of the population genetics parameters that influence the fate of mutant variants. To infer these parameters by maximum likelihood, the mutant frequency is often assumed to evolve according to the Wright-Fisher model. For computational reasons, this discrete model is commonly approximated by a diffusion process that requires the assumption that the forces of natural selection and mutation are weak. This assumption is not always appropriate. For example, mutations that impart drug resistance in pathogens may evolve under strong selective pressure. Here, we present an alternative approximation to the mutant-frequency distribution that does not make any assumptions about the magnitude of selection or mutation and is much more computationally efficient than the standard diffusion approximation. Simulation studies are used to compare the performance of our method to that of the Wright-Fisher and Gaussian diffusion approximations. For large populations, our method is found to provide a much better approximation to the mutant-frequency distribution when selection is strong, while all three methods perform comparably when selection is weak. Importantly, maximum-likelihood estimates of the selection coefficient are severely attenuated when selection is strong under the two diffusion models, but not when our method is used. This is further demonstrated with an application to mutant-frequency data from an experimental study of bacteriophage evolution. We therefore recommend our method for estimating the selection coefficient when the effective population size is too large to utilize the discrete Wright-Fisher model. Copyright © 2014 by the Genetics Society of America.

  9. Characterizing the genetic risk for Type 2 diabetes in a Malaysian multi-ethnic cohort.

    Science.gov (United States)

    Abdullah, N; Abdul Murad, N A; Attia, J; Oldmeadow, C; Mohd Haniff, E A; Syafruddin, S E; Abd Jalal, N; Ismail, N; Ishak, M; Jamal, R; Scott, R J; Holliday, E G

    2015-10-01

    To characterize the association with Type 2 diabetes of known Type 2 diabetes risk variants in people in Malaysia of Malay, Chinese and Indian ancestry who participated in the Malaysian Cohort project. We genotyped 1604 people of Malay ancestry (722 cases, 882 controls), 1654 of Chinese ancestry (819 cases, 835 controls) and 1728 of Indian ancestry (851 cases, 877 controls). First, 62 candidate single-nucleotide polymorphisms previously associated with Type 2 diabetes were assessed for association via logistic regression within ancestral groups and then across ancestral groups using a meta-analysis. Second, estimated odds ratios were assessed for excess directional concordance with previously studied populations. Third, a genetic risk score aggregating allele dosage across the candidate single-nucleotide polymorphisms was tested for association within and across ancestral groups. After Bonferroni correction, seven individual single-nucleotide polymorphisms were associated with Type 2 diabetes in the combined Malaysian sample. We observed a highly significant excess in concordance of effect directions between Malaysian and previously studied populations. The genetic risk score was strongly associated with Type 2 diabetes in all Malaysian groups, explaining from 1.0 to 1.7% of total Type 2 diabetes risk variance. This study suggests there is substantial overlap of the genetic risk alleles underlying Type 2 diabetes in Malaysian and other populations. © 2015 The Authors. Diabetic Medicine © 2015 Diabetes UK.

  10. Personalized Genetic Risk Counseling to Motivate Diabetes Prevention: A randomized trial

    OpenAIRE

    Grant, Richard W.; O’Brien, Kelsey E.; Waxler, Jessica L.; Vassy, Jason L.; Delahanty, Linda M.; Bissett, Laurie G.; Green, Robert C.; Stember, Katherine G.; Guiducci, Candace; Park, Elyse R.; Florez, Jose C.; Meigs, James B.

    2013-01-01

    OBJECTIVE To examine whether diabetes genetic risk testing and counseling can improve diabetes prevention behaviors. RESEARCH DESIGN AND METHODS We conducted a randomized trial of diabetes genetic risk counseling among overweight patients at increased phenotypic risk for type 2 diabetes. Participants were randomly allocated to genetic testing versus no testing. Genetic risk was calculated by summing 36 single nucleotide polymorphisms associated with type 2 diabetes. Participants in the top an...

  11. Environmental chemical mutagens and genetic risks: Lessons from radiation genetics

    International Nuclear Information System (INIS)

    Sankaranarayanan, K.

    1996-01-01

    The last three decades have witnessed substantial progress in the development and use of a variety of in vitro and in vivo assay systems for the testing of environmental chemicals which may pose a mutagenic hazard to humans. This is also true of basic studies in chemical mutagenesis on mechanisms, DNA repair, molecular dosimetry, structure-activity relationships, etc. However, the field of quantitative evaluation of genetic risks of environmental chemicals to humans is still in it infancy. This commentary addresses the question of how our experience in estimating genetic risks of exposure to ionizing radiation can be helpful in similar endeavors with environmental chemical mutagens. 24 refs., 3 tabs

  12. Geoepidemiology, Genetic and Environmental Risk Factors for PBC.

    Science.gov (United States)

    Zhang, Haiyan; Carbone, Marco; Lleo, Ana; Invernizzi, Pietro

    2015-01-01

    Primary biliary cirrhosis (PBC) is the most paradigmatic autoimmune liver disease with still several controversial issues in epidemiology, diagnosis, causation, and therapy. Although we are witnessing an enormous increase in the quantum of our basic knowledge of the disease with an initial translation in clinical practice, there are still a number of key open questions in PBC. Among them are the following questions: Why are there vast geographical variations in disease frequency? What are the reasons for female preponderance? Why do only small-size bile ducts get affected: What is the real role of genetics and epigenetics in its development? In particular, the prevalence of PBC is known to vary both on an international and a regional level, suggesting the existence of substantive geographical differences in terms of genetic susceptibility and environmental factors. New theories on potential environmental triggers, such as chemical xenobiotics, which lead to the breaking of self-tolerance within a unique immunological milieu of the liver, have been suggested. On the other hand, new and solid data on the genetic architecture of PBC are now obtained from recent high-throughput studies, together with data on sex chromosomes defects, and epigenetic abnormalities, thus strongly suggesting a role of genetic and epigenetic factors in the triggering and perpetuation of the autoimmune aggression in PBC. Based on these evidences, a number of novel drugs directed against specific immune-related molecules are currently under development. In this paper, we review a comprehensive collection of current epidemiological reports from various world regions. We also discuss here the most recent data regarding candidate genetic and environmental risk factors for PBC. © 2015 S. Karger AG, Basel.

  13. Low genetic diversity and strong population structure shaped by anthropogenic habitat fragmentation in a critically endangered primate, Trachypithecus leucocephalus.

    Science.gov (United States)

    Wang, W; Qiao, Y; Li, S; Pan, W; Yao, M

    2017-06-01

    Habitat fragmentation may strongly impact population genetic structure and reduce the genetic diversity and viability of small and isolated populations. The white-headed langur (Trachypithecus leucocephalus) is a critically endangered primate species living in a highly fragmented and human-modified habitat in southern China. We examined the population genetic structure and genetic diversity of the species and investigated the environmental and anthropogenic factors that may have shaped its population structure. We used 214 unique multi-locus genotypes from 41 social groups across the main distribution area of T. leucocephalus, and found strong genetic structure and significant genetic differentiation among local populations. Our landscape genetic analyses using a causal modelling framework suggest that a large habitat gap and geographical distance represent the primary landscape elements shaping genetic structure, yet high levels of genetic differentiation also exist between patches separated by a small habitat gap or road. This is the first comprehensive study that has evaluated the population genetic structure and diversity of T. leucocephalus using nuclear markers. Our results indicate strong negative impacts of anthropogenic land modifications and habitat fragmentation on primate genetic connectivity between forest patches. Our analyses suggest that two management units of the species could be defined, and indicate that habitat continuity should be enforced and restored to reduce genetic isolation and enhance population viability.

  14. Genetically elevated fetuin-A levels, fasting glucose levels, and risk of type 2 diabetes: the cardiovascular health study.

    Science.gov (United States)

    Jensen, Majken K; Bartz, Traci M; Djoussé, Luc; Kizer, Jorge R; Zieman, Susan J; Rimm, Eric B; Siscovick, David S; Psaty, Bruce M; Ix, Joachim H; Mukamal, Kenneth J

    2013-10-01

    Fetuin-A levels are associated with higher risk of type 2 diabetes, but it is unknown if the association is causal. We investigated common (>5%) genetic variants in the fetuin-A gene (AHSG) fetuin-A levels, fasting glucose, and risk of type 2 diabetes. Genetic variation, fetuin-A levels, and fasting glucose were assessed in 2,893 Caucasian and 542 African American community-living individuals 65 years of age or older in 1992-1993. Common AHSG variants (rs4917 and rs2248690) were strongly associated with fetuin-A concentrations (Pfasting glucose concentrations (1.9 mg/dL [95% CI, 1.2-2.7] higher per SD in Caucasians), but Mendelian randomization analyses using both SNPs as unbiased proxies for measured fetuin-A did not support an association between genetically predicted fetuin-A levels and fasting glucose (-0.3 mg/dL [95% CI, -1.9 to 1.3] lower per SD in Caucasians). The difference between the associations of fasting glucose with actual and genetically predicted fetuin-A level was statistically significant (P=0.001). Results among the smaller sample of African Americans trended in similar directions but were statistically insignificant. Common variants in the AHSG gene are strongly associated with plasma fetuin-A concentrations, but not with risk of type 2 diabetes or glucose concentrations, raising the possibility that the association between fetuin-A and type 2 diabetes may not be causal.

  15. Ecological Risk Assessment of Genetically Modified Higher Plants (GMHP)

    DEFF Research Database (Denmark)

    Kjær, C.; Damgaard, C.; Kjellsson, G.

    Preface This publication is a first version of a manual identifying the data needs for ecological risk assessment of genetically modified higher plants (GMHP). It is the intention of the authors to stimulate further discussion of what data are needed in order to conduct a proper ecological risk...... of the project Biotechnology: elements in environmental risk assessment of genetically modified plants. December 1999 Christian Kjær Introduction In ecological risk assessment of transgenic plants, information on a wide range of subjects is needed for an effective and reliable assessment procedure...... in the amendment to the directive. This report suggests a structured way to identify the type of data needed to perform a sound ecological risk assessment for genetically modified higher plants (GMHP). The identified data types are intended to support the evaluation of the following risks: risk of invasion...

  16. Assessment of genetic risk for human exposure to radiation

    International Nuclear Information System (INIS)

    Sevcenko, V.A.; Rubanovic, A.V.

    2002-01-01

    Full text: The methodology of assessing the genetic risk of radiation exposure is based on the concept of 'hitting the target' in development of which N.V. Timofeeff-Ressovsky has played and important role. To predict genetic risk posed by irradiation, the U N Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) has worked out direct and indirect methods of assessment, extrapolation, integral and palpitation criteria of risk analysis that together permit calculating the risk from human exposure on the basis of data obtained for mice. Based on the reports of UNSCEAR for the period from 1958 to 2001 the paper presents a retrospective analysis of the use of direct methods and the doubling dose method for quantitative determination of the genetic risk of human exposure expressed as different hereditary diseases. As early as 1962 UNSCEAR estimated the doubling dose (a dose causing as many mutations as those occurring spontaneously during one generation) at 1 Gy for cases of exposure to ionizing radiations with low LET at a low dose rate and this value was confirmed in the next UNSCEAR reports up to now. For cases of acute irradiation the doubling dose was estimated at 0,3-0,4 Gy for the period under review. The paper considers the evolution of the concepts of human natural hereditary variability which is a basis for assessing the risk of exposure by the doubling dose method. The level of human natural genetic variability per 1 000 000 newborns is estimated at 738 000 hereditary diseases including mendelian, chromosomal and multifactorial ones. The greatest difficulties in assessing the doubling dose value were found to occur in the case of multifactorial diseases the pheno typical expression of which depends on mutational events in polygenic systems and on numerous environmental factors. The introduction in calculations of the potential recoverability correction factor (RPCF) made it possible to assess the genetic risk taking into account this class of

  17. Woman's Pre-Conception Evaluation: Genetic and Fetal Risk Considerations for Counselling and Informed Choice.

    Science.gov (United States)

    Wilson, R Douglas

    2017-10-11

    To inform reproductive and other health care providers about genetic and fetal risk information to consider during a woman/couples' pre-conception evaluation, including considerations for genetic risk assessment, genetic screening, or testing to allow for improved counselling and informed choice. This genetic information can be used for patient education, planning, and possible pre-conception and/or prenatal testing. This information may allow improved risk assessment for pre-conception counselling for individual patients and their families. PubMed or Medline and the Cochrane Database were searched in May 2017 using appropriate key words ("pre-conception," "genetic disease," "maternal," "family history," "genetic," "health risk," "genetic health surveillance," "prenatal screening," "prenatal diagnosis," "birth defects," and "teratogen"). Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, and national and international medical specialty societies. The benefits for the patient and her family include an increased understanding of relevant genetic risk pre-conception and in early pregnancy, and better pregnancy outcomes as a result of use of the information. The harm includes potential increased anxiety or psychological stress associated with the possibility of identifying genetic risks. The evidence obtained was peer-reviewed by the Genetics Committee of The Society of Obstetricians and Gynaecologists of Canada. Consideration for Care Statements For this review article, the Consideration for Care Statements use the GRADE strength and quality as it is comparable for the clinician and the patient/public user. [GRADE from the Canadian Task Force on Preventive Health Care (www.canadiantaskforce.ca). For clinicians, Strong = The recommendation would apply to most individuals. Formal discussion aids are not likely to be

  18. Scientific reporting is suboptimal for aspects that characterize genetic risk prediction studies: a review of published articles based on the Genetic RIsk Prediction Studies statement.

    Science.gov (United States)

    Iglesias, Adriana I; Mihaescu, Raluca; Ioannidis, John P A; Khoury, Muin J; Little, Julian; van Duijn, Cornelia M; Janssens, A Cecile J W

    2014-05-01

    Our main objective was to raise awareness of the areas that need improvements in the reporting of genetic risk prediction articles for future publications, based on the Genetic RIsk Prediction Studies (GRIPS) statement. We evaluated studies that developed or validated a prediction model based on multiple DNA variants, using empirical data, and were published in 2010. A data extraction form based on the 25 items of the GRIPS statement was created and piloted. Forty-two studies met our inclusion criteria. Overall, more than half of the evaluated items (34 of 62) were reported in at least 85% of included articles. Seventy-seven percentage of the articles were identified as genetic risk prediction studies through title assessment, but only 31% used the keywords recommended by GRIPS in the title or abstract. Seventy-four percentage mentioned which allele was the risk variant. Overall, only 10% of the articles reported all essential items needed to perform external validation of the risk model. Completeness of reporting in genetic risk prediction studies is adequate for general elements of study design but is suboptimal for several aspects that characterize genetic risk prediction studies such as description of the model construction. Improvements in the transparency of reporting of these aspects would facilitate the identification, replication, and application of genetic risk prediction models. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. Pediatric Predispositional Genetic Risk Communication: Potential Utility for Prevention and Control of Melanoma Risk as an Exemplar.

    Science.gov (United States)

    Wu, Yelena P; Mays, Darren; Kohlmann, Wendy; Tercyak, Kenneth P

    2017-10-01

    Predispositional genetic testing among minor children is intensely debated due to the potential benefits and harms of providing this type of genetic information to children and their families. Existing guidelines on pediatric genetic testing state that predispositional testing could be appropriate for minors if preventive services exist that mitigate children's risk for or severity of the health condition in question. We use the example of hereditary melanoma to illustrate the rationale for and potential application of genetic risk communication for an adult-onset cancer to a pediatric population where childhood behaviors may reduce risk of disease later in life. We draw from the adult melanoma genetic risk communication and pediatric health behavior change literatures to suggest ways in which genetic test reporting and complementary education could be delivered to children who carry a hereditary risk for melanoma and their families in order to foster children's engagement in melanoma preventive behaviors. Genetic discoveries will continue to yield new opportunities to provide predispositional genetic risk information to unaffected individuals, including children, and could be delivered within programs that provide personalized and translational approaches to cancer prevention.

  20. Strong compound-risk factors: efficient discovery through emerging patterns and contrast sets.

    Science.gov (United States)

    Li, Jinyan; Yang, Qiang

    2007-09-01

    Odds ratio (OR), relative risk (RR) (risk ratio), and absolute risk reduction (ARR) (risk difference) are biostatistics measurements that are widely used for identifying significant risk factors in dichotomous groups of subjects. In the past, they have often been used to assess simple risk factors. In this paper, we introduce the concept of compound-risk factors to broaden the applicability of these statistical tests for assessing factor interplays. We observe that compound-risk factors with a high risk ratio or a big risk difference have an one-to-one correspondence to strong emerging patterns or strong contrast sets-two types of patterns that have been extensively studied in the data mining field. Such a relationship has been unknown to researchers in the past, and efficient algorithms for discovering strong compound-risk factors have been lacking. In this paper, we propose a theoretical framework and a new algorithm that unify the discovery of compound-risk factors that have a strong OR, risk ratio, or a risk difference. Our method guarantees that all patterns meeting a certain test threshold can be efficiently discovered. Our contribution thus represents the first of its kind in linking the risk ratios and ORs to pattern mining algorithms, making it possible to find compound-risk factors in large-scale data sets. In addition, we show that using compound-risk factors can improve classification accuracy in probabilistic learning algorithms on several disease data sets, because these compound-risk factors capture the interdependency between important data attributes.

  1. Ionizing radiation, genetic risks and radiation protection

    International Nuclear Information System (INIS)

    Sankaranarayanan, K.

    1992-01-01

    With one method of risk estimation, designed as the doubling dose method, the estimates of total genetic risk (i.e., over all generation) for a population continuously exposed at a rate of 0.01 Gy/generation of low LET irradiation are about 120 cases of Mendelian and chromosomal diseases/10 6 live births and about the same number of cases for multifactorial diseases (i.e., a total of 240 cases/10 6 ). These estimates provide the basis for risk coefficients for genetic effects estimated by ICRP (1991) in its Publication 60. These are: 1.0%/Sv for the general population (which is 40% of 240/10 6 /0.01 Gy), and 0.6%/Sv for radiation workers (which is 60% of that for the general population). The results of genetic studies carried out on the Japanese survivors of A-bombs have shown no significant adverse effects attributable to parental radiation exposures. The studies of Gardner and colleagues suggest that the risk of leukaemia in children born to male workers in the nuclear reprocessing facility in Sellafield, U.K., may be increased. However, this finding is at variance with the results from the Japanese studies and at present, does not lend itself to a simple interpretation based on radiobiological principles. In the light of recent advances in the molecular biology of naturally-occurring human Mendelian diseases and what we presently know about multifactorial diseases, arguments are advanced to support the thesis that (i) current risk estimates for Mendelian diseases may be conservative and (ii) an overall doubling dose for all adverse genetic effects may be higher than the 1 Gy currently used (i.e., the relative risks are probably lower). (author)

  2. Assessing individual risk for AMD with genetic counseling, family history, and genetic testing.

    Science.gov (United States)

    Cascella, R; Strafella, C; Longo, G; Manzo, L; Ragazzo, M; De Felici, C; Gambardella, S; Marsella, L T; Novelli, G; Borgiani, P; Sangiuolo, F; Cusumano, A; Ricci, F; Giardina, E

    2018-02-01

    PurposeThe goal was to develop a simple model for predicting the individual risk profile for age-related macular degeneration (AMD) on the basis of genetic information, disease family history, and smoking habits.Patients and methodsThe study enrolled 151 AMD patients following specific clinical and environmental inclusion criteria: age >55 years, positive family history for AMD, presence of at least one first-degree relative affected by AMD, and smoking habits. All of the samples were genotyped for rs1061170 (CFH) and rs10490924 (ARMS2) with a TaqMan assay, using a 7500 Fast Real Time PCR device. Statistical analysis was subsequently employed to calculate the real individual risk (OR) based on the genetic data (ORgn), family history (ORf), and smoking habits (ORsm).Results and conclusionThe combination of ORgn, ORf, and ORsm allowed the calculation of the Ort that represented the realistic individual risk for developing AMD. In this report, we present a computational model for the estimation of the individual risk for AMD. Moreover, we show that the average distribution of risk alleles in the general population and the knowledge of parents' genotype can be decisive to assess the real disease risk. In this contest, genetic counseling is crucial to provide the patients with an understanding of their individual risk and the availability for preventive actions.

  3. Genetic risk variants for dyslexia on chromosome 18 in a German cohort.

    Science.gov (United States)

    Mueller, B; Ahnert, P; Burkhardt, J; Brauer, J; Czepezauer, I; Quente, E; Boltze, J; Wilcke, A; Kirsten, H

    2014-03-01

    Dyslexia is characterized by impaired reading and spelling. The disorder has a prevalence of about 5% in Germany, and a strong hereditary component. Several loci are thought to be involved in the development of dyslexia. Scerri et al. identified eight potential dyslexia-associated single nucleotide polymorphisms (SNPs) in seven genes on chromosome 18 in an English-speaking population. Here, we present an association analysis that explores the relevance of these SNPs in a German population comprising 388 dyslexia cases and 364 control cases. In case-control analysis, three nominal SNP associations were replicated. The major alleles of NEDD4L-rs12606138 and NEDD4L-rs8094327 were risk associated [odds ratio (OR) = 1.35, 95% confidence interval (CI) = 1.0-1.7, P-value = 0.017 and OR = 1.39, 95% CI = 1.1-1.7, P-value = 0.007, respectively], and both SNPs were in strong linkage disequilibrium (r(2)  = 0.95). For MYO5B-rs555879, the minor allele was risk associated (OR = 1.31, 95% CI = 1.1-1.6, P-value = 0.011). The combined analysis of SNP sets using set enrichment analysis revealed a study-wide significant association for three SNPs with susceptibility for dyslexia. In summary, our results substantiate genetic markers in NEDD4L and MYO5B as risk factors for dyslexia and provide first evidence that the relevance of these markers is not restricted to the English language. © 2013 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  4. Cancer Genetics Risk Assessment and Counseling (PDQ®)—Health Professional Version

    Science.gov (United States)

    Cancer genetics risk assessment and genetic counseling includes family history, psychosocial assessments, and education on hereditary cancer syndromes, testing, and risk. Get more information including the ethical, legal, and social implications of genetic testing in this summary for clinicians.

  5. Medical radiation exposure and genetic risks

    International Nuclear Information System (INIS)

    Baker, D.G.

    1980-01-01

    Everyone is exposed to background radiation throughout life (100 mrem/year to the gonads or 4 to 5 rem during the reproductive years). A lumbosacral series might deliver 2500 mrem to the male or 400 mrem to the female gonads. A radiologic procedure is a cost/benefit decision, and genetic risk is a part of the cost. Although cost is usually very low compared to benefit, if the procedure is unnecessary then the cost may be unacceptable. On the basis of current estimates, the doubling dose is assumed to be 40 rem (range 20 to 200) for an acute dose, and 100 rem for protracted exposure. Although there is no satisfactory way to predict the size of the risk for an individual exposed, any risk should be incentive to avoid unnecessary radiation to the gonads. Conception should be delayed for at least ten months for women and three or four months for men after irradiation of the gonads. The current incidence of genetically related diseases in the United States population is 60,000 per million live births. Based on the most conservative set of assumptions, an average gonadal dose of 1000 mrem to the whole population would increase the incidence of genetically related diseases by 0.2%

  6. How does genetic risk information for Lynch syndrome translate to risk management behaviours?

    Science.gov (United States)

    Steel, Emma; Robbins, Andrew; Jenkins, Mark; Flander, Louisa; Gaff, Clara; Keogh, Louise

    2017-01-01

    There is limited research on why some individuals who have undergone predictive genetic testing for Lynch syndrome do not adhere to screening recommendations. This study aimed to explore qualitatively how Lynch syndrome non-carriers and carriers translate genetic risk information and advice to decisions about risk managment behaviours in the Australian healthcare system. Participants of the Australasian Colorectal Cancer Family Registry who had undergone predictive genetic testing for Lynch syndrome were interviewed on their risk management behaviours. Transcripts were analysed thematically using a comparative coding analysis. Thirty-three people were interviewed. Of the non-carriers ( n  = 16), 2 reported having apparently unnecessary colonoscopies, and 6 were unsure about what population-based colorectal cancer screening entails. Of the carriers ( n  = 17), 2 reported they had not had regular colonoscopies, and spoke about their discomfort with the screening process and a lack of faith in the procedure's ability to reduce their risk of developing colorectal cancer. Of the female carriers ( n  = 9), 2 could not recall being informed about the associated risk of gynaecological cancers. Non-carriers and female carriers of Lynch syndrome could benefit from further clarity and advice about appropriate risk management options. For those carriers who did not adhere to colonoscopy screening, a lack of faith in both genetic test results and screening were evident. It is essential that consistent advice is offered to both carriers and non-carriers of Lynch syndrome.

  7. Implications of host genetic variation on the risk and prevalence of infectious diseases transmitted through the environment.

    Science.gov (United States)

    Doeschl-Wilson, Andrea B; Davidson, R; Conington, J; Roughsedge, T; Hutchings, M R; Villanueva, B

    2011-07-01

    Previous studies have shown that host genetic heterogeneity in the response to infectious challenge can affect the emergence risk and the severity of diseases transmitted through direct contact between individuals. However, there is substantial uncertainty about the degree and direction of influence owing to different definitions of genetic variation, most of which are not in line with the current understanding of the genetic architecture of disease traits. Also, the relevance of previous results for diseases transmitted through environmental sources is unclear. In this article a compartmental genetic-epidemiological model was developed to quantify the impact of host genetic diversity on epidemiological characteristics of diseases transmitted through a contaminated environment. The model was parameterized for footrot in sheep. Genetic variation was defined through continuous distributions with varying shape and degree of dispersion for different disease traits. The model predicts a strong impact of genetic heterogeneity on the disease risk and its progression and severity, as well as on observable host phenotypes, when dispersion in key epidemiological parameters is high. The impact of host variation depends on the disease trait for which variation occurs and on environmental conditions affecting pathogen survival. In particular, compared to homogeneous populations with the same average susceptibility, disease risk and severity are substantially higher in populations containing a large proportion of highly susceptible individuals, and the differences are strongest when environmental contamination is low. The implications of our results for the recording and analysis of disease data and for predicting response to selection are discussed.

  8. Genetic variation of Lymnaea stagnalis tolerance to copper: A test of selection hypotheses and its relevance for ecological risk assessment

    International Nuclear Information System (INIS)

    Côte, Jessica; Bouétard, Anthony; Pronost, Yannick; Besnard, Anne-Laure; Coke, Maïra; Piquet, Fabien; Caquet, Thierry; Coutellec, Marie-Agnès

    2015-01-01

    The use of standardized monospecific testing to assess the ecological risk of chemicals implicitly relies on the strong assumption that intraspecific variation in sensitivity is negligible or irrelevant in this context. In this study, we investigated genetic variation in copper sensitivity of the freshwater snail Lymnaea stagnalis, using lineages stemming from eight natural populations or strains found to be genetically differentiated at neutral markers. Copper-induced mortality varied widely among populations, as did the estimated daily death rate and time to 50% mortality (LT50). Population genetic divergence in copper sensitivity was compared to neutral differentiation using the Q ST -F ST approach. No evidence for homogenizing selection could be detected. This result demonstrates that species-level extrapolations from single population studies are highly unreliable. The study provides a simple example of how evolutionary principles could be incorporated into ecotoxicity testing in order to refine ecological risk assessment. - Highlights: • Genetic variation in copper tolerance occurs between Lymnaea stagnalis populations. • We used the Q ST -F ST approach to test evolutionary patterns in copper tolerance. • No evidence for uniform selection was found. • Results suggest that extrapolations to the species level are not safe. • A method is proposed to refine ecological risk assessment using genetic parameters. - Genetic variation in copper tolerance occurs in Lymnaea stagnalis. A method is proposed for considering evolutionary parameters in ecological risk assessment

  9. Genetic risk score predicting risk of rheumatoid arthritis phenotypes and age of symptom onset.

    Directory of Open Access Journals (Sweden)

    Lori B Chibnik

    Full Text Available Cumulative genetic profiles can help identify individuals at high-risk for developing RA. We examined the impact of 39 validated genetic risk alleles on the risk of RA phenotypes characterized by serologic and erosive status.We evaluated single nucleotide polymorphisms at 31 validated RA risk loci and 8 Human Leukocyte Antigen alleles among 542 Caucasian RA cases and 551 Caucasian controls from Nurses' Health Study and Nurses' Health Study II. We created a weighted genetic risk score (GRS and evaluated it as 7 ordinal groups using logistic regression (adjusting for age and smoking to assess the relationship between GRS group and odds of developing seronegative (RF- and CCP-, seropositive (RF+ or CCP+, erosive, and seropositive, erosive RA phenotypes. In separate case only analyses, we assessed the relationships between GRS and age of symptom onset. In 542 RA cases, 317 (58% were seropositive, 163 (30% had erosions and 105 (19% were seropositive with erosions. Comparing the highest GRS risk group to the median group, we found an OR of 1.2 (95% CI = 0.8-2.1 for seronegative RA, 3.0 (95% CI = 1.9-4.7 for seropositive RA, 3.2 (95% CI = 1.8-5.6 for erosive RA, and 7.6 (95% CI = 3.6-16.3 for seropositive, erosive RA. No significant relationship was seen between GRS and age of onset.Results suggest that seronegative and seropositive/erosive RA have different genetic architecture and support the importance of considering RA phenotypes in RA genetic studies.

  10. Computerised Genetic Risk Assessment and Decision Support in Primary Care

    Directory of Open Access Journals (Sweden)

    Andrew Coulson

    2000-09-01

    To address these issues, a new computer application called RAGs (Risk Assessment in Genetics has been designed. The system allows a doctor to create family trees and assess genetic risk of breast cancer. RAGs possesses two features that distinguish it from similar software: (a a user-centred design, which takes into account the requirements of the doctor-patient encounter; (b risk reporting using qualitative evidence for or against an increased risk, which the authors believe to be more useful and accessible than numerical probabilities are. In that the system allows for any genetic risk guideline to be implemented, it can be used with all diseases for which evaluation guidelines exist. The software may be easily modified to cater for the amount of detail required by different specialists.

  11. Genetic variation in the ABCA1 gene, HDL cholesterol, and risk of ischemic heart disease in the general population

    DEFF Research Database (Denmark)

    Frikke-Schmidt, Ruth

    2010-01-01

    Epidemiological studies consistently demonstrate a strong inverse association between low levels of high-density lipoprotein (HDL) cholesterol and increased risk of ischemic heart disease (IHD). This review focuses on whether both rare and common genetic variation in ABCA1 contributes to plasma...... levels of HDL cholesterol and to risk of IHD in the general population, and further seeks to understand whether low levels of HDL cholesterol per se are causally related to IHD. Studies of the ABCA1 gene demonstrate a general strategy for detecting functional genetic variants, and show that both common...... and rare ABCA1 variants contribute to levels of HDL cholesterol and risk of IHD in the general population. The association between ABCA1 variants and risk of IHD appears, however, to be independent of plasma levels of HDL cholesterol. With the recent identification of the largest number of individuals...

  12. Epidemiology, major risk factors and genetic predisposition for breast cancer in the Pakistani population.

    Science.gov (United States)

    Shaukat, Uzma; Ismail, Muhammad; Mehmood, Nasir

    2013-01-01

    Occurrence of breast cancer is related to genetic as well as cultural, environmental and life-style factors. Variations in diversity of these factors among different ethnic groups and geographical areas emphasize the immense need for studies in all racial-ethnic populations. The incidence of breast cancer in Pakistan is highest in Asians after Jews in Israel and 2.5 times higher than that in neighboring countries like Iran and India, accounting for 34.6% of female cancers. The Pakistani population is deficient in information regarding breast cancer etiology and epidemiology, but efforts done so far had suggested consanguinity as a major risk factor for frequent mutations leading to breast cancer and has also shed light on genetic origins in different ethnic groups within Pakistan. World-wide research efforts on different ethnicities have enhanced our understanding of genetic predisposition to breast cancer but despite these discoveries, 75% of the familial risk of breast cancer remains unexplained, highlighting the fact that the majority of breast cancer susceptibility genes remain unidentified. For this purpose Pakistani population provides a strong genetic pool to elucidate the genetic etiology of breast cancer because of cousin marriages. In this review, we describe the known breast cancer predisposition factors found in the local Pakistani population and the epidemiological research work done to emphasize the importance of exploring factors/variants contributing to breast cance, in order to prevent, cure and decrease its incidence in our country.

  13. Assessing the evidence for shared genetic risks across psychiatric disorders and traits.

    Science.gov (United States)

    Martin, Joanna; Taylor, Mark J; Lichtenstein, Paul

    2017-12-04

    Genetic influences play a significant role in risk for psychiatric disorders, prompting numerous endeavors to further understand their underlying genetic architecture. In this paper, we summarize and review evidence from traditional twin studies and more recent genome-wide molecular genetic analyses regarding two important issues that have proven particularly informative for psychiatric genetic research. First, emerging results are beginning to suggest that genetic risk factors for some (but not all) clinically diagnosed psychiatric disorders or extreme manifestations of psychiatric traits in the population share genetic risks with quantitative variation in milder traits of the same disorder throughout the general population. Second, there is now evidence for substantial sharing of genetic risks across different psychiatric disorders. This extends to the level of characteristic traits throughout the population, with which some clinical disorders also share genetic risks. In this review, we summarize and evaluate the evidence for these two issues, for a range of psychiatric disorders. We then critically appraise putative interpretations regarding the potential meaning of genetic correlation across psychiatric phenotypes. We highlight several new methods and studies which are already using these insights into the genetic architecture of psychiatric disorders to gain additional understanding regarding the underlying biology of these disorders. We conclude by outlining opportunities for future research in this area.

  14. Common Genetic Risk for Melanoma Encourages Preventive Behavior Change

    Directory of Open Access Journals (Sweden)

    Lori Diseati

    2015-02-01

    Full Text Available There is currently great interest in using genetic risk estimates for common disease in personalized healthcare. Here we assess melanoma risk-related preventive behavioral change in the context of the Coriell Personalized Medicine Collaborative (CPMC. As part of on-going reporting activities within the project, participants received a personalized risk assessment including information related to their own self-reported family history of melanoma and a genetic risk variant showing a moderate effect size (1.7, 3.0 respectively for heterozygous and homozygous individuals. Participants who opted to view their report were sent an optional outcome survey assessing risk perception and behavioral change in the months that followed. Participants that report family history risk, genetic risk, or both risk factors for melanoma were significantly more likely to increase skin cancer preventive behaviors when compared to participants with neither risk factor (ORs = 2.04, 2.79, 4.06 and p-values = 0.02, 2.86 × 10−5, 4.67 × 10−5, respectively, and we found the relationship between risk information and behavior to be partially mediated by anxiety. Genomic risk assessments appear to encourage positive behavioral change in a manner that is complementary to family history risk information and therefore may represent a useful addition to standard of care for melanoma prevention.

  15. Genetic modification of risk assessment based on staging of preclinical type 1 diabetes in siblings of affected children.

    Science.gov (United States)

    Mrena, S; Savola, K; Kulmala, P; Reijonen, H; Ilonen, J; Akerblom, H K; Knip, M

    2003-06-01

    We set out to study the association between human leukocyte antigen-defined genetic disease susceptibility and the stage of preclinical type 1 diabetes and whether genetic predisposition affects the natural course of preclinical diabetes in initially nondiabetic siblings of affected children. A total of 701 initially unaffected siblings were graded into four stages of preclinical type 1 diabetes based on the initial number of disease-associated autoantibodies detectable close to the time of diagnosis of the index case: no prediabetes (no antibodies), early (one antibody specificity), advanced (two antibodies), and late prediabetes (three or more antibodies). Another classification system covering 659 siblings was based on a combination of the initial number of antibodies and the first-phase insulin response (FPIR) to iv glucose: no prediabetes (no antibodies), early (one antibody specificity, normal FPIR), advanced (two or more antibodies, normal FPIR), and late prediabetes (at least one antibody, reduced FPIR). Genetic susceptibility to type 1 diabetes was defined by human leukocyte antigen identity and DR and DQ genotypes. There was a higher proportion of siblings with late prediabetes initially among those with strong genetic disease susceptibility than among those with decreased genetic predisposition (16.7% vs. 0.5%; P siblings with no signs of prediabetes among those with genotypes conferring decreased risk (91.2% vs. 70.4% among those with high-risk DQB1 genotypes; P siblings than when combined with genetic susceptibility. Genetic susceptibility played a role in whether the initial prediabetic stage progressed (progression in 29.6% of the high-risk siblings compared with 6.6% of the siblings with DQB1 genotypes conferring decreased risk; P siblings of affected children.

  16. Focusing light through strongly scattering media using genetic algorithm with SBR discriminant

    Science.gov (United States)

    Zhang, Bin; Zhang, Zhenfeng; Feng, Qi; Liu, Zhipeng; Lin, Chengyou; Ding, Yingchun

    2018-02-01

    In this paper, we have experimentally demonstrated light focusing through strongly scattering media by performing binary amplitude optimization with a genetic algorithm. In the experiments, we control 160 000 mirrors of digital micromirror device to modulate and optimize the light transmission paths in the strongly scattering media. We replace the universal target-position-intensity (TPI) discriminant with signal-to-background ratio (SBR) discriminant in genetic algorithm. With 400 incident segments, a relative enhancement value of 17.5% with a ground glass diffuser is achieved, which is higher than the theoretical value of 1/(2π )≈ 15.9 % for binary amplitude optimization. According to our repetitive experiments, we conclude that, with the same segment number, the enhancement for the SBR discriminant is always higher than that for the TPI discriminant, which results from the background-weakening effect of SBR discriminant. In addition, with the SBR discriminant, the diameters of the focus can be changed ranging from 7 to 70 μm at arbitrary positions. Besides, multiple foci with high enhancement are obtained. Our work provides a meaningful reference for the study of binary amplitude optimization in the wavefront shaping field.

  17. Genetic Predisposition to Dyslipidemia and Risk of Preeclampsia.

    Science.gov (United States)

    Spracklen, Cassandra N; Saftlas, Audrey F; Triche, Elizabeth W; Bjonnes, Andrew; Keating, Brendan; Saxena, Richa; Breheny, Patrick J; Dewan, Andrew T; Robinson, Jennifer G; Hoh, Josephine; Ryckman, Kelli K

    2015-07-01

    Large epidemiologic studies support the role of dyslipidemia in preeclampsia; however, the etiology of preeclampsia or whether dyslipidemia plays a causal role remains unclear. We examined the association between the genetic predisposition to dyslipidemia and risk of preeclampsia using validated genetic markers of dyslipidemia. Preeclampsia cases (n = 164) and normotensive controls (n = 110) were selected from live birth certificates to nulliparous Iowa women during the period August 2002 to May 2005. Disease status was verified by medical chart review. Genetic predisposition to dyslipidemia was estimated by 4 genetic risk scores (GRS) (total cholesterol (TC), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), and triglycerides) on the basis of established loci for blood lipids. Logistic regression analyses were used to evaluate the relationships between each of the 4 genotype scores and preeclampsia. Replication analyses were performed in an independent, US population of preeclampsia cases (n = 516) and controls (n = 1,097) of European ancestry. The GRS related to higher levels of TC, LDL-C, and triglycerides demonstrated no association with the risk of preeclampsia in either the Iowa or replication population. The GRS related to lower HDL-C was marginally associated with an increased risk for preeclampsia (odds ratio (OR) = 1.03, 95% confidence interval (CI) = 0.99-1.07; P = 0.10). In the independent replication population, the association with the HDL-C GRS was also marginally significant (OR = 1.03, 95% CI: 1.00-1.06; P = 0.04). Our data suggest a potential effect between the genetic predisposition to dyslipidemic levels of HDL-C and an increased risk of preeclampsia, and, as such, suggest that dyslipidemia may be a component along the causal pathway to preeclampsia. © American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  18. Assessment of genetic risk for human exposure to radiation. State of the art

    International Nuclear Information System (INIS)

    Shevchenko, V.A.

    2000-01-01

    Historical aspects of the conception of genetic risk of human irradiation for recent 40 years. Methodology of assessing the genetic risk of radiation exposure is based on the concept of hitting the target. To predict genetic risk of irradiation, the direct and indirect methods of assessment, extrapolation, integral and populational criteria of risk analysis is widely used. Combination of these methods permits to calculate the risk from human exposure on the basis of data obtained for mice. Method of doubling dose based on determination of the dose doubling the level of natural mutational process in humans is the main one used to predict the genetic risk. Till 1972 the main model for assessing the genetic risk was the human/mouse model (the use of data on the spontaneous human variability and data on the frequency of induced mutations in mice). In the period from 1972 till 1994 the mouse/mouse model was intensively elaborated in many laboratories. This model was also used in this period to analyse the genetic risk of human irradiation. Recent achievements associated with the study of molecular nature of many hereditary human diseases as well as the criticism of a fundamental principles of the mouse/mouse model for estimating the genetic risk on a new basis. Estimates of risk for the different classes of genetic diseases have been obtained using the doubling-dose method [ru

  19. Genetic determinants of facial clefting

    DEFF Research Database (Denmark)

    Jugessur, Astanand; Shi, Min; Gjessing, Håkon Kristian

    2009-01-01

    BACKGROUND: Facial clefts are common birth defects with a strong genetic component. To identify fetal genetic risk factors for clefting, 1536 SNPs in 357 candidate genes were genotyped in two population-based samples from Scandinavia (Norway: 562 case-parent and 592 control-parent triads; Denmark...

  20. Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes.

    Science.gov (United States)

    Miller, F W; Chen, W; O'Hanlon, T P; Cooper, R G; Vencovsky, J; Rider, L G; Danko, K; Wedderburn, L R; Lundberg, I E; Pachman, L M; Reed, A M; Ytterberg, S R; Padyukov, L; Selva-O'Callaghan, A; Radstake, T R; Isenberg, D A; Chinoy, H; Ollier, W E R; Scheet, P; Peng, B; Lee, A; Byun, J; Lamb, J A; Gregersen, P K; Amos, C I

    2015-10-01

    Autoimmune muscle diseases (myositis) comprise a group of complex phenotypes influenced by genetic and environmental factors. To identify genetic risk factors in patients of European ancestry, we conducted a genome-wide association study (GWAS) of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis, 473 juvenile dermatomyositis, 532 polymyositis and 202 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl-tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 4724 controls. Single-nucleotide polymorphisms showing strong associations (Pmyositis phenotypes together, as well as for the four clinical and autoantibody phenotypes studied separately. Imputation and regression analyses found that alleles comprising the human leukocyte antigen (HLA) 8.1 ancestral haplotype (AH8.1) defined essentially all the genetic risk in the phenotypes studied. Although the HLA DRB1*03:01 allele showed slightly stronger associations with adult and juvenile dermatomyositis, and HLA B*08:01 with polymyositis and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for the full risk effects. Our findings establish that alleles of the AH8.1 comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations.

  1. Genetic testing and your cancer risk

    Science.gov (United States)

    ... patientinstructions/000842.htm Genetic testing and your cancer risk To use the sharing features on this page, ... urac.org). URAC's accreditation program is an independent audit to verify that A.D.A.M. follows ...

  2. Dupuytren diathesis and genetic risk

    NARCIS (Netherlands)

    Dolmans, Guido H; de Bock, Geertruida H; Werker, Paul M

    2012-01-01

    PURPOSE: Dupuytren disease (DD) is a benign fibrosing disorder of the hand and fingers. Recently, we identified 9 single nucleotide polymorphisms (SNPs) associated with DD in a genome-wide association study. These SNPs can be used to calculate a genetic risk score for DD. The aim of this study was

  3. Genetics of ischemic stroke: future clinical applications.

    Science.gov (United States)

    Wang, Michael M

    2006-11-01

    Ischemic stroke has long been thought to have a genetic component that is independent of conventional vascular risk factors. It has been estimated that over one half of stroke risk is determined by inherited genes. However, until recently, strong evidence of genetic influence on ischemic stroke has been subject to criticism because the risk factors for stroke are also inherited and because previous studies suffered from limitations imposed by this highly heterogeneous neurological disorder. Recent advances in molecular genetics have led to the identification of specific genetic loci that impart susceptibility to ischemic stroke. We review the studies of these genes and discuss the future potential applications of genetic markers on the management of ischemic stroke patients.

  4. Genetic Allee effects and their interaction with ecological Allee effects.

    Science.gov (United States)

    Wittmann, Meike J; Stuis, Hanna; Metzler, Dirk

    2018-01-01

    It is now widely accepted that genetic processes such as inbreeding depression and loss of genetic variation can increase the extinction risk of small populations. However, it is generally unclear whether extinction risk from genetic causes gradually increases with decreasing population size or whether there is a sharp transition around a specific threshold population size. In the ecological literature, such threshold phenomena are called 'strong Allee effects' and they can arise for example from mate limitation in small populations. In this study, we aim to (i) develop a meaningful notion of a 'strong genetic Allee effect', (ii) explore whether and under what conditions such an effect can arise from inbreeding depression due to recessive deleterious mutations, and (iii) quantify the interaction of potential genetic Allee effects with the well-known mate-finding Allee effect. We define a strong genetic Allee effect as a genetic process that causes a population's survival probability to be a sigmoid function of its initial size. The inflection point of this function defines the critical population size. To characterize survival-probability curves, we develop and analyse simple stochastic models for the ecology and genetics of small populations. Our results indicate that inbreeding depression can indeed cause a strong genetic Allee effect, but only if individuals carry sufficiently many deleterious mutations (lethal equivalents). Populations suffering from a genetic Allee effect often first grow, then decline as inbreeding depression sets in and then potentially recover as deleterious mutations are purged. Critical population sizes of ecological and genetic Allee effects appear to be often additive, but even superadditive interactions are possible. Many published estimates for the number of lethal equivalents in birds and mammals fall in the parameter range where strong genetic Allee effects are expected. Unfortunately, extinction risk due to genetic Allee effects

  5. The impact of direct-to-consumer marketing of cancer genetic testing on women according to their genetic risk.

    Science.gov (United States)

    Lowery, Jan T; Byers, Tim; Axell, Lisen; Ku, Lisa; Jacobellis, Jillian

    2008-12-01

    To assess the impact of direct-to-consumer marketing for genetic testing among women of varying genetic risk for breast and ovarian cancer. Telephone surveys were conducted with 315 women in Denver, Colorado, one target audience for the Myriad BRACAnalysis ad campaign. Genetic risk was determined from personal and family history and grouped by probability of having a BRCA1/2 mutation (low or =10%). High-risk women were more knowledgeable about BRACAnalysis and more likely to recall the media ads than were low-risk women (60 vs. 39%, P audience. Concern about breast cancer was not appreciably increased. A large percentage of low-risk women (not candidates for testing) expressed interest in testing, suggesting the campaign was too broad. A campaign targeted at high-risk women, who may benefit from testing might be preferred.

  6. Gastrointestinal stromal tumors, somatic mutations and candidate genetic risk variants.

    Directory of Open Access Journals (Sweden)

    Katie M O'Brien

    Full Text Available Gastrointestinal stromal tumors (GISTs are rare but treatable soft tissue sarcomas. Nearly all GISTs have somatic mutations in either the KIT or PDGFRA gene, but there are no known inherited genetic risk factors. We assessed the relationship between KIT/PDGFRA mutations and select deletions or single nucleotide polymorphisms (SNPs in 279 participants from a clinical trial of adjuvant imatinib mesylate. Given previous evidence that certain susceptibility loci and carcinogens are associated with characteristic mutations, or "signatures" in other cancers, we hypothesized that the characteristic somatic mutations in the KIT and PDGFRA genes in GIST tumors may similarly be mutational signatures that are causally linked to specific mutagens or susceptibility loci. As previous epidemiologic studies suggest environmental risk factors such as dioxin and radiation exposure may be linked to sarcomas, we chose 208 variants in 39 candidate genes related to DNA repair and dioxin metabolism or response. We calculated adjusted odds ratios (ORs and 95% confidence intervals (CIs for the association between each variant and 7 categories of tumor mutation using logistic regression. We also evaluated gene-level effects using the sequence kernel association test (SKAT. Although none of the association p-values were statistically significant after adjustment for multiple comparisons, SNPs in CYP1B1 were strongly associated with KIT exon 11 codon 557-8 deletions (OR = 1.9, 95% CI: 1.3-2.9 for rs2855658 and OR = 1.8, 95% CI: 1.2-2.7 for rs1056836 and wild type GISTs (OR = 2.7, 95% CI: 1.5-4.8 for rs1800440 and OR = 0.5, 95% CI: 0.3-0.9 for rs1056836. CYP1B1 was also associated with these mutations categories in the SKAT analysis (p = 0.002 and p = 0.003, respectively. Other potential risk variants included GSTM1, RAD23B and ERCC2. This preliminary analysis of inherited genetic risk factors for GIST offers some clues about the disease's genetic

  7. Disturbed functional connectivity of cortical activation during semantic discrimination in patients with schizophrenia and subjects at genetic high-risk.

    Science.gov (United States)

    Li, Xiaobo; Branch, Craig A; Nierenberg, Jay; Delisi, Lynn E

    2010-03-01

    Schizophrenia has a strong genetic component that is relevant to the understanding of the pathophysiology of the syndrome. Thus, recent investigations have shifted from studies of diagnosed patients with schizophrenia to examining their unaffected relatives. Previous studies found that during language processing, relatives thought to be at genetic high-risk for the disorder exhibit aberrant functional activation in regions of language processing, specifically in the left inferior frontal gyrus (Broca's area). However, functional connectivity among the regions involved in language pathways is not well understood. In this study, we examined the functional connectivity between a seed located in Broca's area and the remainder of the brain during a visual lexical decision task, in 20 schizophrenia patients, 21 subjects at genetic high risk for the disorder and 21 healthy controls. Both the high-risk subjects and patients showed significantly reduced activation correlations between seed and regions related to visual language processing. Compared to the high-risk subjects, the schizophrenia patients showed even fewer regions that were correlated with the seed regions. These results suggest that there is aberrant functional connectivity within cortical language circuitry in high-risk subjects and patients with schizophrenia. Broca's area, which is one of the important regions for language processing in healthy controls, had a significantly reduced role in the high-risk subjects and patients with schizophrenia. Our findings are consistent with the existence of an underlying biological disturbance that begins in genetically at risk individuals and progresses to a greater extent in those who eventually develop schizophrenia.

  8. Impact of literacy and numeracy on motivation for behavior change after diabetes genetic risk testing.

    Science.gov (United States)

    Vassy, Jason L; O'Brien, Kelsey E; Waxler, Jessica L; Park, Elyse R; Delahanty, Linda M; Florez, Jose C; Meigs, James B; Grant, Richard W

    2012-01-01

    Type 2 diabetes genetic risk testing might motivate at-risk patients to adopt diabetes prevention behaviors. However, the influence of literacy and numeracy on patient response to diabetes genetic risk is unknown. The authors investigated the association of health literacy, genetic literacy, and health numeracy with patient responses to diabetes genetic risk. and Measurements Overweight patients at high phenotypic risk for type 2 diabetes were recruited for a clinical trial of diabetes genetic risk testing. At baseline, participants predicted how their motivation for lifestyle modification to prevent diabetes might change in response to hypothetical scenarios of receiving "high" and "low" genetic risk results. Responses were analyzed according to participants' health literacy, genetic literacy, and health numeracy. Two-thirds (67%) of participants (n = 175) reported very high motivation to prevent diabetes. Despite high health literacy (92% at high school level), many participants had limited health numeracy (30%) and genetic literacy (38%). Almost all (98%) reported that high-risk genetic results would increase their motivation for lifestyle modification. In contrast, response to low-risk genetic results varied. Higher levels of health literacy (P = 0.04), genetic literacy (P = 0.02), and health numeracy (P = 0.02) were associated with an anticipated decrease in motivation for lifestyle modification in response to low-risk results. While patients reported that high-risk genetic results would motivate them to adopt healthy lifestyle changes, response to low-risk results varied by patient numeracy and literacy. However, anticipated responses may not correlate with true behavior change. If future research justifies the clinical use of genetic testing to motivate behavior change, it may be important to assess how patient characteristics modify that motivational effect.

  9. Peer deviance, parental divorce, and genetic risk in the prediction of drug abuse in a nationwide Swedish sample: evidence of environment-environment and gene-environment interaction.

    Science.gov (United States)

    Kendler, Kenneth S; Ohlsson, Henrik; Sundquist, Kristina; Sundquist, Jan

    2014-04-01

    Peer deviance (PD) strongly predicts externalizing psychopathologic conditions but has not been previously assessable in population cohorts. We sought to develop such an index of PD and to clarify its effects on risk of drug abuse (DA). To examine how strongly PD increases the risk of DA and whether this community-level liability indicator interacts with key DA risk factors at the individual and family levels. Studies of future DA registration in 1,401,698 Swedish probands born from January 1, 1970, through December 31, 1985, and their adolescent peers in approximately 9200 small community areas. Peer deviance was defined as the proportion of individuals born within 5 years of the proband living in the same small community when the proband was 15 years old who eventually were registered for DA. Drug abuse recorded in medical, legal, or pharmacy registry records. Peer deviance was associated with future DA in the proband, with rates of DA in older and male peers more strongly predictive than in younger or female peers. The predictive power of PD was only slightly attenuated by adding measures of community deprivation, collective efficacy, or family socioeconomic status. Probands whose parents were divorced were more sensitive to the pathogenic effects of high PD environments. A robust positive interaction was also seen between genetic risk of DA (indexed by rates of DA in first-, second-, and third-degree relatives) and PD exposure. With sufficient data, PD can be measured in populations and strongly predicts DA. In a nationwide sample, risk factors at the level of the individual (genetic vulnerability), family (parental loss), and community (PD) contribute substantially to risk of DA. Individuals at elevated DA risk because of parental divorce or high genetic liability are more sensitive to the pathogenic effects of PD. Although the effect of our PD measure on DA liability cannot be explained by standard measures of community or family risk, we cannot, with

  10. Health risks (early, delayed and genetic) from the present radiation level

    International Nuclear Information System (INIS)

    Stranden, E.

    1981-01-01

    A general survey is given of the risks of early, delayed and genetic injuries from present radiation environment. Brief data is presented on some industrial and medical accidents. It is stated that in Norway there are 5-10 incidents per year in industrial radiography, none of which have led to radiation syndrome. Delayed radiation effects are discussed and figures quoted for risk due to mining, industrial and medical radiography and natural sources. Genetic effects are similarly discussed and genetically significant doses from similar sources are quoted. It is concluded that the health risk from the radiation environment is very small compared with other risks. (JIW)

  11. Primer Part 1-The building blocks of epilepsy genetics.

    Science.gov (United States)

    Helbig, Ingo; Heinzen, Erin L; Mefford, Heather C

    2016-06-01

    This is the first of a two-part primer on the genetics of the epilepsies within the Genetic Literacy Series of the Genetics Commission of the International League Against Epilepsy. In Part 1, we cover the foundations of epilepsy genetics including genetic epidemiology and the range of genetic variants that can affect the risk for developing epilepsy. We discuss various epidemiologic study designs that have been applied to the genetics of the epilepsies including population studies, which provide compelling evidence for a strong genetic contribution in many epilepsies. We discuss genetic risk factors varying in size, frequency, inheritance pattern, effect size, and phenotypic specificity, and provide examples of how genetic risk factors within the various categories increase the risk for epilepsy. We end by highlighting trends in epilepsy genetics including the increasing use of massive parallel sequencing technologies. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.

  12. Genetic determinants of financial risk taking.

    Science.gov (United States)

    Kuhnen, Camelia M; Chiao, Joan Y

    2009-01-01

    Individuals vary in their willingness to take financial risks. Here we show that variants of two genes that regulate dopamine and serotonin neurotransmission and have been previously linked to emotional behavior, anxiety and addiction (5-HTTLPR and DRD4) are significant determinants of risk taking in investment decisions. We find that the 5-HTTLPR s/s allele carriers take 28% less risk than those carrying the s/l or l/l alleles of the gene. DRD4 7-repeat allele carriers take 25% more risk than individuals without the 7-repeat allele. These findings contribute to the emerging literature on the genetic determinants of economic behavior.

  13. Circulating anti-Mullerian hormone levels in adult men are under a strong genetic influence.

    Science.gov (United States)

    Pietiläinen, Kirsi H; Kaprio, Jaakko; Vaaralahti, Kirsi; Rissanen, Aila; Raivio, Taneli

    2012-01-01

    The determinants of serum anti-Müllerian hormone (AMH) levels in adult men remain unclear. The objective of the study was to investigate the genetic and environmental components in determining postpubertal AMH levels in healthy men. Serum AMH levels, body mass index (BMI), and fat mass (dual energy x-ray absorptiometry) were measured in 64 healthy male (23 monozygotic and 41 dizygotic) twin pairs. Postpubertal AMH levels were highly genetically determined (broad sense heritability 0.92, 95% confidence interval 0.83-0.96). AMH correlated negatively with BMI (r = -0.26, P = 0.030) and fat mass (r = -0.23, P = 0.048). As AMH, BMI had a high heritability (0.68, 95% confidence interval 0.39-0.83), but no genetic correlation was observed between them. AMH levels in men after puberty are under a strong genetic influence. Twin modeling suggests that AMH and BMI are influenced by different sets of genes.

  14. Quantifying introgression risk with realistic population genetics

    OpenAIRE

    Ghosh, Atiyo; Meirmans, Patrick G.; Haccou, Patsy

    2012-01-01

    Introgression is the permanent incorporation of genes from the genome of one population into another. This can have severe consequences, such as extinction of endemic species, or the spread of transgenes. Quantification of the risk of introgression is an important component of genetically modified crop regulation. Most theoretical introgression studies aimed at such quantification disregard one or more of the most important factors concerning introgression: realistic genetical mechanisms, rep...

  15. A genetic risk score combining ten psoriasis risk loci improves disease prediction.

    Directory of Open Access Journals (Sweden)

    Haoyan Chen

    2011-04-01

    Full Text Available Psoriasis is a chronic, immune-mediated skin disease affecting 2-3% of Caucasians. Recent genetic association studies have identified multiple psoriasis risk loci; however, most of these loci contribute only modestly to disease risk. In this study, we investigated whether a genetic risk score (GRS combining multiple loci could improve psoriasis prediction. Two approaches were used: a simple risk alleles count (cGRS and a weighted (wGRS approach. Ten psoriasis risk SNPs were genotyped in 2815 case-control samples and 858 family samples. We found that the total number of risk alleles in the cases was significantly higher than in controls, mean 13.16 (SD 1.7 versus 12.09 (SD 1.8, p = 4.577×10(-40. The wGRS captured considerably more risk than any SNP considered alone, with a psoriasis OR for high-low wGRS quartiles of 10.55 (95% CI 7.63-14.57, p = 2.010×10(-65. To compare the discriminatory ability of the GRS models, receiver operating characteristic curves were used to calculate the area under the curve (AUC. The AUC for wGRS was significantly greater than for cGRS (72.0% versus 66.5%, p = 2.13×10(-8. Additionally, the AUC for HLA-C alone (rs10484554 was equivalent to the AUC for all nine other risk loci combined (66.2% versus 63.8%, p = 0.18, highlighting the dominance of HLA-C as a risk locus. Logistic regression revealed that the wGRS was significantly associated with two subphenotypes of psoriasis, age of onset (p = 4.91×10(-6 and family history (p = 0.020. Using a liability threshold model, we estimated that the 10 risk loci account for only 11.6% of the genetic variance in psoriasis. In summary, we found that a GRS combining 10 psoriasis risk loci captured significantly more risk than any individual SNP and was associated with early onset of disease and a positive family history. Notably, only a small fraction of psoriasis heritability is captured by the common risk variants identified to date.

  16. Genetic and epigenetic risks of assisted reproduction.

    Science.gov (United States)

    Jiang, Ziru; Wang, Yinyu; Lin, Jing; Xu, Jingjing; Ding, Guolian; Huang, Hefeng

    2017-10-01

    Assisted reproductive technology (ART) is used primarily for infertility treatments to achieve pregnancy and involves procedures such as in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), and cryopreservation. Moreover, preimplantation genetic diagnosis (PGD) of ART is used in couples for genetic reasons. In ART treatments, gametes and zygotes are exposed to a series of non-physiological processes and culture media. Although the majority of children born with this treatment are healthy, some concerns remain regarding the safety of this technology. Animal studies and follow-up studies of ART-borne children suggested that ART was associated with an increased incidence of genetic, physical, or developmental abnormalities, although there are also observations that contradict these findings. As IVF, ICSI, frozen-thawed embryo transfer, and PGD manipulate gametes and embryo at a time that is important for reprogramming, they may affect epigenetic stability, leading to gamete/embryo origins of adult diseases. In fact, ART offspring have been reported to have an increased risk of gamete/embryo origins of adult diseases, such as early-onset diabetes, cardiovascular disease, and so on. In this review, we will discuss evidence related to genetic, especially epigenetic, risks of assisted reproduction. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Risk Assessment of Genetically Modified Microorganisms

    DEFF Research Database (Denmark)

    Jacobsen, B. L.; Wilcks, Andrea

    2001-01-01

    the industry, national administration and research institutions were gathered to discuss which elements should be considered in a risk assessment of genetically modified microorganisms used as food or food ingredients. The existing EU and national regulations were presented, together with the experiences......The rapid development of recombinant DNA techniques for food organisms urges for an ongoing discussion on the risk assessment of both new as traditional use of microorganisms in food production. This report, supported by the Nordic Council of Ministers, is the result of a workshop where people from...... with risk assessment of these organisms in each Nordic country....

  18. Disclosing Genetic Risk for Coronary Heart Disease: Attitudes Toward Personal Information in Health Records.

    Science.gov (United States)

    Brown, Sherry-Ann; Jouni, Hayan; Marroush, Tariq S; Kullo, Iftikhar J

    2017-04-01

    Incorporating genetic risk information in electronic health records (EHRs) will facilitate implementation of genomic medicine in clinical practice. However, little is known about patients' attitudes toward incorporation of genetic risk information as a component of personal health information in EHRs. This study investigated whether disclosure of a genetic risk score (GRS) for coronary heart disease influences attitudes toward incorporation of personal health information including genetic risk in EHRs. Participants aged 45-65 years with intermediate 10-year coronary heart disease risk were randomized to receive a conventional risk score (CRS) alone or with a GRS from a genetic counselor, followed by shared decision making with a physician using the same standard presentation and information templates for all study participants. The CRS and GRS were then incorporated into the EHR and made accessible to both patients and physicians. Baseline and post-disclosure surveys were completed to assess whether attitudes differed by GRS disclosure. Data were collected from 2013 to 2015 and analyzed in 2015-2016. GRS and CRS participants reported similar positive attitudes toward incorporation of genetic risk information in the EHR. Compared with CRS participants, participants with high GRS were more concerned about the confidentiality of genetic risk information (OR=3.67, 95% CI=1.29, 12.32, p=0.01). Post-disclosure, frequency of patient portal access was associated with positive attitudes. Participants in this study of coronary heart disease risk disclosure overall had positive attitudes toward incorporation of genetic risk information in EHRs, although those who received genetic risk information had concerns about confidentiality. Copyright © 2016 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

  19. Structured parenting of toddlers at high versus low genetic risk: two pathways to child problems.

    Science.gov (United States)

    Leve, Leslie D; Harold, Gordon T; Ge, Xiaojia; Neiderhiser, Jenae M; Shaw, Daniel; Scaramella, Laura V; Reiss, David

    2009-11-01

    Little is known about how parenting might offset genetic risk to prevent the onset of child problems during toddlerhood. We used a prospective adoption design to separate genetic and environmental influences and test whether associations between structured parenting and toddler behavior problems were conditioned by genetic risk for psychopathology. The sample included 290 linked sets of adoptive families and birth mothers and 95 linked birth fathers. Genetic risk was assessed via birth mother and birth father psychopathology (anxiety, depression, antisociality, and drug use). Structured parenting was assessed via microsocial coding of adoptive mothers' behavior during a cleanup task. Toddler behavior problems were assessed with the Child Behavior Checklist. Controlling for temperamental risk at 9 months, there was an interaction between birth mother psychopathology and adoptive mothers' parenting on toddler behavior problems at 18 months. The interaction indicated two pathways to child problems: structured parenting was beneficial for toddlers at high genetic risk but was related to behavior problems for toddlers at low genetic risk. This crossover interaction pattern was replicated with birth father psychopathology as the index of genetic risk. The effects of structured parenting on toddler behavior problems varied as a function of genetic risk. Children at genetic risk might benefit from parenting interventions during toddlerhood that enhance structured parenting.

  20. Risk Perception and Psychological Distress in Genetic Counselling for Hereditary Breast and/or Ovarian Cancer.

    Science.gov (United States)

    Cicero, G; De Luca, R; Dorangricchia, P; Lo Coco, G; Guarnaccia, C; Fanale, D; Calò, V; Russo, A

    2017-10-01

    Oncological Genetic Counselling (CGO) allows the identification of a genetic component that increases the risk of developing a cancer. Individuals' psychological reactions are influenced by both the content of the received information and the subjective perception of their own risk of becoming ill or being a carrier of a genetic mutation. This study included 120 participants who underwent genetic counselling for breast and/or ovarian cancer. The aim of the study was to examine the relation between their cancer risk perception and the genetic risk during CGO before receiving genetic test results, considering the influence of some psychological variables, in particular distress, anxiety and depression. Participants completed the following tools during a psychological interview: a socio-demographic form, Cancer Risk Perception (CRP) and Genetic Risk Perception (GRP), Hospital Anxiety and Depression Scale (HADS) and Distress Thermometer (DT). The data seem to confirm our hypothesis. Positive and significant correlations were found between the observed variables. Moreover, genetic risk perception determined an increase in depressive symptomatology and cancer risk perception led to an increase in anxious symptomatology, specifically in participants during cancer treatment. The present results suggest the importance of assessing genetic and cancer risk perception in individuals who undergo CGO, to identify those who are at risk of a decrease in psychological well-being and of developing greater psychological distress.

  1. Genetic factors affecting dental caries risk.

    Science.gov (United States)

    Opal, S; Garg, S; Jain, J; Walia, I

    2015-03-01

    This article reviews the literature on genetic aspects of dental caries and provides a framework for the rapidly changing disease model of caries. The scope is genetic aspects of various dental factors affecting dental caries. The PubMed database was searched for articles with keywords 'caries', 'genetics', 'taste', 'diet' and 'twins'. This was followed by extensive handsearching using reference lists from relevant articles. The post-genomic era will present many opportunities for improvement in oral health care but will also present a multitude of challenges. We can conclude from the literature that genes have a role to play in dental caries; however, both environmental and genetic factors have been implicated in the aetiology of caries. Additional studies will have to be conducted to replicate the findings in a different population. Identification of genetic risk factors will help screen and identify susceptible patients to better understand the contribution of genes in caries aetiopathogenesis. Information derived from these diverse studies will provide new tools to target individuals and/or populations for a more efficient and effective implementation of newer preventive measures and diagnostic and novel therapeutic approaches in the management of this disease. © 2015 Australian Dental Association.

  2. Temporal genetic stability in natural populations of the waterflea Daphnia magna in response to strong selection pressure.

    Science.gov (United States)

    Orsini, Luisa; Marshall, Hollie; Cuenca Cambronero, Maria; Chaturvedi, Anurag; Thomas, Kelley W; Pfrender, Michael E; Spanier, Katina I; De Meester, Luc

    2016-12-01

    Studies monitoring changes in genetic diversity and composition through time allow a unique understanding of evolutionary dynamics and persistence of natural populations. However, such studies are often limited to species with short generation times that can be propagated in the laboratory or few exceptional cases in the wild. Species that produce dormant stages provide powerful models for the reconstruction of evolutionary dynamics in the natural environment. A remaining open question is to what extent dormant egg banks are an unbiased representation of populations and hence of the species' evolutionary potential, especially in the presence of strong environmental selection. We address this key question using the water flea Daphnia magna, which produces dormant stages that accumulate in biological archives over time. We assess temporal genetic stability in three biological archives, previously used in resurrection ecology studies showing adaptive evolutionary responses to rapid environmental change. We show that neutral genetic diversity does not decline with the age of the population and it is maintained in the presence of strong selection. In addition, by comparing temporal genetic stability in hatched and unhatched populations from the same biological archive, we show that dormant egg banks can be consulted to obtain a reliable measure of genetic diversity over time, at least in the multidecadal time frame studied here. The stability of neutral genetic diversity through time is likely mediated by the buffering effect of the resting egg bank. © 2016 John Wiley & Sons Ltd.

  3. Genetically decreased vitamin D and risk of Alzheimer disease.

    Science.gov (United States)

    Mokry, Lauren E; Ross, Stephanie; Morris, John A; Manousaki, Despoina; Forgetta, Vincenzo; Richards, J Brent

    2016-12-13

    To test whether genetically decreased vitamin D levels are associated with Alzheimer disease (AD) using mendelian randomization (MR), a method that minimizes bias due to confounding or reverse causation. We selected single nucleotide polymorphisms (SNPs) that are strongly associated with 25-hydroxyvitamin D (25OHD) levels (p risk from the International Genomics of Alzheimer's Project (N = 17,008 AD cases and 37,154 controls). To produce MR estimates, we weighted the effect of each SNP on AD by its effect on 25OHD and meta-analyzed these estimates using a fixed-effects model to provide a summary effect estimate. The SUNLIGHT Consortium identified 4 SNPs to be genome-wide significant for 25OHD, which described 2.44% of the variance in 25OHD in CaMos. All 4 SNPs map to genes within the vitamin D metabolic pathway. MR analyses demonstrated that a 1-SD decrease in natural log-transformed 25OHD increased AD risk by 25% (odds ratio 1.25, 95% confidence interval 1.03-1.51, p = 0.021). After sensitivity analysis in which we removed SNPs possibly influenced by pleiotropy and population stratification, the results were largely unchanged. Our results provide evidence supporting 25OHD as a causal risk factor for AD. These findings provide further rationale to understand the effect of vitamin D supplementation on cognition and AD risk in randomized controlled trials. © 2016 American Academy of Neurology.

  4. Risks and benefits of genetically modified foods

    African Journals Online (AJOL)

    Jane

    2011-09-30

    Sep 30, 2011 ... education on the subject to the public. Modern ... published were on the progress of GMF technology followed by attitude studies (such as perceptions ..... Genetically Modified Corn: Environmental Benefits and. Risks.

  5. Molecular mechanisms of the genetic risk factors in pathogenesis of Alzheimer disease.

    Science.gov (United States)

    Kanatsu, Kunihiko; Tomita, Taisuke

    2017-01-01

    Alzheimer disease (AD) is a neurodegenerative disease characterized by the extensive deposition of senile plaques and neurofibrillary tangles. Until recently, only the APOE gene had been known as a genetic risk factor for late-onset AD (LOAD), which accounts for more than 95% of all AD cases. However, in addition to this well-established genetic risk factor, genome-wide association studies have identified several single nucleotide polymorphisms as genetic risk factors of LOAD, such as PICALM and BIN1 . In addition, whole genome sequencing and exome sequencing have identified rare variants associated with LOAD, including TREM2 . We review the recent findings related to the molecular mechanisms by which these genetic risk factors contribute to AD, and our perspectives regarding the etiology of AD for the development of therapeutic agents.

  6. Design of a randomized trial of diabetes genetic risk testing to motivate behavior change: the Genetic Counseling/lifestyle Change (GC/LC) Study for Diabetes Prevention.

    Science.gov (United States)

    Grant, Richard W; Meigs, James B; Florez, Jose C; Park, Elyse R; Green, Robert C; Waxler, Jessica L; Delahanty, Linda M; O'Brien, Kelsey E

    2011-10-01

    The efficacy of diabetes genetic risk testing to motivate behavior change for diabetes prevention is currently unknown. This paper presents key issues in the design and implementation of one of the first randomized trials (The Genetic Counseling/Lifestyle Change (GC/LC) Study for Diabetes Prevention) to test whether knowledge of diabetes genetic risk can motivate patients to adopt healthier behaviors. Because individuals may react differently to receiving 'higher' vs 'lower' genetic risk results, we designed a 3-arm parallel group study to separately test the hypotheses that: (1) patients receiving 'higher' diabetes genetic risk results will increase healthy behaviors compared to untested controls, and (2) patients receiving 'lower' diabetes genetic risk results will decrease healthy behaviors compared to untested controls. In this paper we describe several challenges to implementing this study, including: (1) the application of a novel diabetes risk score derived from genetic epidemiology studies to a clinical population, (2) the use of the principle of Mendelian randomization to efficiently exclude 'average' diabetes genetic risk patients from the intervention, and (3) the development of a diabetes genetic risk counseling intervention that maintained the ethical need to motivate behavior change in both 'higher' and 'lower' diabetes genetic risk result recipients. Diabetes genetic risk scores were developed by aggregating the results of 36 diabetes-associated single nucleotide polymorphisms. Relative risk for type 2 diabetes was calculated using Framingham Offspring Study outcomes, grouped by quartiles into 'higher', 'average' (middle two quartiles) and 'lower' genetic risk. From these relative risks, revised absolute risks were estimated using the overall absolute risk for the study group. For study efficiency, we excluded all patients receiving 'average' diabetes risk results from the subsequent intervention. This post-randomization allocation strategy was

  7. Applying personal genetic data to injury risk assessment in athletes.

    Directory of Open Access Journals (Sweden)

    Gabrielle T Goodlin

    Full Text Available Recent studies have identified genetic markers associated with risk for certain sports-related injuries and performance-related conditions, with the hope that these markers could be used by individual athletes to personalize their training and diet regimens. We found that we could greatly expand the knowledge base of sports genetic information by using published data originally found in health and disease studies. For example, the results from large genome-wide association studies for low bone mineral density in elderly women can be re-purposed for low bone mineral density in young endurance athletes. In total, we found 124 single-nucleotide polymorphisms associated with: anterior cruciate ligament tear, Achilles tendon injury, low bone mineral density and stress fracture, osteoarthritis, vitamin/mineral deficiencies, and sickle cell trait. Of these single nucleotide polymorphisms, 91% have not previously been used in sports genetics. We conducted a pilot program on fourteen triathletes using this expanded knowledge base of genetic variants associated with sports injury. These athletes were genotyped and educated about how their individual genetic make-up affected their personal risk profile during an hour-long personal consultation. Overall, participants were favorable of the program, found it informative, and most acted upon their genetic results. This pilot program shows that recent genetic research provides valuable information to help reduce sports injuries and to optimize nutrition. There are many genetic studies for health and disease that can be mined to provide useful information to athletes about their individual risk for relevant injuries.

  8. Genetic and environmental-genetic interaction rules for the myopia based on a family exposed to risk from a myopic environment.

    Science.gov (United States)

    Wenbo, Li; Congxia, Bai; Hui, Liu

    2017-08-30

    To quantitatively assess the role of heredity and environmental factors in myopia based on the family with enough exposed to risk from myopic environment for establishment of environmental and genetic index (EGI). A pedigree analysis unit was defined as one child (university student), father, and mother. Information pertaining to visual acuity, experience in participating in the college entrance examination in mainland of China (regarded as a strong environmental risk for myopia), and occupation for pedigree analysis units were obtained. The difference between effect of both genetic and environmental factors (myopia prevalence in children with two myopic parents) and environmental factors (myopia prevalence in children of whom neither parent was myopic) was defined as the EGI. Multiple regression analysis was performed for 114 pedigree using diopters of father, mother, average diopters in parents, maximum and minimum diopters in father and mother as variables. A total of 353 farmers and 162 farmer families were used as a control group. A distinct difference in myopia rate (96.2% versus 57.7%) was observed for children from parents with myopia and parents without myopia (EGI=0.385). The maximum diopter was included to regression equation which was statistically significant. The prevalence of myopia was 9.9% in the farmer. The prevalence in children is similar between the farmer and other families. A new genetic rule that myopia in children was directly related with maximum diopters in father and mother may be suggested. Environmental factors may play a leading role in the formation of myopia. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Risk factors for Alzheimer's disease : a genetic-epidemiologic study

    NARCIS (Netherlands)

    C.M. van Duijn (Cornelia)

    1992-01-01

    textabstractThe work presented in this thesis has been motivated by the Jack of knowledge of risk factors for Alzheimer's disease. It has been long recognised that genetic factors are implicated, in particular in early-onset Alzheimer's disease.4 But to what extent are genetic factors involved?

  10. Genetic liability for schizophrenia predicts risk of immune disorders

    NARCIS (Netherlands)

    Stringer, Sven; Kahn, René S.; de Witte, Lot D.; Ophoff, Roel A.; Derks, Eske M.

    2014-01-01

    Schizophrenia patients and their parents have an increased risk of immune disorders compared to population controls and their parents. This may be explained by genetic overlap in the pathogenesis of both types of disorders. The purpose of this study was to investigate the genetic overlap between

  11. Genetic liability for schizophrenia predicts risk of immune disorders

    NARCIS (Netherlands)

    Stringer, Sven; Kahn, René S; de Witte, Lot D; Ophoff, Roel A; Derks, Eske M

    2014-01-01

    BACKGROUND: Schizophrenia patients and their parents have an increased risk of immune disorders compared to population controls and their parents. This may be explained by genetic overlap in the pathogenesis of both types of disorders. The purpose of this study was to investigate the genetic overlap

  12. Eating disorder-specific risk factors moderate the relationship between negative urgency and binge eating: A behavioral genetic investigation.

    Science.gov (United States)

    Racine, Sarah E; VanHuysse, Jessica L; Keel, Pamela K; Burt, S Alexandra; Neale, Michael C; Boker, Steven; Klump, Kelly L

    2017-07-01

    Theoretical models of binge eating and eating disorders include both transdiagnostic and eating disorder-specific risk factors. Negative urgency (i.e., the tendency to act impulsively when distressed) is a critical transdiagnostic risk factor for binge eating, but limited research has examined interactions between negative urgency and disorder-specific variables. Investigating these interactions can help identify the circumstances under which negative urgency is most strongly associated with binge eating. We examined whether prominent risk factors (i.e., appearance pressures, thin-ideal internalization, body dissatisfaction, dietary restraint) specified in well-established etiologic models of eating disorders moderate negative urgency-binge eating associations. Further, we investigated whether phenotypic moderation effects were due to genetic and/or environmental associations between negative urgency and binge eating. Participants were 988 female twins aged 11-25 years from the Michigan State University Twin Registry. Appearance pressures, thin-ideal internalization, and body dissatisfaction, but not dietary restraint, significantly moderated negative urgency-binge eating associations, with high levels of these risk factors and high negative urgency associated with the greatest binge eating. Twin moderation models revealed that genetic, but not environmental, sharing between negative urgency and binge eating was enhanced at higher levels of these eating disorder-specific variables. Future longitudinal research should investigate whether eating disorder risk factors shape genetic influences on negative urgency into manifesting as binge eating. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  13. Genetic variation of Lymnaea stagnalis tolerance to copper: A test of selection hypotheses and its relevance for ecological risk assessment.

    Science.gov (United States)

    Côte, Jessica; Bouétard, Anthony; Pronost, Yannick; Besnard, Anne-Laure; Coke, Maïra; Piquet, Fabien; Caquet, Thierry; Coutellec, Marie-Agnès

    2015-10-01

    The use of standardized monospecific testing to assess the ecological risk of chemicals implicitly relies on the strong assumption that intraspecific variation in sensitivity is negligible or irrelevant in this context. In this study, we investigated genetic variation in copper sensitivity of the freshwater snail Lymnaea stagnalis, using lineages stemming from eight natural populations or strains found to be genetically differentiated at neutral markers. Copper-induced mortality varied widely among populations, as did the estimated daily death rate and time to 50% mortality (LT50). Population genetic divergence in copper sensitivity was compared to neutral differentiation using the QST-FST approach. No evidence for homogenizing selection could be detected. This result demonstrates that species-level extrapolations from single population studies are highly unreliable. The study provides a simple example of how evolutionary principles could be incorporated into ecotoxicity testing in order to refine ecological risk assessment. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Genetic Variants in the Wnt/β-Catenin Signaling Pathway as Indicators of Bladder Cancer Risk.

    Science.gov (United States)

    Pierzynski, Jeanne A; Hildebrandt, Michelle A; Kamat, Ashish M; Lin, Jie; Ye, Yuanqing; Dinney, Colin P N; Wu, Xifeng

    2015-12-01

    Genetic factors that influence bladder cancer risk remain largely unknown. Previous research has suggested that there is a strong genetic component underlying the risk of bladder cancer. The Wnt/β-catenin signaling pathway is a key modulator of cellular proliferation through its regulation of stem cell homeostasis. Furthermore, variants in the Wnt/β-catenin signaling pathway have been implicated in the development of other cancers, leading us to believe that this pathway may have a vital role in bladder cancer development. A total of 230 single nucleotide polymorphisms in 40 genes in the Wnt/β-catenin signaling pathway were genotyped in 803 bladder cancer cases and 803 healthy controls. A total of 20 single nucleotide polymorphisms were nominally significant for risk. Individuals with 2 variants of LRP6: rs10743980 were associated with a decreased risk of bladder cancer in the recessive model in the initial analysis (OR 0.76, 95% CI 0.58-0.99, p=0.039). This was validated using the bladder genome-wide association study chip (OR 0.51, 95% CI 0.27-1.00, p=0.049 and for combined analysis p=0.007). Together these findings implicate variants in the Wnt/β-catenin stem cell pathway as having a role in bladder cancer etiology. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  15. Guidance on the environmental risk assessment of genetically modified plants

    DEFF Research Database (Denmark)

    Bartsch, Detlef; Chueca, Cristina; De-Schrijver, Adinda

    risk evaluation. The scientific Panel on Genetically Modified Organisms (of the European Food Safety Authority (EFSA GMO Panel) considers seven specific areas of concern to be addressed by applicants and risk assessors during the ERA (1) persistence and invasiveness of the GM plant , or its compatible......This document provides guidance for the environmental risk assessment (ERA) of genetically modified (GM) plants submitted within the framework of Regulation (EC) No. 1829/2003 on GM food and feed or under Directive 2001/18/EC on the deliberate release into the environment of genetically modified...... organisms (GMOs). This document provides guidance for assessing potential effects of GM plants on the environment and the rationales for the data requirements for a comprehensive ERA of GM plants. The ERA should be carried out on a case-by-case basis, following a step-by-step assessment approach...

  16. An audit of clinical service examining the uptake of genetic testing by at-risk family members.

    Science.gov (United States)

    Forrest, Laura; Delatycki, Martin; Curnow, Lisette; Gen Couns, M; Skene, Loane; Aitken, Maryanne

    2012-01-01

    The aim of this study was to investigate the uptake of genetic testing by at-risk family members for four genetic conditions: chromosomal translocations, fragile X syndrome, Huntington disease, and spinal muscular atrophy. A clinical audit was undertaken using genetics files from Genetic Health Services Victoria. Data were extracted from the files regarding the number of at-risk family members and the proportion tested. Information was also collected about whether discussion of at-risk family members and family communication during the genetic consultation was recorded. The proportion of at-risk family members who had genetic testing ranged from 11% to 18%. First-degree family members were most frequently tested and the proportion of testing decreased by degree of relatedness to the proband. Smaller families were significantly more likely to have genetic testing for all conditions except Huntington disease. Female at-risk family members were significantly more likely to have testing for fragile X syndrome. The majority of at-risk family members do not have genetic testing. Family communication is likely to influence the uptake of genetic testing by at-risk family members and therefore it is important that families are supported while communicating to ensure that at-risk family members are able to make informed decisions about genetic testing.

  17. Comparison of weighting approaches for genetic risk scores in gene-environment interaction studies.

    Science.gov (United States)

    Hüls, Anke; Krämer, Ursula; Carlsten, Christopher; Schikowski, Tamara; Ickstadt, Katja; Schwender, Holger

    2017-12-16

    Weighted genetic risk scores (GRS), defined as weighted sums of risk alleles of single nucleotide polymorphisms (SNPs), are statistically powerful for detection gene-environment (GxE) interactions. To assign weights, the gold standard is to use external weights from an independent study. However, appropriate external weights are not always available. In such situations and in the presence of predominant marginal genetic effects, we have shown in a previous study that GRS with internal weights from marginal genetic effects ("GRS-marginal-internal") are a powerful and reliable alternative to single SNP approaches or the use of unweighted GRS. However, this approach might not be appropriate for detecting predominant interactions, i.e. interactions showing an effect stronger than the marginal genetic effect. In this paper, we present a weighting approach for such predominant interactions ("GRS-interaction-training") in which parts of the data are used to estimate the weights from the interaction terms and the remaining data are used to determine the GRS. We conducted a simulation study for the detection of GxE interactions in which we evaluated power, type I error and sign-misspecification. We compared this new weighting approach to the GRS-marginal-internal approach and to GRS with external weights. Our simulation study showed that in the absence of external weights and with predominant interaction effects, the highest power was reached with the GRS-interaction-training approach. If marginal genetic effects were predominant, the GRS-marginal-internal approach was more appropriate. Furthermore, the power to detect interactions reached by the GRS-interaction-training approach was only slightly lower than the power achieved by GRS with external weights. The power of the GRS-interaction-training approach was confirmed in a real data application to the Traffic, Asthma and Genetics (TAG) Study (N = 4465 observations). When appropriate external weights are unavailable, we

  18. Genetic and other factors determining mannose-binding lectin levels in American Indians: the Strong Heart Study

    DEFF Research Database (Denmark)

    Best, Lyle G; Ferrell, Robert E; Decroo, Susan

    2009-01-01

    control of MBL2 expression is complex and genetic background effects in specific populations are largely unknown. METHODS: The Strong Heart Study is a longitudinal, cohort study of cardiovascular disease among American Indians. A subset of individuals genotyped for the above mentioned case-control study...... in Caucasian and other populations, result in markedly reduced expression of functional protein. Prospective epidemiologic studies, including a nested, case-control study from the present population, have demonstrated the ability of MBL2 genotypes to predict complications of atherosclerosis,. The genetic...

  19. Cerivastatin, Genetic Variants, and the Risk of Rhabdomyolysis

    Science.gov (United States)

    Marciante, Kristin D.; Durda, Jon P.; Heckbert, Susan R.; Lumley, Thomas; Rice, Ken; McKnight, Barbara; Totah, Rheem A.; Tamraz, Bani; Kroetz, Deanna L.; Fukushima, Hisayo; Kaspera, Rüdiger; Bis, Joshua C.; Glazer, Nicole L.; Li, Guo; Austin, Thomas R.; Taylor, Kent D.; Rotter, Jerome I.; Jaquish, Cashell E.; Kwok, Pui-Yan; Tracy, Russell P.; Psaty, Bruce M.

    2011-01-01

    Objective The withdrawal of cerivastatin involved an uncommon but serious adverse reaction, rhabdomyolysis. The bimodal response--rhabdomyolysis in a small proportion of users-- points to genetic factors as a potential cause. We conducted a case-control study to evaluate genetic markers for cerivastatin-associated rhabdomyolysis. Methods The study had two components: a candidate gene study to evaluate variants in CYP2C8, UGT1A1, UGT1A3, and SLCO1B1; and a genome-wide association (GWA) study to identify risk factors in other regions of the genome. 185 rhabdomyolysis cases were frequency matched to statin-using controls from the Cardiovascular Health Study (n=374) and the Heart and Vascular Health Study (n=358). Validation relied on functional studies. Results Permutation test results suggested an association between cerivastatin-associated rhabdomyolysis and variants in SLCO1B1 (p = 0.002), but not variants in CYP2C8 (p = 0.073) or the UGTs (p = 0.523). An additional copy of the minor allele of SLCO1B1 rs4149056 (p.Val174Ala) was associated with the risk of rhabdomyolysis (OR: 1.89, 95% CI: 1.40 to 2.56). In transfected cells, this variant reduced cerivastatin transport by 40% compared with the reference transporter (p rhabdomyolysis (OR: 0.48; 95% CI: 0.36 to 0.63). Conclusion We identified modest genetic risk factors for an extreme response to cerivastatin. Disabling genetic variants in the candidate genes were not responsible for the bimodal response to cerivastatin. PMID:21386754

  20. Quantitative autistic trait measurements index background genetic risk for ASD in Hispanic families.

    Science.gov (United States)

    Page, Joshua; Constantino, John Nicholas; Zambrana, Katherine; Martin, Eden; Tunc, Ilker; Zhang, Yi; Abbacchi, Anna; Messinger, Daniel

    2016-01-01

    Recent studies have indicated that quantitative autistic traits (QATs) of parents reflect inherited liabilities that may index background genetic risk for clinical autism spectrum disorder (ASD) in their offspring. Moreover, preferential mating for QATs has been observed as a potential factor in concentrating autistic liabilities in some families across generations. Heretofore, intergenerational studies of QATs have focused almost exclusively on Caucasian populations-the present study explored these phenomena in a well-characterized Hispanic population. The present study examined QAT scores in siblings and parents of 83 Hispanic probands meeting research diagnostic criteria for ASD, and 64 non-ASD controls, using the Social Responsiveness Scale-2 (SRS-2). Ancestry of the probands was characterized by genotype, using information from 541,929 single nucleotide polymorphic markers. In families of Hispanic children with an ASD diagnosis, the pattern of quantitative trait correlations observed between ASD-affected children and their first-degree relatives (ICCs on the order of 0.20), between unaffected first-degree relatives in ASD-affected families (sibling/mother ICC = 0.36; sibling/father ICC = 0.53), and between spouses (mother/father ICC = 0.48) were in keeping with the influence of transmitted background genetic risk and strong preferential mating for variation in quantitative autistic trait burden. Results from analysis of ancestry-informative genetic markers among probands in this sample were consistent with that from other Hispanic populations. Quantitative autistic traits represent measurable indices of inherited liability to ASD in Hispanic families. The accumulation of autistic traits occurs within generations, between spouses, and across generations, among Hispanic families affected by ASD. The occurrence of preferential mating for QATs-the magnitude of which may vary across cultures-constitutes a mechanism by which background genetic liability

  1. Modelling the genetic risk in age-related macular degeneration.

    Directory of Open Access Journals (Sweden)

    Felix Grassmann

    Full Text Available Late-stage age-related macular degeneration (AMD is a common sight-threatening disease of the central retina affecting approximately 1 in 30 Caucasians. Besides age and smoking, genetic variants from several gene loci have reproducibly been associated with this condition and likely explain a large proportion of disease. Here, we developed a genetic risk score (GRS for AMD based on 13 risk variants from eight gene loci. The model exhibited good discriminative accuracy, area-under-curve (AUC of the receiver-operating characteristic of 0.820, which was confirmed in a cross-validation approach. Noteworthy, younger AMD patients aged below 75 had a significantly higher mean GRS (1.87, 95% CI: 1.69-2.05 than patients aged 75 and above (1.45, 95% CI: 1.36-1.54. Based on five equally sized GRS intervals, we present a risk classification with a relative AMD risk of 64.0 (95% CI: 14.11-1131.96 for individuals in the highest category (GRS 3.44-5.18, 0.5% of the general population compared to subjects with the most common genetic background (GRS -0.05-1.70, 40.2% of general population. The highest GRS category identifies AMD patients with a sensitivity of 7.9% and a specificity of 99.9% when compared to the four lower categories. Modeling a general population around 85 years of age, 87.4% of individuals in the highest GRS category would be expected to develop AMD by that age. In contrast, only 2.2% of individuals in the two lowest GRS categories which represent almost 50% of the general population are expected to manifest AMD. Our findings underscore the large proportion of AMD cases explained by genetics particularly for younger AMD patients. The five-category risk classification could be useful for therapeutic stratification or for diagnostic testing purposes once preventive treatment is available.

  2. Prefrontal gray matter volume mediates genetic risks for obesity.

    Science.gov (United States)

    Opel, N; Redlich, R; Kaehler, C; Grotegerd, D; Dohm, K; Heindel, W; Kugel, H; Thalamuthu, A; Koutsouleris, N; Arolt, V; Teuber, A; Wersching, H; Baune, B T; Berger, K; Dannlowski, U

    2017-05-01

    Genetic and neuroimaging research has identified neurobiological correlates of obesity. However, evidence for an integrated model of genetic risk and brain structural alterations in the pathophysiology of obesity is still absent. Here we investigated the relationship between polygenic risk for obesity, gray matter structure and body mass index (BMI) by the use of univariate and multivariate analyses in two large, independent cohorts (n=330 and n=347). Higher BMI and higher polygenic risk for obesity were significantly associated with medial prefrontal gray matter decrease, and prefrontal gray matter was further shown to significantly mediate the effect of polygenic risk for obesity on BMI in both samples. Building on this, the successful individualized prediction of BMI by means of multivariate pattern classification algorithms trained on whole-brain imaging data and external validations in the second cohort points to potential clinical applications of this imaging trait marker.

  3. Diffusion-weighted MRI for detecting prostate tumour in men at increased genetic risk

    International Nuclear Information System (INIS)

    Souza, Nandita M. de; Morgan, Veronica A.; Bancroft, Elizabeth; Sohaib, S. Aslam; Giles, Sharon L.; Kote-Jarai, Zsofia; Castro, Elena; Hazell, Steven; Jafar, Maysam; Eeles, Rosalind

    2014-01-01

    •Endorectal T2W + DW-MRI is potentially useful for prostate cancer screening.•MRI is specific for detecting prostate cancer in men with increased genetic risk.•Detection of prostate cancer in men at genetically low risk with MRI is limited. Endorectal T2W + DW-MRI is potentially useful for prostate cancer screening. MRI is specific for detecting prostate cancer in men with increased genetic risk. Detection of prostate cancer in men at genetically low risk with MRI is limited. Diffusion-weighted (DW)-MRI is invaluable in detecting prostate cancer. We determined its sensitivity and specificity and established interobserver agreement for detecting tumour in men with a family history of prostate cancer stratified by genetic risk. 51 men with a family history of prostate cancer underwent T2-W + DW-endorectal MRI at 3.0 T. Presence of tumour was noted at right and left apex, mid and basal prostate sextants by 2 independent observers, 1 experienced and the other inexperienced in endorectal MRI. Sensitivity and specificity against a 10-core sampling technique (lateral and medial cores at each level considered together) in men with >2× population risk based on 71 SNP analysis versus those with lower genetic risk scores was established. Interobserver agreement was determined at a subject level. Biopsies indicated cancer in 28 sextants in 13/51 men; 32 of 51 men had twice the population risk (>0.25) based on 71 SNP profiling. Sensitivity/specificity per-subject for patients was 90.0%/86.4% (high-risk) vs. 66.7%/100% (low-risk, observer 1) and 60.0%/86.3% (high-risk) vs. 33.3%/93.8% (low-risk, observer 2) with moderate overall inter-observer agreement (kappa = 0.42). Regional sensitivities/specificities for high-risk vs. low-risk for observer 1 apex 72.2%/100% [33.3%/100%], mid 100%/93.1% [100%/97.3%], base 16.7%/98.3% [0%/100%] and for observer 2 apex 36.4%/98.1% [0%/100%], mid 28.6%/96.5% [100%/100%], base 20%/100% [0%/97.3%] were poorer as they failed to detect

  4. Genetically Predicted Body Mass Index and Breast Cancer Risk

    DEFF Research Database (Denmark)

    Guo, Yan; Warren Andersen, Shaneda; Shu, Xiao-Ou

    2016-01-01

    BACKGROUND: Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or enviro...

  5. Easy calculations of lod scores and genetic risks on small computers.

    Science.gov (United States)

    Lathrop, G M; Lalouel, J M

    1984-01-01

    A computer program that calculates lod scores and genetic risks for a wide variety of both qualitative and quantitative genetic traits is discussed. An illustration is given of the joint use of a genetic marker, affection status, and quantitative information in counseling situations regarding Duchenne muscular dystrophy. PMID:6585139

  6. Quantifying introgression risk with realistic population genetics

    NARCIS (Netherlands)

    Ghosh, A.; Meirmans, P.G.; Haccou, P.

    2012-01-01

    Introgression is the permanent incorporation of genes from the genome of one population into another. This can have severe consequences, such as extinction of endemic species, or the spread of transgenes. Quantification of the risk of introgression is an important component of genetically modified

  7. Women-specific risk factors for heart failure: A genetic approach.

    Science.gov (United States)

    van der Kemp, Jet; van der Schouw, Yvonne T; Asselbergs, Folkert W; Onland-Moret, N Charlotte

    2018-03-01

    Heart failure is a complex disease, which is presented differently by men and women. Several studies have shown that reproductive factors, such as age at natural menopause, parity and polycystic ovarian syndrome (PCOS), may play a role in the development of heart failure. Shared genetics may provide clues to underlying mechanisms; however, this has never been examined. Therefore, the aim of the current study was to explore whether any reproductive factor is potentially related to heart failure in women, based on genetic similarities. Conducting a systematic literature review, single nucleotide polymorphisms (SNPs) associated with reproductive factors, heart failure and its risk factors were extracted from recent genome-wide association studies. We tested whether there was any overlap between the SNPs and their proxies of reproductive risk factors with those known for heart failure or its risk factors. In total, 520 genetic variants were found that are associated with reproductive factors, namely age at menarche, age at natural menopause, menstrual cycle length, PCOS, preeclampsia, preterm delivery and spontaneous dizygotic twinning. For heart failure and associated phenotypes, 25 variants were found. Genetic variants for reproductive factors did not overlap with those for heart failure. However, age at menarche, gestational diabetes and PCOS were found to be genetically linked to risk factors for heart failure, such as atrial fibrillation, diabetes and smoking. Corresponding implicated genes, such as TNNI3K, ErbB3, MKL2, MTNR1B and PRKD1, may explain the associations between reproductive factors and heart failure. Exact effector mechanisms of these genes remain to be investigated further. Copyright © 2017. Published by Elsevier B.V.

  8. Facial emotion perception differs in young persons at genetic and clinical high-risk for psychosis.

    Science.gov (United States)

    Kohler, Christian G; Richard, Jan A; Brensinger, Colleen M; Borgmann-Winter, Karin E; Conroy, Catherine G; Moberg, Paul J; Gur, Ruben C; Gur, Raquel E; Calkins, Monica E

    2014-05-15

    A large body of literature has documented facial emotion perception impairments in schizophrenia. More recently, emotion perception has been investigated in persons at genetic and clinical high-risk for psychosis. This study compared emotion perception abilities in groups of young persons with schizophrenia, clinical high-risk, genetic risk and healthy controls. Groups, ages 13-25, included 24 persons at clinical high-risk, 52 first-degree relatives at genetic risk, 91 persons with schizophrenia and 90 low risk persons who completed computerized testing of emotion recognition and differentiation. Groups differed by overall emotion recognition abilities and recognition of happy, sad, anger and fear expressions. Pairwise comparisons revealed comparable impairments in recognition of happy, angry, and fearful expressions for persons at clinical high-risk and schizophrenia, while genetic risk participants were less impaired, showing reduced recognition of fearful expressions. Groups also differed for differentiation of happy and sad expressions, but differences were mainly between schizophrenia and control groups. Emotion perception impairments are observable in young persons at-risk for psychosis. Preliminary results with clinical high-risk participants, when considered along findings in genetic risk relatives, suggest social cognition abilities to reflect pathophysiological processes involved in risk of schizophrenia. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  9. Strong population genetic structuring in an annual fish, Nothobranchius furzeri, suggests multiple savannah refugia in southern Mozambique.

    Science.gov (United States)

    Bartáková, Veronika; Reichard, Martin; Janko, Karel; Polačik, Matej; Blažek, Radim; Reichwald, Kathrin; Cellerino, Alessandro; Bryja, Josef

    2013-09-12

    Intraspecific genetic variation of African fauna has been significantly affected by pronounced climatic fluctuations in Plio-Pleistocene, but, with the exception of large mammals, very limited empirical data on diversity of natural populations are available for savanna-dwelling animals. Nothobranchius furzeri is an annual fish from south-eastern Africa, inhabiting discrete temporary savannah pools outside main river alluvia. Their dispersal is limited and population processes affecting its genetic structure are likely a combination of those affecting terrestrial and aquatic taxa. N. furzeri is a model taxon in ageing research and several populations of known geographical origin are used in laboratory studies. Here, we analysed the genetic structure, diversity, historical demography and temporal patterns of divergence in natural populations of N. furzeri across its entire distribution range. Genetic structure and historical demography of N. furzeri were analysed using a combination of mitochondrial (partial cytochrome b sequences, 687 bp) and nuclear (13 microsatellites) markers in 693 fish from 36 populations. Genetic markers consistently demonstrated strong population structuring and suggested two main genetic groups associated with river basins. The split was dated to the Pliocene (>2 Mya). The northern group inhabits savannah pools across the basin of the intermittent river Chefu in south-western Mozambique and eastern Zimbabwe. The southern group (from southernmost Mozambique) is subdivided, with the River Limpopo forming a barrier (maximum divergence time 1 Mya). A strong habitat fragmentation (isolated temporary pools) is reflected in significant genetic structuring even between adjacent pools, with a major influence of genetic drift and significant isolation-by-distance. Analysis of historical demography revealed that the expansion of both groups is ongoing, supported by frequent founder effects in marginal parts of the range and evidence of secondary

  10. Genetic risk analysis of coronary artery disease in Pakistani subjects using a genetic risk score of 21 variants.

    Science.gov (United States)

    Shahid, Saleem Ullah; Shabana; Cooper, Jackie A; Beaney, Katherine E; Li, Kawah; Rehman, Abdul; Humphries, Steve E

    2017-03-01

    Conventional coronary artery disease (CAD) risk factors like age, gender, blood lipids, hypertension and smoking have been the basis of CAD risk prediction algorithms, but provide only modest discrimination. Genetic risk score (GRS) may provide improved discrimination over and above conventional risk factors. Here we analyzed the genetic risk of CAD in subjects from Pakistan, using a GRS of 21 variants in 18 genes and examined whether the GRS is associated with blood lipid levels. 625 (405 cases and 220 controls) subjects were genotyped for variants, NOS3 rs1799983, SMAD3 rs17228212, APOB rs1042031, LPA rs3798220, LPA rs10455872, SORT1 rs646776, APOE rs429358, GLUL rs10911021, FTO rs9939609, MIA3 rs17465637, CDKN2Ars10757274, DAB2IP rs7025486, CXCL12 rs1746048, ACE rs4341, APOA5 rs662799, CETP rs708272, MRAS rs9818870, LPL rs328, LPL rs1801177, PCSK9 rs11591147 and APOE rs7412 by TaqMan and KASPar allele discrimination techniques. Individually, the single SNPs were not associated with CAD except APOB rs1042031 and FTO rs993969 (p = 0.01 and 0.009 respectively). However, the combined GRS of 21 SNPs was significantly higher in cases than controls (19.37 ± 2.56 vs. 18.47 ± 2.45, p = 2.9 × 10 -5 ), and compared to the bottom quintile, CAD risk in the top quintile of the GRS was 2.96 (95% CI 1.71-5.13). Atherogenic blood lipids showed significant positive association with GRS. The GRS was quantitatively associated with CAD risk and showed association with blood lipid levels, suggesting that the mechanism of these variants is likely to be, in part at least, through creating an atherogenic lipid profile in subjects carrying high numbers of risk alleles. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Common Gene Variants Account for Most Genetic Risk for Autism

    Science.gov (United States)

    ... gene variants account for most genetic risk for autism Roles of heritability, mutations, environment estimated – NIH-funded study. The bulk of risk, or liability, for autism spectrum disorders (ASD) was traced to inherited variations ...

  12. Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer in Women

    Science.gov (United States)

    ... their family history of cancer. Depending on a woman’s family history, the doctor or nurse may then use a ... against routine genetic counseling or BRCA testing of women whose family history is not associated with an increased risk for ...

  13. Smoking modifies the associated increased risk of future cardiovascular disease by genetic variation on chromosome 9p21.

    Directory of Open Access Journals (Sweden)

    Viktor Hamrefors

    Full Text Available AIMS: Genetic predisposition for cardiovascular disease (CVD is likely to be modified by environmental exposures. We tested if the associated risk of CVD and CVD-mortality by the single nucleotide polymorphism rs4977574 on chromosome 9p21 is modified by life-style factors. METHODS AND RESULTS: A total of 24,944 middle-aged subjects (62% females from the population-based Malmö-Diet-and-Cancer-Cohort were genotyped. Smoking, education and physical activity-levels were recorded. Subjects were followed for 15 years for incidence of coronary artery disease (CAD; N = 2309, ischemic stroke (N = 1253 and CVD-mortality (N = 1156. Multiplicative interactions between rs4977574 and life-style factors on endpoints were tested in Cox-regression-models. We observed an interaction between rs4977574 and smoking on incident CAD (P = 0.035 and CVD-mortality (P = 0.012. The hazard ratios (HR per risk allele of rs4977574 were highest in never smokers (N = 9642 for CAD (HR = 1.26; 95% CI 1.13-1.40; P<0.001 and for CVD-mortality (HR = 1.40; 95% CI 1.20-1.63; P<0.001, whereas the risk increase by rs4977574 was attenuated in current smokers (N = 7000 for both CAD (HR = 1.05; 95%CI 0.95-1.16; P = 0.326 and CVD-mortality (HR = 1.08; 95%CI 0.94-1.23; P = 0.270. A meta-analysis supported the finding that the associated increased risk of CAD by the risk-allele was attenuated in smokers. Neither education nor physical activity-levels modified the associated risk of CAD, ischemic stroke and CVD mortality conferred by rs4977574. CONCLUSION: Smoking may modify the associated risk of CAD and CVD-mortality conferred by genetic variation on chromosome 9p21. Whether the observed attenuation of the genetic risk reflects a pathophysiological mechanism or is a result of smoking being such a strong risk-factor that it may eliminate the associated genetic effect, requires further investigation.

  14. Risk assessment: the importance of genetic polymorphisms in man

    DEFF Research Database (Denmark)

    Knudsen, Lisbeth E.; Loft, S H; Autrup, H

    2001-01-01

    and increased cancer risk, such results indicate effect modification regarding cancer risk. In risk assessment the safety 'factor' of 10 is generally accepted to allow for variation in individual susceptibility. Reviewing the literature justifies the factor of 10 when considering single polymorphisms. However......Many genetic polymorphisms in metabolism enzymes are important for the risk of cancer as shown in a large number of case-control studies. The relative risk estimates have shown large variations between such population studies. However, in most studies the relative risk estimates are in the range...

  15. Risk perception among women receiving genetic counseling: a population-based follow-up study

    DEFF Research Database (Denmark)

    Mikkelsen, Ellen M; Sunde, Lone; Johansen, Christoffer

    2007-01-01

    -up study of 213 women who received genetic counseling for hereditary breast and ovarian cancer, 319 women who underwent mammography (Reference Group I), and a random sample of 1070 women from the general population (Reference Group II). RESULTS: Women who received genetic counseling decreased...... counseling, compared to a reduction of 5% (p=0.03) and 2% (p=0.01) in Reference Groups I and II, respectively. Risk communicated only in words, inaccurate risk perception at baseline, and presence of a familial mutation appeared to be predictors of inaccurate risk perception 12 months after counseling......BACKGROUND: We aimed to explore the impact of genetic counseling on perceived personal lifetime risk of breast cancer, the accuracy of risk perception, and possible predictors of inaccurate risk perception 1 year following counseling. METHODS: We conducted a population-based prospective follow...

  16. Identification of novel genetic risk loci in Maltese dogs with necrotizing meningoencephalitis and evidence of a shared genetic risk across toy dog breeds.

    Directory of Open Access Journals (Sweden)

    Isabelle Schrauwen

    Full Text Available Necrotizing meningoencephalitis (NME affects toy and small breed dogs causing progressive, often fatal, inflammation and necrosis in the brain. Genetic risk loci for NME previously were identified in pug dogs, particularly associated with the dog leukocyte antigen (DLA class II complex on chromosome 12, but have not been investigated in other susceptible breeds. We sought to evaluate Maltese and Chihuahua dogs, in addition to pug dogs, to identify novel or shared genetic risk factors for NME development. Genome-wide association testing of single nucleotide polymorphisms (SNPs in Maltese dogs with NME identified 2 regions of genome-wide significance on chromosomes 4 (chr4:74522353T>A, p = 8.1×10-7 and 15 (chr15:53338796A>G, p = 1.5×10-7. Haplotype analysis and fine-mapping suggests that ILR7 and FBXW7, respectively, both important for regulation of immune system function, could be the underlying associated genes. Further evaluation of these regions and the previously identified DLA II locus across all three breeds, revealed an enrichment of nominal significant SNPs associated with chromosome 15 in pug dogs and DLA II in Maltese and Chihuahua dogs. Meta-analysis confirmed effect sizes the same direction in all three breeds for both the chromosome 15 and DLA II loci (p = 8.6×10-11 and p = 2.5×10-7, respectively. This suggests a shared genetic background exists between all breeds and confers susceptibility to NME, but effect sizes might be different among breeds. In conclusion, we identified the first genetic risk factors for NME development in the Maltese, chromosome 4 and chromosome 15, and provide evidence for a shared genetic risk between breeds associated with chromosome 15 and DLA II. Last, DLA II and IL7R both have been implicated in human inflammatory diseases of the central nervous system such as multiple sclerosis, suggesting that similar pharmacotherapeutic targets across species should be investigated.

  17. Identification of novel genetic risk loci in Maltese dogs with necrotizing meningoencephalitis and evidence of a shared genetic risk across toy dog breeds.

    Science.gov (United States)

    Schrauwen, Isabelle; Barber, Renee M; Schatzberg, Scott J; Siniard, Ashley L; Corneveaux, Jason J; Porter, Brian F; Vernau, Karen M; Keesler, Rebekah I; Matiasek, Kaspar; Flegel, Thomas; Miller, Andrew D; Southard, Teresa; Mariani, Christopher L; Johnson, Gayle C; Huentelman, Matthew J

    2014-01-01

    Necrotizing meningoencephalitis (NME) affects toy and small breed dogs causing progressive, often fatal, inflammation and necrosis in the brain. Genetic risk loci for NME previously were identified in pug dogs, particularly associated with the dog leukocyte antigen (DLA) class II complex on chromosome 12, but have not been investigated in other susceptible breeds. We sought to evaluate Maltese and Chihuahua dogs, in addition to pug dogs, to identify novel or shared genetic risk factors for NME development. Genome-wide association testing of single nucleotide polymorphisms (SNPs) in Maltese dogs with NME identified 2 regions of genome-wide significance on chromosomes 4 (chr4:74522353T>A, p = 8.1×10-7) and 15 (chr15:53338796A>G, p = 1.5×10-7). Haplotype analysis and fine-mapping suggests that ILR7 and FBXW7, respectively, both important for regulation of immune system function, could be the underlying associated genes. Further evaluation of these regions and the previously identified DLA II locus across all three breeds, revealed an enrichment of nominal significant SNPs associated with chromosome 15 in pug dogs and DLA II in Maltese and Chihuahua dogs. Meta-analysis confirmed effect sizes the same direction in all three breeds for both the chromosome 15 and DLA II loci (p = 8.6×10-11 and p = 2.5×10-7, respectively). This suggests a shared genetic background exists between all breeds and confers susceptibility to NME, but effect sizes might be different among breeds. In conclusion, we identified the first genetic risk factors for NME development in the Maltese, chromosome 4 and chromosome 15, and provide evidence for a shared genetic risk between breeds associated with chromosome 15 and DLA II. Last, DLA II and IL7R both have been implicated in human inflammatory diseases of the central nervous system such as multiple sclerosis, suggesting that similar pharmacotherapeutic targets across species should be investigated.

  18. Strong spatial genetic structure in five tropical Piper species: should the Baker–Fedorov hypothesis be revived for tropical shrubs?

    Science.gov (United States)

    Lasso, E; Dalling, J W; Bermingham, E

    2011-01-01

    Fifty years ago, Baker and Fedorov proposed that the high species diversity of tropical forests could arise from the combined effects of inbreeding and genetic drift leading to population differentiation and eventually to sympatric speciation. Decades of research, however have failed to support the Baker–Fedorov hypothesis (BFH), and it has now been discarded in favor of a paradigm where most trees are self-incompatible or strongly outcrossing, and where long-distance pollen dispersal prevents population drift. Here, we propose that several hyper-diverse genera of tropical herbs and shrubs, including Piper (>1,000 species), may provide an exception. Species in this genus often have aggregated, high-density populations with self-compatible breeding systems; characteristics which the BFH would predict lead to high local genetic differentiation. We test this prediction for five Piper species on Barro Colorado Island, Panama, using Amplified Fragment Length Polymorphism (AFLP) markers. All species showed strong genetic structure at both fine- and large-spatial scales. Over short distances (200–750 m) populations showed significant genetic differentiation (Fst 0.11–0.46, P < 0.05), with values of spatial genetic structure that exceed those reported for other tropical tree species (Sp = 0.03–0.136). This genetic structure probably results from the combined effects of limited seed and pollen dispersal, clonal spread, and selfing. These processes are likely to have facilitated the diversification of populations in response to local natural selection or genetic drift and may explain the remarkable diversity of this rich genus. PMID:22393518

  19. Subjective versus objective risk in genetic counseling for hereditary breast and/or ovarian cancers

    Directory of Open Access Journals (Sweden)

    Sperduti Isabella

    2009-12-01

    Full Text Available Abstract Background Despite the fact that genetic counseling in oncology provides information regarding objective risks, it can be found a contrast between the subjective and objective risk. The aims of this study were to evaluate the accuracy of the perceived risk compared to the objective risk estimated by the BRCApro computer model and to evaluate any associations between medical, demographic and psychological variables and the accuracy of risk perception. Methods 130 subjects were given medical-demographic file, Cancer and Genetic Risk Perception, Hospital Anxiety-Depression Scale. It was also computed an objective evaluation of the risk by the BRCApro model. Results The subjective risk was significantly higher than objective risk. The risk of tumour was overestimated by 56%, and the genetic risk by 67%. The subjects with less cancer affected relatives significantly overestimated their risk of being mutation carriers and made a more innacurate estimation than high risk subjects. Conclusion The description of this sample shows: general overestimation of the risk, inaccurate perception compared to BRCApro calculation and a more accurate estimation in those subjects with more cancer affected relatives (high risk subjects. No correlation was found between the levels of perception of risk and anxiety and depression. Based on our findings, it is worth pursuing improved communication strategies about the actual cancer and genetic risk, especially for subjects at "intermediate and slightly increased risk" of developing an hereditary breast and/or ovarian cancer or of being mutation carrier.

  20. Genetic Analysis of Elevated Mastitis Risk Based on Mastitis Indicator Data

    DEFF Research Database (Denmark)

    Sørensen, Lars Peter; Løvendahl, Peter

    Whole-genome sequences and multiple trait phenotypes from large numbers of individuals will soon be available. Well established statistical modeling approaches enable the genetic analyses of complex trait phenotypes while accounting for a variety of additive and non-additive genetic mechanisms....... These modeling approaches have proven to be highly useful to determine population genetic parameters as well as prediction of genetic risk or value. We present statistical modelling approaches that use prior biological information for evaluating the collective action of sets of genetic variants. We have applied...

  1. Perceptions regarding genetic testing in populations at risk for nephropathy.

    Science.gov (United States)

    Freedman, Barry I; Fletcher, Alison J; Sanghani, Vivek R; Spainhour, Mitzie; Graham, Angelina W; Russell, Gregory B; Cooke Bailey, Jessica N; Iltis, Ana S; King, Nancy M P

    2013-01-01

    Population ancestry-based differences exist in genetic risk for many kidney diseases. Substantial debate remains regarding returning genetic test results to participants. African-Americans (AAs) and European-Americans (EAs) at risk for end-stage kidney disease were queried for views on the value and use of genetic testing in research. A standardized survey regarding attitudes toward genetic testing was administered to 130 individuals (64 AA, 66 EA) with first-degree relatives on dialysis. Fisher's exact test was used to assess differences in participant attitudes between population groups. Mean (SD) age of surveyed AAs and EAs was 45.5 (12.8) and 50.5 (14.4) years, respectively (p = 0.04), with similar familial relationships (p = 0.22). AAs and EAs wished to know their test results if risk could be: (1) reduced by diet or exercise (100 and 98%, p = 0.99); (2) reduced by medical treatment (100 and 98%, p = 0.99), or (3) if no treatments were available (90 and 82%, p = 0.21). If informed they lacked a disease susceptibility variant, 87% of AAs and 88% of EAs would be extremely or pretty likely to inform family members (p = 0.84). If informed they had a disease susceptibility variant, 92% of AAs and 89% of EAs would be extremely or pretty likely to inform their family (p = 0.43). Attitudes toward obtaining and using genetic test results for disease in research contexts were similar in AAs and EAs at risk for end-stage kidney disease. A substantial majority would want information regardless of available treatments and would share the information with the family. These results have important implications for patient care, study design and the informed consent process. © 2013 S. Karger AG, Basel.

  2. 'Battling my biology': psychological effects of genetic testing for risk of weight gain.

    Science.gov (United States)

    Meisel, S F; Wardle, J

    2014-04-01

    The availability of genetic tests for multifactorial conditions such as obesity raises concerns that higher-risk results could lead to fatalistic reactions or lower-risk results to complacency. No study has investigated the effects of genetic test feedback for the risk of obesity in non-clinical samples. The present study explored psychological and behavioral reactions to genetic test feedback for a weight related gene (FTO) in a volunteer sample (n = 18) using semi-structured interviews. Respondents perceived the gene test result as scientifically objective; removing some of the emotion attached to the issue of weight control. Those who were struggling with weight control reported relief of self-blame. There was no evidence for either complacency or fatalism; all respondents emphasized the importance of lifestyle choices in long-term weight management, although they recognized the role of both genes and environment. Regardless of the test result, respondents evaluated the testing positively and found it motivating and informative. Genetic test feedback for risk of weight gain may offer psychological benefits beyond its objectively limited clinical utility. As the role of genetic counselors is likely to expand, awareness of reasons for genetic testing for common, complex conditions and reactions to the test result is important.

  3. Developing genetic epidemiological models to predict risk for nasopharyngeal carcinoma in high-risk population of China.

    Directory of Open Access Journals (Sweden)

    Hong-Lian Ruan

    Full Text Available To date, the only established model for assessing risk for nasopharyngeal carcinoma (NPC relies on the sero-status of the Epstein-Barr virus (EBV. By contrast, the risk assessment models proposed here include environmental risk factors, family history of NPC, and information on genetic variants. The models were developed using epidemiological and genetic data from a large case-control study, which included 1,387 subjects with NPC and 1,459 controls of Cantonese origin. The predictive accuracy of the models were then assessed by calculating the area under the receiver-operating characteristic curves (AUC. To compare the discriminatory improvement of models with and without genetic information, we estimated the net reclassification improvement (NRI and integrated discrimination index (IDI. Well-established environmental risk factors for NPC include consumption of salted fish and preserved vegetables and cigarette smoking (in pack years. The environmental model alone shows modest discriminatory ability (AUC = 0.68; 95% CI: 0.66, 0.70, which is only slightly increased by the addition of data on family history of NPC (AUC = 0.70; 95% CI: 0.68, 0.72. With the addition of data on genetic variants, however, our model's discriminatory ability rises to 0.74 (95% CI: 0.72, 0.76. The improvements in NRI and IDI also suggest the potential usefulness of considering genetic variants when screening for NPC in endemic areas. If these findings are confirmed in larger cohort and population-based case-control studies, use of the new models to analyse data from NPC-endemic areas could well lead to earlier detection of NPC.

  4. The impact of advances in human molecular biology on radiation genetic risk estimation in man

    International Nuclear Information System (INIS)

    Sankaranarayanan, K.

    1996-01-01

    This paper provides an overview of the conceptual framework, the data base, methods and assumptions used thus far to assess the genetic risks of exposure of human populations to ionising radiation. These are then re-examined in the contemporary context of the rapidly expanding knowledge of the molecular biology of human mendelian diseases. This re-examination reveals that (i) many of the assumptions used thus far in radiation genetic risk estimation may not be fully valid and (ii) the current genetic risk estimates are probably conservative, but provide an adequate margin of safety for radiological protection. The view is expressed that further advances in the field of genetic risk estimation will be largely driven by advances in the molecular biology of human genetic diseases. (author). 37 refs., 5 tabs

  5. Genetic association of telomere length with hepatocellular carcinoma risk: A Mendelian randomization analysis.

    Science.gov (United States)

    Cheng, Yue; Yu, Chengxiao; Huang, Mingtao; Du, Fangzhi; Song, Ci; Ma, Zijian; Zhai, Xiangjun; Yang, Yuan; Liu, Jibin; Bei, Jin-Xin; Jia, Weihua; Jin, Guangfu; Li, Shengping; Zhou, Weiping; Liu, Jianjun; Dai, Juncheng; Hu, Zhibin

    2017-10-01

    Observational studies show an association between telomere length and Hepatocellular carcinoma (HCC) risk, but the relationship is controversial. Particularly, it remains unclear whether the association is due to confounding or biases inherent in conventional epidemiological studies. Here, we applied Mendelian randomization approach to evaluate whether telomere length is causally associated with HCC risk. Individual-level data were from HBV-related HCC Genome-wide association studies (1,538 HBV positive HCC patients and 1,465 HBV positive controls). Genetic risk score, as proxy for actual measured telomere length, derived from nine telomere length-associated genetic variants was used to evaluate the effect of telomere length on HCC risk. We observed a significant risk signal between genetically increased telomere length and HBV-related HCC risk (OR=2.09, 95% CI 1.32-3.31, P=0.002). Furthermore, a U-shaped curve was fitted by the restricted cubic spline curve, which indicated that either short or long telomere length would increase HCC risk (P=0.0022 for non-linearity test). Subgroup analysis did not reveal significant heterogeneity between different age, gender, smoking status and drinking status groups. Our results indicated that a genetic background that favors longer or shorter telomere length may increase HBV-related HCC risk-a U-shaped association. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Genetic risk from diagnostic X-ray procedures

    International Nuclear Information System (INIS)

    Stephan, G.

    1980-01-01

    This essay introduces epidemiologic studies concerned with the question whether diagnostic X-ray procedures might be the cause of an increased genetic risk. All studies have selected Down's syndrome (mongolism) as genetic indicator. They indiscriminately present the opinion of the respective author. Approximately one half of the studies conclude that radiation exposure will not influence the spontaneous incidence of Down's syndrome in diagnostics, the other half finds a positive relationship between frequent radiation exposure and the incidence of the syndrome. For various reasons, explained in detail, the results of the studies under discussion are suitable for forming hypotheses, but should not be viewed as providing evidence. (orig.) [de

  7. Joint modeling of genetically correlated diseases and functional annotations increases accuracy of polygenic risk prediction.

    Directory of Open Access Journals (Sweden)

    Yiming Hu

    2017-06-01

    Full Text Available Accurate prediction of disease risk based on genetic factors is an important goal in human genetics research and precision medicine. Advanced prediction models will lead to more effective disease prevention and treatment strategies. Despite the identification of thousands of disease-associated genetic variants through genome-wide association studies (GWAS in the past decade, accuracy of genetic risk prediction remains moderate for most diseases, which is largely due to the challenges in both identifying all the functionally relevant variants and accurately estimating their effect sizes. In this work, we introduce PleioPred, a principled framework that leverages pleiotropy and functional annotations in genetic risk prediction for complex diseases. PleioPred uses GWAS summary statistics as its input, and jointly models multiple genetically correlated diseases and a variety of external information including linkage disequilibrium and diverse functional annotations to increase the accuracy of risk prediction. Through comprehensive simulations and real data analyses on Crohn's disease, celiac disease and type-II diabetes, we demonstrate that our approach can substantially increase the accuracy of polygenic risk prediction and risk population stratification, i.e. PleioPred can significantly better separate type-II diabetes patients with early and late onset ages, illustrating its potential clinical application. Furthermore, we show that the increment in prediction accuracy is significantly correlated with the genetic correlation between the predicted and jointly modeled diseases.

  8. TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis

    DEFF Research Database (Denmark)

    Gregory, Adam P; Dendrou, Calliope A; Attfield, Kathrine E

    2012-01-01

    ), but not with other autoimmune conditions such as rheumatoid arthritis, psoriasis and Crohn’s disease. By analysing MS GWAS data in conjunction with the 1000 Genomes Project data we provide genetic evidence that strongly implicates this SNP, rs1800693, as the causal variant in the TNFRSF1A region. We further...... make to disease risk has raised questions regarding their medical relevance. Here we have investigated a single nucleotide polymorphism (SNP) in the TNFRSF1A gene, that encodes tumour necrosis factor receptor 1 (TNFR1), which was discovered through GWAS to be associated with multiple sclerosis (MS...... substantiate this through functional studies showing that the MS risk allele directs expression of a novel, soluble form of TNFR1 that can block TNF. Importantly, TNF-blocking drugs can promote onset or exacerbation of MS, but they have proven highly efficacious in the treatment of autoimmune diseases...

  9. Genetic assessment of age-associated Alzheimer disease risk: Development and validation of a polygenic hazard score.

    Directory of Open Access Journals (Sweden)

    Rahul S Desikan

    2017-03-01

    Full Text Available Identifying individuals at risk for developing Alzheimer disease (AD is of utmost importance. Although genetic studies have identified AD-associated SNPs in APOE and other genes, genetic information has not been integrated into an epidemiological framework for risk prediction.Using genotype data from 17,008 AD cases and 37,154 controls from the International Genomics of Alzheimer's Project (IGAP Stage 1, we identified AD-associated SNPs (at p < 10-5. We then integrated these AD-associated SNPs into a Cox proportional hazard model using genotype data from a subset of 6,409 AD patients and 9,386 older controls from Phase 1 of the Alzheimer's Disease Genetics Consortium (ADGC, providing a polygenic hazard score (PHS for each participant. By combining population-based incidence rates and the genotype-derived PHS for each individual, we derived estimates of instantaneous risk for developing AD, based on genotype and age, and tested replication in multiple independent cohorts (ADGC Phase 2, National Institute on Aging Alzheimer's Disease Center [NIA ADC], and Alzheimer's Disease Neuroimaging Initiative [ADNI], total n = 20,680. Within the ADGC Phase 1 cohort, individuals in the highest PHS quartile developed AD at a considerably lower age and had the highest yearly AD incidence rate. Among APOE ε3/3 individuals, the PHS modified expected age of AD onset by more than 10 y between the lowest and highest deciles (hazard ratio 3.34, 95% CI 2.62-4.24, p = 1.0 × 10-22. In independent cohorts, the PHS strongly predicted empirical age of AD onset (ADGC Phase 2, r = 0.90, p = 1.1 × 10-26 and longitudinal progression from normal aging to AD (NIA ADC, Cochran-Armitage trend test, p = 1.5 × 10-10, and was associated with neuropathology (NIA ADC, Braak stage of neurofibrillary tangles, p = 3.9 × 10-6, and Consortium to Establish a Registry for Alzheimer's Disease score for neuritic plaques, p = 6.8 × 10-6 and in vivo markers of AD neurodegeneration (ADNI

  10. Additional mechanisms conferring genetic susceptibility to Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Miguel eCalero

    2015-04-01

    Full Text Available Familial Alzheimer's disease (AD, mostly associated with early onset, is caused by mutations in three genes (APP, PSEN1 and PSEN2 involved in the production of the amyloid  peptide. In contrast, the molecular mechanisms that trigger the most common late onset sporadic AD remain largely unknown. With the implementation of an increasing number of case-control studies and the upcoming of large-scale genome-wide association studies (GWAS there is a mounting list of genetic risk factors associated to common genetic variants that have been associated to sporadic AD. Besides APOE, that presents a strong association with the disease (OR~4, the rest of these genes have moderate or low degrees of association, with OR ranging from 0.88 to 1.23. Taking together, these genes may account only for a fraction of the attributable AD risk and therefore, rare variants and epistastic gene interactions should be taken into account in order to get the full picture of the genetic risks associated to AD. Here, we review recent whole-exome studies looking for rare variants, somatic brain mutations with a strong association to the disease, and several studies dealing with epistasis as additional mechanisms conferring genetic susceptibility to AD. Altogether, recent evidence underlines the importance of defining molecular and genetic pathways and networks rather than the contribution of specific genes.

  11. Structured Parenting of Toddlers at High versus Low Genetic Risk: Two Pathways to Child Problems

    Science.gov (United States)

    Leve, Leslie D.; Harold, Gordon T.; Ge, Xiaojia; Neiderhiser, Jenae M.; Shaw, Daniel; Scaramella, Laura V.; Reiss, David

    2009-01-01

    Objective: Little is known about how parenting might offset genetic risk to prevent the onset of child problems during toddlerhood. We used a prospective adoption design to separate genetic and environmental influences and test whether associations between structured parenting and toddler behavior problems were conditioned by genetic risk for…

  12. The role of genetics in stroke risk factors; the discussion of two rare genetic syndroms associated with stroke and review of the literature

    Directory of Open Access Journals (Sweden)

    Eda Kılıç Çoban

    2015-09-01

    Full Text Available Stroke is defined as a focal or at times global neurological impairment of sudden onset, that lasts more than 24 hours or that leads to death. The nonmodifiable risk factors for stroke include age, race, gender and acquired risk factors include smoking, hypertension, diabetes and obesity. Previous studies have shown that these mentioned risk factors might be responsible for approximately 50% of patients presenting stroke. However for the remaining half of the stroke patients no risk factors could be detected and genetics might be responsible for this group. In this manuscript we would like to present 2 cases who were being followed-up with the rare genetic syndromes as Marfan syndrome and Robinow syndrome respectively. These patients presented to our clinic with stroke and no identifiable risk factors other than these genetic syndromes could be detected. By this case-series we would like to further discuss the relationship between genetic syndromes and stroke.

  13. Hopes and Expectations Regarding Genetic Testing for Schizophrenia Among Young Adults at Clinical High-Risk for Psychosis.

    Science.gov (United States)

    Friesen, Phoebe; Lawrence, Ryan E; Brucato, Gary; Girgis, Ragy R; Dixon, Lisa

    2016-11-01

    Genetic tests for schizophrenia could introduce both risks and benefits. Little is known about the hopes and expectations of young adults at clinical high-risk for psychosis concerning genetic testing for schizophrenia, despite the fact that these youth could be among those highly affected by such tests. We conducted semistructured interviews with 15 young adults at clinical high-risk for psychosis to ask about their interest, expectations, and hopes regarding genetic testing for schizophrenia. Most participants reported a high level of interest in genetic testing for schizophrenia, and the majority said they would take such a test immediately if it were available. Some expressed far-reaching expectations for a genetic test, such as predicting symptom severity and the timing of symptom onset. Several assumed that genetic testing would be accompanied by interventions to prevent schizophrenia. Participants anticipated mixed reactions on finding out they had a genetic risk for schizophrenia, suggesting that they might feel both a sense of relief and a sense of hopelessness. We suggest that genetic counseling could play an important role in counteracting a culture of genetic over-optimism and helping young adults at clinical high-risk for psychosis understand the limitations of genetic testing. Counseling sessions could also invite individuals to explore how receiving genetic risk information might impact their well-being, as early evidence suggests that some psychological factors help individuals cope, whereas others heighten distress related to genetic test results.

  14. Ionizing radiation and genetic risks

    International Nuclear Information System (INIS)

    Sankaranarayanan, K.; Wassom, J.S.

    2005-01-01

    Recent estimates of genetic risks from exposure of human populations to ionizing radiation are those presented in the 2001 report of the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR). These estimates incorporate two important concepts, namely, the following: (1) most radiation-induced mutations are DNA deletions, often encompassing multiple genes, but only a small proportion of the induced deletions is compatible with offspring viability; and (2) the viability-compatible deletions induced in germ cells are more likely to manifest themselves as multi-system developmental anomalies rather than as single gene disorders. This paper: (a) pursues these concepts further in the light of knowledge of mechanisms of origin of deletions and other rearrangements from two fields of contemporary research: repair of radiation-induced DNA double-strand breaks (DSBs) in mammalian somatic cells and human molecular genetics; and (b) extends them to deletions induced in the germ cell stages of importance for radiation risk estimation, namely, stem cell spermatogonia in males and oocytes in females. DSB repair studies in somatic cells have elucidated the roles of two mechanistically distinct pathways, namely, homologous recombination repair (HRR) that utilizes extensive sequence homology and non-homologous end-joining (NHEJ) that requires little or no homology at the junctions. A third process, single-strand annealing (SSA), which utilizes short direct repeat sequences, is considered a variant of HRR. HRR is most efficient in late S and G 2 phases of the cell cycle and is a high fidelity mechanism. NHEJ operates in all cell cycle phases, but is especially important in G 1 . In the context of radiation-induced DSBs, NHEJ is error-prone. SSA is also an error-prone mechanism and its role is presumably similar to that of HRR. Studies in human molecular genetics have demonstrated that the occurrence of large deletions, duplications or other rearrangements

  15. Ionizing radiation and genetic risks

    Energy Technology Data Exchange (ETDEWEB)

    Sankaranarayanan, K. [Department of Toxicogenetics, Leiden University Medical Centre, Sylvius Laboratories, Wassenaarseweg 72, 2333 AL Leiden (Netherlands)]. E-mail: sankaran@lumc.nl; Wassom, J.S. [YAHSGS, LLC, Richland, WA 99352 (United States); Life Sciences Division, Oak Ridge National Laboratory, Oak Ridge, TN 37830 (United States)

    2005-10-15

    Recent estimates of genetic risks from exposure of human populations to ionizing radiation are those presented in the 2001 report of the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR). These estimates incorporate two important concepts, namely, the following: (1) most radiation-induced mutations are DNA deletions, often encompassing multiple genes, but only a small proportion of the induced deletions is compatible with offspring viability; and (2) the viability-compatible deletions induced in germ cells are more likely to manifest themselves as multi-system developmental anomalies rather than as single gene disorders. This paper: (a) pursues these concepts further in the light of knowledge of mechanisms of origin of deletions and other rearrangements from two fields of contemporary research: repair of radiation-induced DNA double-strand breaks (DSBs) in mammalian somatic cells and human molecular genetics; and (b) extends them to deletions induced in the germ cell stages of importance for radiation risk estimation, namely, stem cell spermatogonia in males and oocytes in females. DSB repair studies in somatic cells have elucidated the roles of two mechanistically distinct pathways, namely, homologous recombination repair (HRR) that utilizes extensive sequence homology and non-homologous end-joining (NHEJ) that requires little or no homology at the junctions. A third process, single-strand annealing (SSA), which utilizes short direct repeat sequences, is considered a variant of HRR. HRR is most efficient in late S and G{sub 2} phases of the cell cycle and is a high fidelity mechanism. NHEJ operates in all cell cycle phases, but is especially important in G{sub 1}. In the context of radiation-induced DSBs, NHEJ is error-prone. SSA is also an error-prone mechanism and its role is presumably similar to that of HRR. Studies in human molecular genetics have demonstrated that the occurrence of large deletions, duplications or other

  16. Genetic and other risk factors for suicidal ideation and the relationship with depression.

    Science.gov (United States)

    Dutta, R; Ball, H A; Siribaddana, S H; Sumathipala, A; Samaraweera, S; McGuffin, P; Hotopf, M

    2017-10-01

    There is a genetic contribution to the risk of suicide, but sparse prior research on the genetics of suicidal ideation. Active and passive suicidal ideation were assessed in a Sri Lankan population-based twin registry (n = 3906 twins) and a matched non-twin sample (n = 2016). Logistic regression models were used to examine associations with socio-demographic factors, environmental exposures and psychiatric symptoms. The heritability of suicidal ideation was assessed using structural equation modelling. The lifetime prevalence of any suicidal ideation was 13.0% (11.7-14.3%) for men; 21.8% (20.3-23.2%) for women, with no significant difference between twins and non-twins. Factors that predicted suicidal ideation included female gender, termination of marital relationship, low education level, urban residence, losing a parent whilst young, low standard of living and stressful life events in the preceding 12 months. Suicidal ideation was strongly associated with depression, but also with abnormal fatigue and alcohol and tobacco use. The best fitting structural equation model indicated a substantial contribution from genetic factors (57%; CI 47-66) and from non-shared environmental factors (43%; CI 34-53) in both men and women. In women this genetic component was largely mediated through depression, but in men there was a significant heritable component to suicidal ideation that was independent of depression. These are the first results to show a genetic contribution to suicidal ideation that is independent of depression outside of a high-income country. These phenomena may be generalizable, because previous research highlights similarities between the aetiology of mental disorders in Sri Lanka and higher-income countries.

  17. Possible modification of Alzheimer's disease by statins in midlife: interactions with genetic and non-genetic risk factors.

    Science.gov (United States)

    Shinohara, Mitsuru; Sato, Naoyuki; Shimamura, Munehisa; Kurinami, Hitomi; Hamasaki, Toshimitsu; Chatterjee, Amarnath; Rakugi, Hiromi; Morishita, Ryuichi

    2014-01-01

    The benefits of statins, commonly prescribed for hypercholesterolemia, in treating Alzheimer's disease (AD) have not yet been fully established. A recent randomized clinical trial did not show any therapeutic effects of two statins on cognitive function in AD. Interestingly, however, the results of the Rotterdam study, one of the largest prospective cohort studies, showed reduced risk of AD in statin users. Based on the current understanding of statin actions and AD pathogenesis, it is still worth exploring whether statins can prevent AD when administered decades before the onset of AD or from midlife. This review discusses the possible beneficial effects of statins, drawn from previous clinical observations, pathogenic mechanisms, which include β-amyloid (Aβ) and tau metabolism, genetic and non-genetic risk factors (apolipoprotein E, cholesterol, sex, hypertension, and diabetes), and other clinical features (vascular dysfunction and oxidative and inflammatory stress) of AD. These findings suggest that administration of statins in midlife might prevent AD in late life by modifying genetic and non-genetic risk factors for AD. It should be clarified whether statins inhibit Aβ accumulation, tau pathological features, and brain atrophy in humans. To answer this question, a randomized controlled study using amyloid positron emission tomography (PET), tau-PET, and magnetic resonance imaging would be useful. This clinical evaluation could help us to overcome this devastating disease.

  18. Inflammatory Genetic Markers of Prostate Cancer Risk

    International Nuclear Information System (INIS)

    Tindall, Elizabeth A.; Hayes, Vanessa M.; Petersen, Desiree C.

    2010-01-01

    Prostate cancer is the most common cancer in Western society males, with incidence rates predicted to rise with global aging. Etiology of prostate cancer is however poorly understood, while current diagnostic tools can be invasive (digital rectal exam or biopsy) and/or lack specificity for the disease (prostate-specific antigen (PSA) testing). Substantial histological, epidemiological and molecular genetic evidence indicates that inflammation is important in prostate cancer pathogenesis. In this review, we summarize the current status of inflammatory genetic markers influencing susceptibility to prostate cancer. The focus will be on inflammatory cytokines regulating T-helper cell and chemokine homeostasis, together with the Toll-like receptors as key players in the host innate immune system. Although association studies indicating a genetic basis for prostate cancer are presently limited mainly due to lack of replication, larger and more ethnically and clinically defined study populations may help elucidate the true contribution of inflammatory gene variants to prostate cancer risk

  19. Inflammatory Genetic Markers of Prostate Cancer Risk

    Energy Technology Data Exchange (ETDEWEB)

    Tindall, Elizabeth A.; Hayes, Vanessa M. [Cancer Genetics Group, Children’s Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, University of New South Wales, PO Box 81, Randwick, NSW 2031 (Australia); University of New South Wales, Kensington Campus, Sydney, NSW 2052 (Australia); Petersen, Desiree C., E-mail: dpetersen@ccia.unsw.edu.au [Cancer Genetics Group, Children’s Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, University of New South Wales, PO Box 81, Randwick, NSW 2031 (Australia)

    2010-06-08

    Prostate cancer is the most common cancer in Western society males, with incidence rates predicted to rise with global aging. Etiology of prostate cancer is however poorly understood, while current diagnostic tools can be invasive (digital rectal exam or biopsy) and/or lack specificity for the disease (prostate-specific antigen (PSA) testing). Substantial histological, epidemiological and molecular genetic evidence indicates that inflammation is important in prostate cancer pathogenesis. In this review, we summarize the current status of inflammatory genetic markers influencing susceptibility to prostate cancer. The focus will be on inflammatory cytokines regulating T-helper cell and chemokine homeostasis, together with the Toll-like receptors as key players in the host innate immune system. Although association studies indicating a genetic basis for prostate cancer are presently limited mainly due to lack of replication, larger and more ethnically and clinically defined study populations may help elucidate the true contribution of inflammatory gene variants to prostate cancer risk.

  20. Genetic risk load according to the site of intracranial aneurysms

    NARCIS (Netherlands)

    van 't Hof, Femke N. G.; Kurki, Mitja I.; Kleinloog, Rachel; de Bakker, Paul I. W.; von Und Zu Fraunberg, Mikael; Jääskeläinen, Juha E.; Gaál, Emília I.; Lehto, Hanna; Kivisaari, Riku; Laakso, Aki; Niemelä, Mika; Hernesniemi, Juha; Brouwer, Matthijs C.; van de Beek, Diederik; Rinkel, Gabriël J. E.; Ruigrok, Ynte M.

    2014-01-01

    We investigated whether risk alleles of single nucleotide polymorphisms associated with intracranial aneurysm (IA) are enriched in patients with familial IA, IA located at the middle cerebral artery (MCA), or IA rupture at a younger age. In this case-only study, we calculated genetic risk scores

  1. Genetic testing and its implications: human genetics researchers grapple with ethical issues.

    Science.gov (United States)

    Rabino, Isaac

    2003-01-01

    To better understand ethical issues involved in the field of human genetics and promote debate within the scientific community, the author surveyed scientists who engage in human genetics research about the pros, cons, and ethical implications of genetic testing. This study contributes systematic data on attitudes of scientific experts. The survey finds respondents are highly supportive of voluntary testing and the right to know one's genetic heritage. The majority consider in utero testing and consequent pregnancy termination acceptable for cases involving likelihood of serious disease but disapprove for genetic reasons they consider arbitrary, leaving a gray area of distinguishing between treatment of disorders and enhancement still to be resolved. While safeguarding patient confidentiality versus protecting at-risk third parties (kin, reproductive partners) presents a dilemma, preserving privacy from misuse by institutional third parties (employers, insurers) garners strong consensus for legislation against discrimination. Finally, a call is made for greater genetic literacy.

  2. Methodological approach for substantiating disease freedom in a heterogeneous small population. Application to ovine scrapie, a disease with a strong genetic susceptibility.

    Science.gov (United States)

    Martinez, Marie-José; Durand, Benoit; Calavas, Didier; Ducrot, Christian

    2010-06-01

    Demonstrating disease freedom is becoming important in different fields including animal disease control. Most methods consider sampling only from a homogeneous population in which each animal has the same probability of becoming infected. In this paper, we propose a new methodology to calculate the probability of detecting the disease if it is present in a heterogeneous population of small size with potentially different risk groups, differences in risk being defined using relative risks. To calculate this probability, for each possible arrangement of the infected animals in the different groups, the probability that all the animals tested are test-negative given this arrangement is multiplied by the probability that this arrangement occurs. The probability formula is developed using the assumption of a perfect test and hypergeometric sampling for finite small size populations. The methodology is applied to scrapie, a disease affecting small ruminants and characterized in sheep by a strong genetic susceptibility defining different risk groups. It illustrates that the genotypes of the tested animals influence heavily the confidence level of detecting scrapie. The results present the statistical power for substantiating disease freedom in a small heterogeneous population as a function of the design prevalence, the structure of the sample tested, the structure of the herd and the associated relative risks. (c) 2010 Elsevier B.V. All rights reserved.

  3. Chronic disease risk management: Combining genetic testing with ...

    African Journals Online (AJOL)

    Nutrigenetics has been used for decades to prevent rare monogenic disorders such as phenylketonuria. Gene-diet interaction can now also be targeted to prevent or reduce the risk of many chronic conditions long before clinical manifestation. This multidisciplinary approach unites conventional medicine with genetics and ...

  4. [Genetically modified organisms in food--production, detection and risks].

    Science.gov (United States)

    Zeljezić, Davor

    2004-11-01

    The first genetically modified plant (GMP) was a tobacco resistant to antibiotics in 1983. In 1996, the first genetically altered crop, a delayed-ripening tomato was commercially released. In the year 2003, the estimated global area of GM crops for was 67.7 million hectares. To produce such a plant a gene of interest has to be isolated from the donor. Together with a promoter, terminator sequence and marker gene it has to be introduced into the plant cell which is then stimulated to generate a whole GMP expressing new characteristics (herbicide/insect resistance, delayed ripening). The last few months have seen a strong public debate over genetically modified organisms which has raised scientific, economic, political, and ethical issues. Some questions concerning the safety of GMPs are still to be answered, and decisions about their future should be based on scientifically validated information.

  5. Measures of abdominal adiposity and the risk of stroke: the MOnica Risk, Genetics, Archiving and Monograph (MORGAM) study.

    Science.gov (United States)

    Bodenant, Marie; Kuulasmaa, Kari; Wagner, Aline; Kee, Frank; Palmieri, Luigi; Ferrario, Marco M; Montaye, Michèle; Amouyel, Philippe; Dallongeville, Jean

    2011-10-01

    Excess fat accumulates in the subcutaneous and visceral adipose tissue compartments. We tested the hypothesis that indicators of visceral adiposity, namely, waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR), are better predictors of stroke risk than body mass index (BMI). The association of BMI, WC, WHR, and WHtR with stroke was assessed in 31,201 men and 23,516 women, free of vascular disease at baseline, from the MOnica Risk, Genetics, Archiving and Monograph (MORGAM) study. During a mean follow-up of 11 years, 1130 strokes were recorded. Relative risks (95% CI) were calculated by Cox regression after stratification for center and adjustment for age, smoking, educational level, alcohol consumption, hypertension, diabetes, total cholesterol, high-density lipoprotein cholesterol, and BMI and model fit was assessed using log-likelihoods. BMI, WC, WHR, and WHtR were associated with the risk of stroke in men. After full adjustment including BMI, the relative risks for stroke remained significant for WC (1.19 [1.02 to 1.34] per 1 SD increase in WC), WHR (1.14 [1.03 to 1.26]), and WHtR (1.50 [1.28 to 1.77]). Among women, the extent of the associations with stroke risk was similar for WHtR (1.31 [1.04 to 1.65]), WC (1.19 [0.96 to 1.47]), and WHR (1.08 [0.97 to 1.22]). Further analyses by World Health Organization obesity categories showed that WC, WHR, and WHtR were associated with the risk of stroke also in lean men and women (BMI<25 kg/m2), independently of confounders, cardiovascular risk factors, and BMI. Indicators of abdominal adiposity, especially WHtR, are more strongly associated with stroke risk than BMI. These results emphasize the importance of measuring abdominal adiposity, especially in lean subjects.

  6. Ethnic Background and Genetic Variation in the Evaluation of Cancer Risk: A Systematic Review

    OpenAIRE

    Jing, Lijun; Su, Li; Ring, Brian Z.

    2014-01-01

    The clinical use of genetic variation in the evaluation of cancer risk is expanding, and thus understanding how determinants of cancer susceptibility identified in one population can be applied to another is of growing importance. However there is considerable debate on the relevance of ethnic background in clinical genetics, reflecting both the significance and complexity of genetic heritage. We address this via a systematic review of reported associations with cancer risk for 82 markers in ...

  7. Strong Genetic Overlap Between Executive Functions and Intelligence

    OpenAIRE

    Engelhardt, Laura E.; Mann, Frank D.; Briley, Daniel A.; Church, Jessica A.; Harden, K. Paige; Tucker-Drob, Elliot M.

    2016-01-01

    Executive functions (EFs) are cognitive processes that control, monitor, and coordinate more basic cognitive processes. EFs play instrumental roles in models of complex reasoning, learning, and decision-making, and individual differences in EFs have been consistently linked with individual differences in intelligence. By middle childhood, genetic factors account for a moderate proportion of the variance in intelligence, and these effects increase in magnitude through adolescence. Genetic infl...

  8. Imaging-Genetics in Dyslexia: Connecting risk genetic variants to brain neuroimaging and ultimately to reading impairments

    Science.gov (United States)

    Eicher, John D.; Gruen, Jeffrey R.

    2013-01-01

    Dyslexia is a common pediatric disorder that affects 5-17% of schoolchildren in the United States. It is marked by unexpected difficulties in fluent reading despite adequate intelligence, opportunity, and instruction. Classically, neuropsychologists have studied dyslexia using a variety of neurocognitive batteries to gain insight into the specific deficits and impairments in affected children. Since dyslexia is a complex genetic trait with high heritability, analyses conditioned on performance on these neurocognitive batteries have been used to try to identify associated genes. This has led to some successes in identifying contributing genes, although much of the heritability remains unexplained. Additionally, the lack of relevant human brain tissue for analysis and the challenges of modeling a uniquely human trait in animals are barriers to advancing our knowledge of the underlying pathophysiology. In vivo imaging technologies, however, present new opportunities to examine dyslexia and reading skills in a clearly relevant context in human subjects. Recent investigations have started to integrate these imaging data with genetic data in attempts to gain a more complete and complex understanding of reading processes. In addition to bridging the gap from genetic risk variant to a discernible neuroimaging phenotype and ultimately to the clinical impairments in reading performance, the use of neuroimaging phenotypes will reveal novel risk genes and variants. In this article, we briefly discuss the genetic and imaging investigations and take an in-depth look at the recent imaging-genetics investigations of dyslexia. PMID:23916419

  9. Genetic Risk Score Modelling for Disease Progression in New-Onset Type 1 Diabetes Patients

    DEFF Research Database (Denmark)

    Brorsson, Caroline A; Nielsen, Lotte B; Andersen, Marie-Louise

    2016-01-01

    Genome-wide association studies (GWAS) have identified over 40 type 1 diabetes risk loci. The clinical impact of these loci on β-cell function during disease progression is unknown. We aimed at testing whether a genetic risk score could predict glycemic control and residual β-cell function in type...... 1 diabetes (T1D). As gene expression may represent an intermediate phenotype between genetic variation and disease, we hypothesized that genes within T1D loci which are expressed in islets and transcriptionally regulated by proinflammatory cytokines would be the best predictors of disease...... constructed a genetic risk score based on the cumulative number of risk alleles carried in children with newly diagnosed T1D. With each additional risk allele carried, HbA1c levels increased significantly within first year after diagnosis. Network and gene ontology (GO) analyses revealed that several...

  10. Deposit Insurance and Risk Shifting in a Strong Regulatory Environment

    DEFF Research Database (Denmark)

    Bartholdy, Jan; Justesen, Lene Gilje

    This study provides empirical evidence on the moral hazard implications of introducing deposit insurance into a strong regulatory environment. Denmark offers a unique setting because commercial banks and savings banks have different ownership structures, but are subject to the same set...... of regulations. The ownership structure in savings banks implies that they have no incentive to increase risk after the implementation of a deposit insurance scheme whereas commercial banks have. Also, at the time of introduction, Denmark had high capital requirements and a strict closure policy. Using...... a difference-in-difference framework we show that commercial banks did not increase their risk compared to savings banks when deposit insurance was introduced. The results also hold for large commercial banks, indicating that the systemic risk did not increase either. Thus for a system with high capital...

  11. Childhood socioeconomic status and longitudinal patterns of alcohol problems: Variation across etiological pathways in genetic risk.

    Science.gov (United States)

    Barr, Peter B; Silberg, Judy; Dick, Danielle M; Maes, Hermine H

    2018-05-14

    Childhood socioeconomic status (SES) is an important aspect of early life environment associated with later life health/health behaviors, including alcohol misuse. However, alcohol misuse is modestly heritable and involves differing etiological pathways. Externalizing disorders show significant genetic overlap with substance use, suggesting an impulsivity pathway to alcohol misuse. Alcohol misuse also overlaps with internalizing disorders, suggesting alcohol is used to cope. These differing pathways could lead to different patterns over time and/or differential susceptibility to environmental conditions, such as childhood SES. We examine whether: 1) genetic risk for externalizing and internalizing disorders influence trajectories of alcohol problems across adolescence to adulthood, 2) childhood SES alters genetic risk these disorders on trajectories of alcohol problems, and 3) these patterns are consistent across sex. We find modest evidence of gene-environment interaction. Higher childhood SES increases the risk of alcohol problems in late adolescence/early adulthood, while lower childhood SES increases the risk of alcohol problems in later adulthood, but only among males at greater genetic risk of externalizing disorders. Females from lower SES families with higher genetic risk of internalizing or externalizing disorders have greater risk of developing alcohol problems. Copyright © 2018 Elsevier Ltd. All rights reserved.

  12. Genetic Risk by Experience Interaction for Childhood Internalizing Problems: Converging Evidence across Multiple Methods

    Science.gov (United States)

    Vendlinski, Matthew K.; Lemery-Chalfant, Kathryn; Essex, Marilyn J.; Goldsmith, H. Hill

    2011-01-01

    Background: Identifying how genetic risk interacts with experience to predict psychopathology is an important step toward understanding the etiology of mental health problems. Few studies have examined genetic risk by experience interaction (GxE) in the development of childhood psychopathology. Methods: We used both co-twin and parent mental…

  13. A population-based survey in Australia of men's and women's perceptions of genetic risk and predictive genetic testing and implications for primary care.

    Science.gov (United States)

    Taylor, S

    2011-01-01

    Community attitudes research regarding genetic issues is important when contemplating the potential value and utilisation of predictive testing for common diseases in mainstream health services. This article aims to report population-based attitudes and discuss their relevance to integrating genetic services in primary health contexts. Men's and women's attitudes were investigated via population-based omnibus telephone survey in Queensland, Australia. Randomly selected adults (n = 1,230) with a mean age of 48.8 years were interviewed regarding perceptions of genetic determinants of health; benefits of genetic testing that predict 'certain' versus 'probable' future illness; and concern, if any, regarding potential misuse of genetic test information. Most (75%) respondents believed genetic factors significantly influenced health status; 85% regarded genetic testing positively although attitudes varied with age. Risk-based information was less valued than certainty-based information, but women valued risk information significantly more highly than men. Respondents reported 'concern' (44%) and 'no concern' (47%) regarding potential misuse of genetic information. This study contributes important population-based data as most research has involved selected individuals closely impacted by genetic disorders. While community attitudes were positive regarding genetic testing, genetic literacy is important to establish. The nature of gender differences regarding risk perception merits further study and has policy and service implications. Community concern about potential genetic discrimination must be addressed if health benefits of testing are to be maximised. Larger questions remain in scientific, policy, service delivery, and professional practice domains before predictive testing for common disorders is efficacious in mainstream health care. Copyright © 2011 S. Karger AG, Basel.

  14. Prediction of Adulthood Obesity Using Genetic and Childhood Clinical Risk Factors in the Cardiovascular Risk in Young Finns Study.

    Science.gov (United States)

    Seyednasrollah, Fatemeh; Mäkelä, Johanna; Pitkänen, Niina; Juonala, Markus; Hutri-Kähönen, Nina; Lehtimäki, Terho; Viikari, Jorma; Kelly, Tanika; Li, Changwei; Bazzano, Lydia; Elo, Laura L; Raitakari, Olli T

    2017-06-01

    Obesity is a known risk factor for cardiovascular disease. Early prediction of obesity is essential for prevention. The aim of this study is to assess the use of childhood clinical factors and the genetic risk factors in predicting adulthood obesity using machine learning methods. A total of 2262 participants from the Cardiovascular Risk in YFS (Young Finns Study) were followed up from childhood (age 3-18 years) to adulthood for 31 years. The data were divided into training (n=1625) and validation (n=637) set. The effect of known genetic risk factors (97 single-nucleotide polymorphisms) was investigated as a weighted genetic risk score of all 97 single-nucleotide polymorphisms (WGRS97) or a subset of 19 most significant single-nucleotide polymorphisms (WGRS19) using boosting machine learning technique. WGRS97 and WGRS19 were validated using external data (n=369) from BHS (Bogalusa Heart Study). WGRS19 improved the accuracy of predicting adulthood obesity in training (area under the curve [AUC=0.787 versus AUC=0.744, P obesity. Predictive accuracy is highest among young children (3-6 years), whereas among older children (9-18 years) the risk can be identified using childhood clinical factors. The model is helpful in screening children with high risk of developing obesity. © 2017 American Heart Association, Inc.

  15. A genome-wide association study demonstrates significant genetic variation for fracture risk in Thoroughbred racehorses

    Science.gov (United States)

    2014-01-01

    Background Thoroughbred racehorses are subject to non-traumatic distal limb bone fractures that occur during racing and exercise. Susceptibility to fracture may be due to underlying disturbances in bone metabolism which have a genetic cause. Fracture risk has been shown to be heritable in several species but this study is the first genetic analysis of fracture risk in the horse. Results Fracture cases (n = 269) were horses that sustained catastrophic distal limb fractures while racing on UK racecourses, necessitating euthanasia. Control horses (n = 253) were over 4 years of age, were racing during the same time period as the cases, and had no history of fracture at the time the study was carried out. The horses sampled were bred for both flat and National Hunt (NH) jump racing. 43,417 SNPs were employed to perform a genome-wide association analysis and to estimate the proportion of genetic variance attributable to the SNPs on each chromosome using restricted maximum likelihood (REML). Significant genetic variation associated with fracture risk was found on chromosomes 9, 18, 22 and 31. Three SNPs on chromosome 18 (62.05 Mb – 62.15 Mb) and one SNP on chromosome 1 (14.17 Mb) reached genome-wide significance (p fracture than cases, p = 1 × 10-4), while a second haplotype increases fracture risk (cases at 3.39 times higher risk of fracture than controls, p = 0.042). Conclusions Fracture risk in the Thoroughbred horse is a complex condition with an underlying genetic basis. Multiple genomic regions contribute to susceptibility to fracture risk. This suggests there is the potential to develop SNP-based estimators for genetic risk of fracture in the Thoroughbred racehorse, using methods pioneered in livestock genetics such as genomic selection. This information would be useful to racehorse breeders and owners, enabling them to reduce the risk of injury in their horses. PMID:24559379

  16. Genetic modification and genetic determinism

    Science.gov (United States)

    Resnik, David B; Vorhaus, Daniel B

    2006-01-01

    In this article we examine four objections to the genetic modification of human beings: the freedom argument, the giftedness argument, the authenticity argument, and the uniqueness argument. We then demonstrate that each of these arguments against genetic modification assumes a strong version of genetic determinism. Since these strong deterministic assumptions are false, the arguments against genetic modification, which assume and depend upon these assumptions, are therefore unsound. Serious discussion of the morality of genetic modification, and the development of sound science policy, should be driven by arguments that address the actual consequences of genetic modification for individuals and society, not by ones propped up by false or misleading biological assumptions. PMID:16800884

  17. Genetic modification and genetic determinism

    Directory of Open Access Journals (Sweden)

    Vorhaus Daniel B

    2006-06-01

    Full Text Available Abstract In this article we examine four objections to the genetic modification of human beings: the freedom argument, the giftedness argument, the authenticity argument, and the uniqueness argument. We then demonstrate that each of these arguments against genetic modification assumes a strong version of genetic determinism. Since these strong deterministic assumptions are false, the arguments against genetic modification, which assume and depend upon these assumptions, are therefore unsound. Serious discussion of the morality of genetic modification, and the development of sound science policy, should be driven by arguments that address the actual consequences of genetic modification for individuals and society, not by ones propped up by false or misleading biological assumptions.

  18. Genetic, nongenetic and epigenetic risk determinants in developmental programming of type 2 diabetes

    DEFF Research Database (Denmark)

    Vaag, Allan; Brøns, Charlotte; Gillberg, Linn

    2014-01-01

    Low birthweight (LBW) individuals and offspring of women with gestational diabetes mellitus (GDM) exhibit increased risk of developing type 2 diabetes (T2D) and associated cardiometabolic traits in adulthood, which for both groups may be mediated by adverse events and developmental changes in fetal...... factors. Indeed, it has been shown that genetic changes influencing risk of diabetes may also be associated with reduced fetal growth as a result of reduced insulin secretion and/or action. Similarly, increased risk of T2D among offspring could be explained by T2D susceptibility genes shared between...... life. T2D is a multifactorial disease occurring as a result of complicated interplay between genetic and both prenatal and postnatal nongenetic factors, and it remains unknown to what extent the increased risk of T2D associated with LBW or GDM in the mother may be due to, or confounded by, genetic...

  19. Associations between self-referral and health behavior responses to genetic risk information.

    Science.gov (United States)

    Christensen, Kurt D; Roberts, J Scott; Zikmund-Fisher, Brian J; Kardia, Sharon Lr; McBride, Colleen M; Linnenbringer, Erin; Green, Robert C

    2015-01-01

    Studies examining whether genetic risk information about common, complex diseases can motivate individuals to improve health behaviors and advance planning have shown mixed results. Examining the influence of different study recruitment strategies may help reconcile inconsistencies. Secondary analyses were conducted on data from the REVEAL study, a series of randomized clinical trials examining the impact of genetic susceptibility testing for Alzheimer's disease (AD). We tested whether self-referred participants (SRPs) were more likely than actively recruited participants (ARPs) to report health behavior and advance planning changes after AD risk and APOE genotype disclosure. Of 795 participants with known recruitment status, 546 (69%) were self-referred and 249 (31%) had been actively recruited. SRPs were younger, less likely to identify as African American, had higher household incomes, and were more attentive to AD than ARPs (all P change to at least one health behavior 6 weeks and 12 months after genetic risk disclosure, nor in intentions to change at least one behavior in the future. However, interaction effects were observed where ε4-positive SRPs were more likely than ε4-negative SRPs to report changes specifically to mental activities (38% vs 19%, p change long-term care insurance among SRPs (20% vs 5%, p behavior changes than those who respond to genetic testing offers. These results demonstrate how the behavioral impact of genetic risk information may vary according to the models by which services are provided, and suggest that how participants are recruited into translational genomics research can influence findings. ClinicalTrials.gov NCT00089882 and NCT00462917.

  20. Risk assesment in the context of EC directives on genetically modified organisms

    Energy Technology Data Exchange (ETDEWEB)

    Meer, P.J. van der [Ministry for the Environment (Netherlands)

    1992-07-01

    The introduction of these new molecular technologies initiated an international discussion on the safety in biotechnology. In 1974 one of the pioneers of this new technology, Paul Berg, expressed his view on the potential risks of recombinant DNA applications in the famous 'Berg letter', leading to a self-imposed moratorium on certain experiments. Following the Berg letter and the Asilomar convention, much international attention has been given to the question of safety in biotechnology. This attention resulted in hundreds of documents, research programmes, guidelines and regulations. This resulted, among others, in two EC Directives on genetically modified organisms: the EC Directive 90/219/EEC on the contained use of genetically modified micro-organisms, and Directive 90/220/EEC on the release of genetically modified organisms. These directives lay down a system for harmonization of risk assessment and risk management with regard to the safety for human health and the environment.

  1. Risk assesment in the context of EC directives on genetically modified organisms

    International Nuclear Information System (INIS)

    Meer, P.J. van der

    1992-01-01

    The introduction of these new molecular technologies initiated an international discussion on the safety in biotechnology. In 1974 one of the pioneers of this new technology, Paul Berg, expressed his view on the potential risks of recombinant DNA applications in the famous 'Berg letter', leading to a self-imposed moratorium on certain experiments. Following the Berg letter and the Asilomar convention, much international attention has been given to the question of safety in biotechnology. This attention resulted in hundreds of documents, research programmes, guidelines and regulations. This resulted, among others, in two EC Directives on genetically modified organisms: the EC Directive 90/219/EEC on the contained use of genetically modified micro-organisms, and Directive 90/220/EEC on the release of genetically modified organisms. These directives lay down a system for harmonization of risk assessment and risk management with regard to the safety for human health and the environment

  2. Obesity during childhood and adolescence increases susceptibility to multiple sclerosis after accounting for established genetic and environmental risk factors

    Science.gov (United States)

    Gianfrancesco, Milena A.; Acuna, Brigid; Shen, Ling; Briggs, Farren B.S.; Quach, Hong; Bellesis, Kalliope H.; Bernstein, Allan; Hedstrom, Anna K.; Kockum, Ingrid; Alfredsson, Lars; Olsson, Tomas; Schaefer, Catherine; Barcellos, Lisa F.

    2014-01-01

    Objective To investigate the association between obesity and multiple sclerosis (MS) while accounting for established genetic and environmental risk factors. Methods Participants included members of Kaiser Permanente Medical Care Plan, Northern California Region (KPNC) (1,235 MS cases and 697 controls). Logistic regression models were used to estimate odds ratios (ORs) with 95% confidence intervals (95% CI). Body mass index (BMI) or body size was the primary predictor of each model. Both incident and prevalent MS cases were studied. Results In analyses stratified by gender, being overweight at age 10 and 20 were associated with MS in females (prisk of MS for females with a BMI ≥ 30 kg/m2 was observed (OR = 2.15, 95% CI 1.18, 3.92). Significant associations between BMI in 20’s and MS in males were not observed. Multivariate modeling demonstrated that significant associations between BMI or body size with MS in females persisted after adjusting for history of infectious mononucleosis and genetic risk factors, including HLA-DRB1*15:01 and established non-HLA risk alleles. Interpretation Results show that childhood and adolescence obesity confer increased risk of MS in females beyond established heritable and environmental risk factors. Strong evidence for a dose-effect of BMI in 20’s and MS was observed. The magnitude of BMI association with MS is as large as other known MS risk factors. PMID:25263833

  3. Genetically modified foods: safety, risks and public concerns-a review.

    Science.gov (United States)

    Bawa, A S; Anilakumar, K R

    2013-12-01

    Genetic modification is a special set of gene technology that alters the genetic machinery of such living organisms as animals, plants or microorganisms. Combining genes from different organisms is known as recombinant DNA technology and the resulting organism is said to be 'Genetically modified (GM)', 'Genetically engineered' or 'Transgenic'. The principal transgenic crops grown commercially in field are herbicide and insecticide resistant soybeans, corn, cotton and canola. Other crops grown commercially and/or field-tested are sweet potato resistant to a virus that could destroy most of the African harvest, rice with increased iron and vitamins that may alleviate chronic malnutrition in Asian countries and a variety of plants that are able to survive weather extremes. There are bananas that produce human vaccines against infectious diseases such as hepatitis B, fish that mature more quickly, fruit and nut trees that yield years earlier and plants that produce new plastics with unique properties. Technologies for genetically modifying foods offer dramatic promise for meeting some areas of greatest challenge for the 21st century. Like all new technologies, they also pose some risks, both known and unknown. Controversies and public concern surrounding GM foods and crops commonly focus on human and environmental safety, labelling and consumer choice, intellectual property rights, ethics, food security, poverty reduction and environmental conservation. With this new technology on gene manipulation what are the risks of "tampering with Mother Nature"?, what effects will this have on the environment?, what are the health concerns that consumers should be aware of? and is recombinant technology really beneficial? This review will also address some major concerns about the safety, environmental and ecological risks and health hazards involved with GM foods and recombinant technology.

  4. The potential of large studies for building genetic risk prediction models

    Science.gov (United States)

    NCI scientists have developed a new paradigm to assess hereditary risk prediction in common diseases, such as prostate cancer. This genetic risk prediction concept is based on polygenic analysis—the study of a group of common DNA sequences, known as singl

  5. Perceptions of genetic discrimination among people at risk for Huntington's disease: a cross sectional survey.

    Science.gov (United States)

    Bombard, Yvonne; Veenstra, Gerry; Friedman, Jan M; Creighton, Susan; Currie, Lauren; Paulsen, Jane S; Bottorff, Joan L; Hayden, Michael R

    2009-06-09

    To assess the nature and prevalence of genetic discrimination experienced by people at risk for Huntington's disease who had undergone genetic testing or remained untested. Cross sectional, self reported survey. Seven genetics and movement disorders clinics servicing rural and urban communities in Canada. 233 genetically tested and untested asymptomatic people at risk for Huntington's disease (response rate 80%): 167 underwent testing (83 had the Huntington's disease mutation, 84 did not) and 66 chose not to be tested. Self reported experiences of genetic discrimination and related psychological distress based on family history or genetic test results. Discrimination was reported by 93 respondents (39.9%). Reported experiences occurred most often in insurance (29.2%), family (15.5%), and social (12.4%) settings. There were few reports of discrimination in employment (6.9%), health care (8.6%), or public sector settings (3.9%). Although respondents who were aware that they carried the Huntington's disease mutation reported the highest levels of discrimination, participation in genetic testing was not associated with increased levels of genetic discrimination. Family history of Huntington's disease, rather than the result of genetic testing, was the main reason given for experiences of genetic discrimination. Psychological distress was associated with genetic discrimination (PGenetic discrimination was commonly reported by people at risk for Huntington's disease and was a source of psychological distress. Family history, and not genetic testing, was the major reason for genetic discrimination.

  6. Genetic variants influencing circulating lipid levels and risk of coronary artery disease

    NARCIS (Netherlands)

    D. Waterworth (Dawn); S.L. Ricketts (Sally); K. Song (Kijoung); L. Chen (Leslie); J.H. Zhao (Jing Hua); S. Ripatti (Samuli); Y.S. Aulchenko (Yurii); W. Zhang (Weihua); X. Yuan (Xin); N. Lim (Noha); J. Luan; S. Ashford (Sofie); E. Wheeler (Eleanor); E.H. Young (Elizabeth); D. Hadley (David); J.R. Thompson (John); P.S. Braund (Peter); T. Johnson (Toby); M.V. Struchalin (Maksim); I. Surakka (Ida); R.N. Luben (Robert); K-T. Khaw (Kay-Tee); S.A. Rodwell (Sheila); R.J.F. Loos (Ruth); S.M. Boekholdt (Matthijs); M. Inouye (Michael); P. Deloukas (Panagiotis); P. Elliott (Paul); D. Schlessinger; S. Sanna (Serena); A. Scuteri (Angelo); A.U. Jackson (Anne); K.L. Mohlke (Karen); J. Tuomilehto (Jaakko); R. Roberts (Robert); A. Stewart (Alison); Y.A. Kesaniemi (Antero); R. Mahley (Robert); S.M. Grundy (Scott); W.L. McArdle (Wendy); L. Cardon (Lon); G. Waeber (Gérard); P. Vollenweider (Peter); J.C. Chambers (John); M. Boehnke (Michael); G.R. Abecasis (Gonçalo); V. Salomaa (Veikko); M.R. Järvelin; A. Ruokonen (Aimo); I.E. Barroso (Inês); S.E. Epstein (Stephen); H. Hakonarson (Hakon); D.J. Rader (Daniel); M.P. Reilly (Muredach); J.C.M. Witteman (Jacqueline); A.S. Hall (Alistair); N.J. Samani (Nilesh); D.P. Strachan (David); P. Barter (Phil); P. Tikka-Kleemola (Päivi); J.S. Kooner (Jaspal); L. Peltonen (Leena Johanna); N.J. Wareham (Nick); R. McPherson (Ruth); V. Mooser (Vincent); M.S. Sandhu (Manjinder)

    2010-01-01

    textabstractOBJECTIVE-: Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of low-density lipoprotein cholesterol (LDL-C), high-density

  7. Genetic Variants Influencing Circulating Lipid Levels and Risk of Coronary Artery Disease

    NARCIS (Netherlands)

    Waterworth, Dawn M.; Ricketts, Sally L.; Song, Kijoung; Chen, Li; Zhao, Jing Hua; Ripatti, Samuli; Aulchenko, Yurii S.; Zhang, Weihua; Yuan, Xin; Lim, Noha; Luan, Jian'an; Ashford, Sofie; Wheeler, Eleanor; Young, Elizabeth H.; Hadley, David; Thompson, John R.; Braund, Peter S.; Johnson, Toby; Struchalin, Maksim; Surakka, Ida; Luben, Robert; Khaw, Kay-Tee; Rodwell, Sheila A.; Loos, Ruth J. F.; Boekholdt, S. Matthijs; Inouye, Michael; Deloukas, Panagiotis; Elliott, Paul; Schlessinger, David; Sanna, Serena; Scuteri, Angelo; Jackson, Anne; Mohlke, Karen L.; Tuomilehto, Jaako; Roberts, Robert; Stewart, Alexandre; Kesäniemi, Y. Antero; Mahley, Robert W.; Grundy, Scott M.; McArdle, Wendy; Cardon, Lon; Waeber, Gérard; Vollenweider, Peter; Chambers, John C.; Boehnke, Michael; Abecasis, Gonçalo R.; Salomaa, Veikko; Järvelin, Marjo-Riitta; Ruokonen, Aimo; Barroso, Inês; Epstein, Stephen E.; Hakonarson, Hakon H.; Rader, Daniel J.; Reilly, Muredach P.; Witteman, Jacqueline C. M.; Hall, Alistair S.; Samani, Nilesh J.; Strachan, David P.; Barter, Philip; van Duijn, Cornelia M.; Kooner, Jaspal S.; Peltonen, Leena; Wareham, Nicholas J.; McPherson, Ruth; Mooser, Vincent; Sandhu, Manjinder S.

    2010-01-01

    Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol

  8. Interaction of a genetic risk score with physical activity, physical inactivity, and body mass index in relation to venous thromboembolism risk.

    Science.gov (United States)

    Kim, Jihye; Kraft, Peter; Hagan, Kaitlin A; Harrington, Laura B; Lindstroem, Sara; Kabrhel, Christopher

    2018-06-01

    Venous thromboembolism (VTE) is highly heritable. Physical activity, physical inactivity and body mass index (BMI) are also risk factors, but evidence of interaction between genetic and environmental risk factors is limited. Data on 2,134 VTE cases and 3,890 matched controls were obtained from the Nurses' Health Study (NHS), Nurses' Health Study II (NHS II), and Health Professionals Follow-up Study (HPFS). We calculated a weighted genetic risk score (wGRS) using 16 single nucleotide polymorphisms associated with VTE risk in published genome-wide association studies (GWAS). Data on three risk factors, physical activity (metabolic equivalent [MET] hours per week), physical inactivity (sitting hours per week) and BMI, were obtained from biennial questionnaires. VTE cases were incident since cohort inception; controls were matched to cases on age, cohort, and genotype array. Using conditional logistic regression, we assessed joint effects and interaction effects on both additive and multiplicative scales. We also ran models using continuous wGRS stratified by risk-factor categories. We observed a supra-additive interaction between wGRS and BMI. Having both high wGRS and high BMI was associated with a 3.4-fold greater risk of VTE (relative excess risk due to interaction = 0.69, p = 0.046). However, we did not find evidence for a multiplicative interaction with BMI. No interactions were observed for physical activity or inactivity. We found a synergetic effect between a genetic risk score and high BMI on the risk of VTE. Intervention efforts lowering BMI to decrease VTE risk may have particularly large beneficial effects among individuals with high genetic risk. © 2018 WILEY PERIODICALS, INC.

  9. Summary of the BEIR V committee's estimates of genetic risks

    International Nuclear Information System (INIS)

    Grahn, D.

    1990-01-01

    The Committee on the Biological Effects of Ionizing Radiations (BEIR V) was constituted in late 1986 to conduct a comprehensive review of the biological effects of ionizing radiations focusing on information reported since the conclusion of the 1980 BEIR study, and to provide new estimates of the risks of genetic and somatic effects in humans due to low-level exposures of ionizing radiation. The Committee preferred the doubling-dose method of genetic risk estimation over the direct method. Data from animal (mouse) studies provide a median value of 100 to 114 cGy for long-term low dose rate exposure doubling doses. These values are lower than the median from human studies. The BEIR Committee believed that a doubling dose of 100 cGy would be a prudent value leading to conservative estimates. The estimated risks themselves are not much different from those generated by previous BEIR committees, UNSCEAR, and other published estimates. The Committee estimates that between 100 and 200 added cases per million live births will be observed at genetic equilibrium if the population is exposed each generation to a dose of 0.01 Sv (1 rem). Nearly half ware attributed to clinically mild dominant defects, and the balance to congenital abnormalities. (L.L.) (2 tabs.)

  10. Uniform risk functionals for characterization of strong earthquake ground motions

    International Nuclear Information System (INIS)

    Anderson, J.G.; Trifunac, M.D.

    1978-01-01

    A uniform risk functional (e.g., Fourier spectrum, response spectrum, duration, etc.) is defined so that the probability that it is exceeded by some earthquake during a selected period of time is independent of the frequency of seismic waves. Such a functional is derived by an independent calculation, at each frequency, for the probability that the quantity being considered will be exceeded. Different aspects of the seismicity can control the amplitude of a uniform risk functional in different frequency ranges, and a uniform risk functional does not necessarily describe the strong shaking from any single earthquake. To be useful for calculating uniform risk functionals, a scaling relationship must provide an independent estimate of amplitudes of the functional in several frequency bands. The scaling relationship of Trifunac (1976) for Fourier spectra satisfies this requirement and further describes the distribution of spectral amplitudes about the mean trend; here, it is applied to find uniform risk Fourier amplitude spectra. In an application to finding the uniform risk spectra at a realistic site, this method is quite sensitive to the description of seismicity. Distinct models of seismicity, all consistent with our current level of knowledge of an area, can give significantly different risk estimates

  11. Genetic Counselors' Experiences Regarding Communication of Reproductive Risks with Autosomal Recessive Conditions found on Cancer Panels.

    Science.gov (United States)

    Mets, Sarah; Tryon, Rebecca; Veach, Patricia McCarthy; Zierhut, Heather A

    2016-04-01

    The development of hereditary cancer genetic testing panels has altered genetic counseling practice. Mutations within certain genes on cancer panels pose not only a cancer risk, but also a reproductive risk for autosomal recessive conditions such as Fanconi anemia, constitutional mismatch repair deficiency syndrome, and ataxia telangiectasia. This study aimed to determine if genetic counselors discuss reproductive risks for autosomal recessive conditions associated with genes included on cancer panels, and if so, under what circumstances these risks are discussed. An on-line survey was emailed through the NSGC list-serv. The survey assessed 189 cancer genetic counselors' experiences discussing reproductive risks with patients at risk to carry a mutation or variant of uncertain significance (VUS) in a gene associated with both an autosomal dominant cancer risk and an autosomal recessive syndrome. Over half (n = 82, 55 %) reported having discussed reproductive risks; the remainder (n = 66, 45 %) had not. Genetic counselors who reported discussing reproductive risks primarily did so when patients had a positive result and were of reproductive age. Reasons for not discussing these risks included when a patient had completed childbearing or when a VUS was identified. Most counselors discussed reproductive risk after obtaining results and not during the informed consent process. There is inconsistency as to if and when the discussion of reproductive risks is taking place. The wide variation in responses suggests a need to develop professional guidelines for when and how discussions of reproductive risk for autosomal recessive conditions identified through cancer panels should occur with patients.

  12. Genetic Alterations and Their Clinical Implications in High-Recurrence Risk Papillary Thyroid Cancer.

    Science.gov (United States)

    Lee, Min-Young; Ku, Bo Mi; Kim, Hae Su; Lee, Ji Yun; Lim, Sung Hee; Sun, Jong-Mu; Lee, Se-Hoon; Park, Keunchil; Oh, Young Lyun; Hong, Mineui; Jeong, Han-Sin; Son, Young-Ik; Baek, Chung-Hwan; Ahn, Myung-Ju

    2017-10-01

    Papillary thyroid carcinomas (PTCs) frequently involve genetic alterations. The objective of this study was to investigate genetic alterations and further explore the relationships between these genetic alterations and clinicopathological characteristics in a high-recurrence risk (node positive, N1) PTC group. Tumor tissue blocks were obtained from 240 surgically resected patients with histologically confirmed stage III/IV (pT3/4 or N1) PTCs. We screened gene fusions using NanoString's nCounter technology and mutational analysis was performed by direct DNA sequencing. Data describing the clinicopathological characteristics and clinical courses were retrospectively collected. Of the 240 PTC patients, 207 (86.3%) had at least one genetic alteration, including BRAF mutation in 190 patients (79.2%), PIK3CA mutation in 25 patients (10.4%), NTRK1/3 fusion in six patients (2.5%), and RET fusion in 24 patients (10.0%). Concomitant presence of more than two genetic alterations was seen in 36 patients (15%). PTCs harboring BRAF mutation were associated with RET wild-type expression (p=0.001). RET fusion genes have been found to occur with significantly higher frequency in N1b stage patients (p=0.003) or groups of patients aged 45 years or older (p=0.031); however, no significant correlation was found between other genetic alterations. There was no trend toward favorable recurrence-free survival or overall survival among patients lacking genetic alterations. In the selected high-recurrence risk PTC group, most patients had more than one genetic alteration. However, these known alterations could not entirely account for clinicopathological features of high-recurrence risk PTC.

  13. Tutorial dialogues and gist explanations of genetic breast cancer risk.

    Science.gov (United States)

    Widmer, Colin L; Wolfe, Christopher R; Reyna, Valerie F; Cedillos-Whynott, Elizabeth M; Brust-Renck, Priscila G; Weil, Audrey M

    2015-09-01

    The intelligent tutoring system (ITS) BRCA Gist is a Web-based tutor developed using the Shareable Knowledge Objects (SKO) platform that uses latent semantic analysis to engage women in natural-language dialogues to teach about breast cancer risk. BRCA Gist appears to be the first ITS designed to assist patients' health decision making. Two studies provide fine-grained analyses of the verbal interactions between BRCA Gist and women responding to five questions pertaining to breast cancer and genetic risk. We examined how "gist explanations" generated by participants during natural-language dialogues related to outcomes. Using reliable rubrics, scripts of the participants' verbal interactions with BRCA Gist were rated for content and for the appropriateness of the tutor's responses. Human researchers' scores for the content covered by the participants were strongly correlated with the coverage scores generated by BRCA Gist, indicating that BRCA Gist accurately assesses the extent to which people respond appropriately. In Study 1, participants' performance during the dialogues was consistently associated with learning outcomes about breast cancer risk. Study 2 was a field study with a more diverse population. Participants with an undergraduate degree or less education who were randomly assigned to BRCA Gist scored higher on tests of knowledge than those assigned to the National Cancer Institute website or than a control group. We replicated findings that the more expected content that participants included in their gist explanations, the better they performed on outcome measures. As fuzzy-trace theory suggests, encouraging people to develop and elaborate upon gist explanations appears to improve learning, comprehension, and decision making.

  14. Perceptions of genetic discrimination among people at risk for Huntington?s disease: a cross sectional survey

    OpenAIRE

    Bombard, Yvonne; Veenstra, Gerry; Friedman, Jan M; Creighton, Susan; Currie, Lauren; Paulsen, Jane S; Bottorff, Joan L; Hayden, Michael R

    2009-01-01

    Objective To assess the nature and prevalence of genetic discrimination experienced by people at risk for Huntington?s disease who had undergone genetic testing or remained untested. Design Cross sectional, self reported survey. Setting Seven genetics and movement disorders clinics servicing rural and urban communities in Canada. Participants 233 genetically tested and untested asymptomatic people at risk for Huntington?s disease (response rate 80%): 167 underwent testing (83 had the Huntingt...

  15. On the use of sibling recurrence risks to select environmental factors liable to interact with genetic risk factors.

    Science.gov (United States)

    Kazma, Rémi; Bonaïti-Pellié, Catherine; Norris, Jill M; Génin, Emmanuelle

    2010-01-01

    Gene-environment interactions are likely to be involved in the susceptibility to multifactorial diseases but are difficult to detect. Available methods usually concentrate on some particular genetic and environmental factors. In this paper, we propose a new method to determine whether a given exposure is susceptible to interact with unknown genetic factors. Rather than focusing on a specific genetic factor, the degree of familial aggregation is used as a surrogate for genetic factors. A test comparing the recurrence risks in sibs according to the exposure of indexes is proposed and its power is studied for varying values of model parameters. The Exposed versus Unexposed Recurrence Analysis (EURECA) is valuable for common diseases with moderate familial aggregation, only when the role of exposure has been clearly outlined. Interestingly, accounting for a sibling correlation for the exposure increases the power of EURECA. An application on a sample ascertained through one index affected with type 2 diabetes is presented where gene-environment interactions involving obesity and physical inactivity are investigated. Association of obesity with type 2 diabetes is clearly evidenced and a potential interaction involving this factor is suggested in Hispanics (P=0.045), whereas a clear gene-environment interaction is evidenced involving physical inactivity only in non-Hispanic whites (P=0.028). The proposed method might be of particular interest before genetic studies to help determine the environmental risk factors that will need to be accounted for to increase the power to detect genetic risk factors and to select the most appropriate samples to genotype.

  16. Defining the genetic susceptibility to cervical neoplasia-A genome-wide association study.

    Directory of Open Access Journals (Sweden)

    Paul J Leo

    2017-08-01

    Full Text Available A small percentage of women with cervical HPV infection progress to cervical neoplasia, and the risk factors determining progression are incompletely understood. We sought to define the genetic loci involved in cervical neoplasia and to assess its heritability using unbiased unrelated case/control statistical approaches. We demonstrated strong association of cervical neoplasia with risk and protective HLA haplotypes that are determined by the amino-acids carried at positions 13 and 71 in pocket 4 of HLA-DRB1 and position 156 in HLA-B. Furthermore, 36% (standard error 2.4% of liability of HPV-associated cervical pre-cancer and cancer is determined by common genetic variants. Women in the highest 10% of genetic risk scores have approximately >7.1% risk, and those in the highest 5% have approximately >21.6% risk, of developing cervical neoplasia. Future studies should examine genetic risk prediction in assessing the risk of cervical neoplasia further, in combination with other screening methods.

  17. Genetic Testing for Type 2 Diabetes in High-Risk Children: the Case for Primordial Prevention

    Directory of Open Access Journals (Sweden)

    Jennifer Wessel

    2017-09-01

    Full Text Available Extensive research now demonstrates that lifestyle modification can significantly lower risk of developing type 2 diabetes (T2D in high-risk adults. In children, the evidence for lifestyle modification is not as robust, but the rapidly rising rate of obesity in children coupled with the substantial difficulty in changing behaviors later in life illuminates the need to implement prevention efforts early in the life course of children. Genetic data can now be used early in the life course to identify children at high-risk of developing T2D before traditional clinical measures can detect the presence of prediabetes; a metabolic condition associated with obesity that significantly increases risk for developing T2D.  Such early detection of risk may enable the promotion of “primordial prevention” in which parents implement behavior change for their at risk children.  Young children with genetic risk are a novel target population.  Here we review the literature on genetic testing for prevention as it relates to chronic diseases and specifically use T2D as a model. We discuss the history of primordial prevention, the need for primordial prevention of T2D and the role genetic testing has in primordial prevention of high-risk families.

  18. Genetic variation in the base excision repair pathway, environmental risk factors, and colorectal adenoma risk.

    Directory of Open Access Journals (Sweden)

    Roman Corral

    Full Text Available Cigarette smoking, high alcohol intake, and low dietary folate levels are risk factors for colorectal adenomas. Oxidative damage caused by these three factors can be repaired through the base excision repair pathway (BER. We hypothesized that genetic variation in BER might modify colorectal adenoma risk. In a sigmoidoscopy-based study, we examined associations between 182 haplotype tagging SNPs in 14 BER genes, and colorectal adenoma risk, and examined their potential role as modifiers of the effect cigarette smoking, alcohol intake, and dietary folate levels. Among all individuals, no statistically significant associations between BER SNPs and adenoma risk persisted after correction for multiple comparisons. However, among Asian-Pacific Islanders we observed two SNPs in FEN1 and one in NTHL1, and among African-Americans one SNP in APEX1 that were associated with colorectal adenoma risk. Significant associations were also observed between SNPs in the NEIL2 gene and rectal adenoma risk. Three SNPS modified the effect of smoking (MUTYH interaction p = 0.002; OGG1 interaction p = 0.013; FEN1 interaction p = 0.013, one SNP in LIG3 modified the effect of alcohol consumption (interaction p = 0.024 and two SNPs in LIG3 modified the effect of dietary folate (interaction p = 0.001 and p = 0.08 on colorectal adenoma risk. These findings support a role for genetic variants in the BER pathway as potential modifiers of colorectal adenoma risk. Our findings strengthen the role of oxidative damage induced by key lifestyle and dietary risk factors in colorectal adenoma formation.

  19. The genetic validation of heterogeneity in schizophrenia

    Directory of Open Access Journals (Sweden)

    Moritani Makiko

    2011-10-01

    Full Text Available Abstract Introduction Schizophrenia is a heritable disorder, however clear genetic architecture has not been detected. To overcome this state of uncertainty, the SZGene database has been established by including all published case-control genetic association studies appearing in peer-reviewed journals. In the current study, we aimed to determine if genetic variants strongly suggested by SZGene are associated with risk of schizophrenia in our case-control samples of Japanese ancestry. In addition, by employing the additive model for aggregating the effect of seven variants, we aimed to verify the genetic heterogeneity of schizophrenia diagnosed by an operative diagnostic manual, the DSM-IV. Methods Each positively suggested genetic polymorphism was ranked according to its p-value, then the seven top-ranked variants (p Results No statistically significant deviation between cases and controls was observed in the genetic risk-index derived from all seven variants on the top-ranked polymorphisms. In fact, the average risk-index score in the schizophrenia group (6.5+/-1.57 was slightly lower than among controls (6.6+/-1.39. Conclusion The current work illustrates the difficulty in identifying universal and definitive risk-conferring polymorphisms for schizophrenia. Our employed number of samples was small, so we can not preclude the possibility that some or all of these variants are minor risk factors for schizophrenia in the Japanese population. It is also important to aggregate the updated positive variants in the SZGene database when the replication work is conducted.

  20. Prediction of Adult Dyslipidemia Using Genetic and Childhood Clinical Risk Factors: The Cardiovascular Risk in Young Finns Study.

    Science.gov (United States)

    Nuotio, Joel; Pitkänen, Niina; Magnussen, Costan G; Buscot, Marie-Jeanne; Venäläinen, Mikko S; Elo, Laura L; Jokinen, Eero; Laitinen, Tomi; Taittonen, Leena; Hutri-Kähönen, Nina; Lyytikäinen, Leo-Pekka; Lehtimäki, Terho; Viikari, Jorma S; Juonala, Markus; Raitakari, Olli T

    2017-06-01

    Dyslipidemia is a major modifiable risk factor for cardiovascular disease. We examined whether the addition of novel single-nucleotide polymorphisms for blood lipid levels enhances the prediction of adult dyslipidemia in comparison to childhood lipid measures. Two thousand four hundred and twenty-two participants of the Cardiovascular Risk in Young Finns Study who had participated in 2 surveys held during childhood (in 1980 when aged 3-18 years and in 1986) and at least once in a follow-up study in adulthood (2001, 2007, and 2011) were included. We examined whether inclusion of a lipid-specific weighted genetic risk score based on 58 single-nucleotide polymorphisms for low-density lipoprotein cholesterol, 71 single-nucleotide polymorphisms for high-density lipoprotein cholesterol, and 40 single-nucleotide polymorphisms for triglycerides improved the prediction of adult dyslipidemia compared with clinical childhood risk factors. Adjusting for age, sex, body mass index, physical activity, and smoking in childhood, childhood lipid levels, and weighted genetic risk scores were associated with an increased risk of adult dyslipidemia for all lipids. Risk assessment based on 2 childhood lipid measures and the lipid-specific weighted genetic risk scores improved the accuracy of predicting adult dyslipidemia compared with the approach using only childhood lipid measures for low-density lipoprotein cholesterol (area under the receiver-operating characteristic curve 0.806 versus 0.811; P =0.01) and triglycerides (area under the receiver-operating characteristic curve 0.740 versus area under the receiver-operating characteristic curve 0.758; P dyslipidemia in adulthood. © 2017 American Heart Association, Inc.

  1. Eleven loci with new reproducible genetic associations with allergic disease risk

    NARCIS (Netherlands)

    Ferreira, Manuel A.R.; Vonk, Judith M; Baurecht, Hansjörg; Marenholz, Ingo; Tian, Chao; Hoffman, Joshua D; Helmer, Quinta; Tillander, Annika; Ullemar, Vilhelmina; Lu, Yi; Rüschendorf, Franz; Hinds, David A; Hübner, Norbert; Weidinger, Stephan; Magnusson, Patrik Ke; Jorgenson, Eric; Lee, Young-Ae; Boomsma, Dorret I; Karlsson, Robert; Almqvist, Catarina; Koppelman, Gerard H; Paternoster, Lavinia

    2018-01-01

    BACKGROUND: A recent genome-wide association study (GWAS) identified 99 loci that contain genetic risk variants shared between asthma, hay fever and eczema. Many more risk loci shared between these common allergic diseases remain to be discovered, which could point to new therapeutic opportunities.

  2. Pathways and barriers to genetic testing and screening: Molecular genetics meets the high-risk family. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Duster, T.

    1998-11-01

    The proliferation of genetic screening and testing is requiring increasing numbers of Americans to integrate genetic knowledge and interventions into their family life and personal experience. This study examines the social processes that occur as families at risk for two of the most common autosomal recessive diseases, sickle cell disease (SC) and cystic fibrosis (CF), encounter genetic testing. Each of these diseases is found primarily in a different ethnic/racial group (CF in Americans of North European descent and SC in Americans of West African descent). This has permitted them to have a certain additional lens on the role of culture in integrating genetic testing into family life and reproductive planning. A third type of genetic disorder, the thalassemias was added to the sample in order to extent the comparative frame and to include other ethnic and racial groups.

  3. The association of XRCC3 Thr241Met genetic variant with risk of ...

    African Journals Online (AJOL)

    genetic variant could be potentially associated with the risk of prostate cancer. However ... Results: Overall, significant associations were detected in the heterozygote comparison genetic model. (CT versus (vs.) ..... Quantifying hetero- geneity in ...

  4. Investigating Married Adults' Communal Coping with Genetic Health Risk and Perceived Discrimination

    Science.gov (United States)

    Smith, Rachel A.; Sillars, Alan; Chesnut, Ryan P.; Zhu, Xun

    2017-01-01

    Increased genetic testing in personalized medicine presents unique challenges for couples, including managing disease risk and potential discrimination as a couple. This study investigated couples' conflicts and support gaps as they coped with perceived genetic discrimination. We also explored the degree to which communal coping was beneficial in reducing support gaps, and ultimately stress. Dyadic analysis of married adults (N = 266, 133 couples), in which one person had the genetic risk for serious illness, showed that perceived discrimination predicted more frequent conflicts about AATD-related treatment, privacy boundaries, and finances, which, in turn, predicted wider gaps in emotion and esteem support, and greater stress for both spouses. Communal coping predicted lower support gaps for both partners and marginally lower stress. PMID:29731540

  5. Investigating Married Adults' Communal Coping with Genetic Health Risk and Perceived Discrimination.

    Science.gov (United States)

    Smith, Rachel A; Sillars, Alan; Chesnut, Ryan P; Zhu, Xun

    2018-01-01

    Increased genetic testing in personalized medicine presents unique challenges for couples, including managing disease risk and potential discrimination as a couple. This study investigated couples' conflicts and support gaps as they coped with perceived genetic discrimination. We also explored the degree to which communal coping was beneficial in reducing support gaps, and ultimately stress. Dyadic analysis of married adults ( N = 266, 133 couples), in which one person had the genetic risk for serious illness, showed that perceived discrimination predicted more frequent conflicts about AATD-related treatment, privacy boundaries, and finances, which, in turn, predicted wider gaps in emotion and esteem support, and greater stress for both spouses. Communal coping predicted lower support gaps for both partners and marginally lower stress.

  6. Predicting type 2 diabetes using genetic and environmental risk factors in a multi-ethnic Malaysian cohort.

    Science.gov (United States)

    Abdullah, N; Abdul Murad, N A; Mohd Haniff, E A; Syafruddin, S E; Attia, J; Oldmeadow, C; Kamaruddin, M A; Abd Jalal, N; Ismail, N; Ishak, M; Jamal, R; Scott, R J; Holliday, E G

    2017-08-01

    Malaysia has a high and rising prevalence of type 2 diabetes (T2D). While environmental (non-genetic) risk factors for the disease are well established, the role of genetic variations and gene-environment interactions remain understudied in this population. This study aimed to estimate the relative contributions of environmental and genetic risk factors to T2D in Malaysia and also to assess evidence for gene-environment interactions that may explain additional risk variation. This was a case-control study including 1604 Malays, 1654 Chinese and 1728 Indians from the Malaysian Cohort Project. The proportion of T2D risk variance explained by known genetic and environmental factors was assessed by fitting multivariable logistic regression models and evaluating McFadden's pseudo R 2 and the area under the receiver-operating characteristic curve (AUC). Models with and without the genetic risk score (GRS) were compared using the log likelihood ratio Chi-squared test and AUCs. Multiplicative interaction between genetic and environmental risk factors was assessed via logistic regression within and across ancestral groups. Interactions were assessed for the GRS and its 62 constituent variants. The models including environmental risk factors only had pseudo R 2 values of 16.5-28.3% and AUC of 0.75-0.83. Incorporating a genetic score aggregating 62 T2D-associated risk variants significantly increased the model fit (likelihood ratio P-value of 2.50 × 10 -4 -4.83 × 10 -12 ) and increased the pseudo R 2 by about 1-2% and AUC by 1-3%. None of the gene-environment interactions reached significance after multiple testing adjustment, either for the GRS or individual variants. For individual variants, 33 out of 310 tested associations showed nominal statistical significance with 0.001 variation in Malaysian population groups. If gene-environment interactions involving common genetic variants exist, they are likely of small effect, requiring substantially larger samples for

  7. The evolving genetic risk for sporadic ALS.

    Science.gov (United States)

    Gibson, Summer B; Downie, Jonathan M; Tsetsou, Spyridoula; Feusier, Julie E; Figueroa, Karla P; Bromberg, Mark B; Jorde, Lynn B; Pulst, Stefan M

    2017-07-18

    To estimate the genetic risk conferred by known amyotrophic lateral sclerosis (ALS)-associated genes to the pathogenesis of sporadic ALS (SALS) using variant allele frequencies combined with predicted variant pathogenicity. Whole exome sequencing and repeat expansion PCR of C9orf72 and ATXN2 were performed on 87 patients of European ancestry with SALS seen at the University of Utah. DNA variants that change the protein coding sequence of 31 ALS-associated genes were annotated to determine which were rare and deleterious as predicted by MetaSVM. The percentage of patients with SALS with a rare and deleterious variant or repeat expansion in an ALS-associated gene was calculated. An odds ratio analysis was performed comparing the burden of ALS-associated genes in patients with SALS vs 324 normal controls. Nineteen rare nonsynonymous variants in an ALS-associated gene, 2 of which were found in 2 different individuals, were identified in 21 patients with SALS. Further, 5 deleterious C9orf72 and 2 ATXN2 repeat expansions were identified. A total of 17.2% of patients with SALS had a rare and deleterious variant or repeat expansion in an ALS-associated gene. The genetic burden of ALS-associated genes in patients with SALS as predicted by MetaSVM was significantly higher than in normal controls. Previous analyses have identified SALS-predisposing variants only in terms of their rarity in normal control populations. By incorporating variant pathogenicity as well as variant frequency, we demonstrated that the genetic risk contributed by these genes for SALS is substantially lower than previous estimates. © 2017 American Academy of Neurology.

  8. Biodiversity analyses for risk assessment of genetically modified potato

    NARCIS (Netherlands)

    Lazebnik, Jenny; Dicke, Marcel; Braak, ter Cajo J.F.; Loon, van Joop J.A.

    2017-01-01

    An environmental risk assessment for the introduction of genetically modified crops includes assessing the consequences for biodiversity. In this study arthropod biodiversity was measured using pitfall traps in potato agro-ecosystems in Ireland and The Netherlands over two years. We tested the

  9. Cost sharing and hereditary cancer risk: predictors of willingness-to-pay for genetic testing.

    Science.gov (United States)

    Matro, Jennifer M; Ruth, Karen J; Wong, Yu-Ning; McCully, Katen C; Rybak, Christina M; Meropol, Neal J; Hall, Michael J

    2014-12-01

    Increasing use of predictive genetic testing to gauge hereditary cancer risk has been paralleled by rising cost-sharing practices. Little is known about how demographic and psychosocial factors may influence individuals' willingness-to-pay for genetic testing. The Gastrointestinal Tumor Risk Assessment Program Registry includes individuals presenting for genetic risk assessment based on personal/family cancer history. Participants complete a baseline survey assessing cancer history and psychosocial items. Willingness-to-pay items include intention for: genetic testing only if paid by insurance; testing with self-pay; and amount willing-to-pay ($25-$2,000). Multivariable models examined predictors of willingness-to-pay out-of-pocket (versus only if paid by insurance) and willingness-to-pay a smaller versus larger sum (≤$200 vs. ≥$500). All statistical tests are two-sided (α = 0.05). Of 385 evaluable participants, a minority (42%) had a personal cancer history, while 56% had ≥1 first-degree relative with colorectal cancer. Overall, 21.3% were willing to have testing only if paid by insurance, and 78.7% were willing-to-pay. Predictors of willingness-to-pay were: 1) concern for positive result; 2) confidence to control cancer risk; 3) fewer perceived barriers to colorectal cancer screening; 4) benefit of testing to guide screening (all p testing (all p testing, and anticipate benefits to reducing cancer risk. Identifying factors associated with willingness-to-pay for genetic services is increasingly important as testing is integrated into routine cancer care.

  10. Concerns about Genetic Testing for Schizophrenia among Young Adults at Clinical High Risk for Psychosis.

    Science.gov (United States)

    Lawrence, Ryan E; Friesen, Phoebe; Brucato, Gary; Girgis, Ragy R; Dixon, Lisa

    Genetic tests for schizophrenia may introduce risks and benefits. Among young adults at clinical high-risk for psychosis, little is known about their concerns and how they assess potential risks. We conducted semi-structured interviews with 15 young adults at clinical high-risk for psychosis to ask about their concerns. Participants expressed concerns about test reliability, data interpretation, stigma, psychological harm, family planning, and privacy. Participants' responses showed some departure from the ethics literature insofar as participants were primarily interested in reporting their results to people to whom they felt emotionally close, and expressed little consideration of biological closeness. Additionally, if tests showed an increased genetic risk for schizophrenia, four clinical high-risk persons felt obligated to tell an employer and another three would "maybe" tell an employer, even in the absence of clinical symptoms. These findings suggest opportunities for clinicians and genetic counselors to intervene with education and support.

  11. An overall genetic risk assessment for radiological protection purposes

    International Nuclear Information System (INIS)

    Oftedal, P.; Searle, A.G.

    1980-01-01

    Risks of serious hereditary damage in the first and second generations after low level radiation exposure and at equilibrium were calculated by using a doubling dose of 100 rem (based on experimental work with the mouse) and by considering separately the various categories of genic and chromosomal defect. Prenatal lethality was not included. It is estimated that after the exposure of a population of future parents to a collective dose of 1 million man-rem, about 125 extra cases of serious genetic ill health would appear in children and grandchildren. In all future generations, a total of about 320 cases is expected, provided the population remains of constant size. It is emphasised however, that a number of major assumptions have to be made in order to arrive at any overall genetic risk estimate, so that the confidence limits of these figures are bound to be wide. (author)

  12. What risk assessments of genetically modified organisms can learn from institutional analyses of public health risks.

    Science.gov (United States)

    Rajan, S Ravi; Letourneau, Deborah K

    2012-01-01

    The risks of genetically modified organisms (GMOs) are evaluated traditionally by combining hazard identification and exposure estimates to provide decision support for regulatory agencies. We question the utility of the classical risk paradigm and discuss its evolution in GMO risk assessment. First, we consider the problem of uncertainty, by comparing risk assessment for environmental toxins in the public health domain with genetically modified organisms in the environment; we use the specific comparison of an insecticide to a transgenic, insecticidal food crop. Next, we examine normal accident theory (NAT) as a heuristic to consider runaway effects of GMOs, such as negative community level consequences of gene flow from transgenic, insecticidal crops. These examples illustrate how risk assessments are made more complex and contentious by both their inherent uncertainty and the inevitability of failure beyond expectation in complex systems. We emphasize the value of conducting decision-support research, embracing uncertainty, increasing transparency, and building interdisciplinary institutions that can address the complex interactions between ecosystems and society. In particular, we argue against black boxing risk analysis, and for a program to educate policy makers about uncertainty and complexity, so that eventually, decision making is not the burden that falls upon scientists but is assumed by the public at large.

  13. What Risk Assessments of Genetically Modified Organisms Can Learn from Institutional Analyses of Public Health Risks

    Directory of Open Access Journals (Sweden)

    S. Ravi Rajan

    2012-01-01

    Full Text Available The risks of genetically modified organisms (GMOs are evaluated traditionally by combining hazard identification and exposure estimates to provide decision support for regulatory agencies. We question the utility of the classical risk paradigm and discuss its evolution in GMO risk assessment. First, we consider the problem of uncertainty, by comparing risk assessment for environmental toxins in the public health domain with genetically modified organisms in the environment; we use the specific comparison of an insecticide to a transgenic, insecticidal food crop. Next, we examine normal accident theory (NAT as a heuristic to consider runaway effects of GMOs, such as negative community level consequences of gene flow from transgenic, insecticidal crops. These examples illustrate how risk assessments are made more complex and contentious by both their inherent uncertainty and the inevitability of failure beyond expectation in complex systems. We emphasize the value of conducting decision-support research, embracing uncertainty, increasing transparency, and building interdisciplinary institutions that can address the complex interactions between ecosystems and society. In particular, we argue against black boxing risk analysis, and for a program to educate policy makers about uncertainty and complexity, so that eventually, decision making is not the burden that falls upon scientists but is assumed by the public at large.

  14. A Model for Understanding the Genetic Basis for Disparity in Prostate Cancer Risk

    Science.gov (United States)

    2017-10-01

    AWARD NUMBER: W81XWH-15-1-0529 TITLE: A Model for Understanding the Genetic Basis for Disparity in Prostate Cancer Risk PRINCIPAL INVESTIGATOR...AND SUBTITLE A Model for Understanding the Genetic Basis for Disparity in Prostate Cancer Risk 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-15-1...STATEMENT Approved for Public Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Prostate cancer is the most commonly diagnosed cancer in

  15. Genetic predisposition to an impaired metabolism of the branched chain amino acids and risk of type 2 diabetes: A Mendelian randomisation analysis

    OpenAIRE

    Lotta, LA; Scott, RA; Sharp, SJ; Burgess, S; Luan, J; Tillin, T; Schmidt, AF; Imamura, F; Stewart, ID; Perry, JRB; Marney, L; Koulman, A; Karoly, ED; Forouhi, NG; Sjögren, RJO

    2016-01-01

    $\\textbf{BACKGROUND}$: Higher circulating levels of the branched-chain amino acids (BCAAs; i.e., isoleucine, leucine, and valine) are strongly associated with higher type 2 diabetes risk, but it is not known whether this association is causal. We undertook large-scale human genetic analyses to address this question. $\\textbf{METHODS AND FINDINGS}$: Genome-wide studies of BCAA levels in 16,596 individuals revealed five genomic regions associated at genome-wide levels of significance (p < ...

  16. Genetic modifiers of menopausal hormone replacement therapy and breast cancer risk

    DEFF Research Database (Denmark)

    Rudolph, Anja; Hein, Rebecca; Lindström, Sara

    2013-01-01

    Women using menopausal hormone therapy (MHT) are at increased risk of developing breast cancer (BC). To detect genetic modifiers of the association between current use of MHT and BC risk, we conducted a meta-analysis of four genome-wide case-only studies followed by replication in 11 case...

  17. Multiobjective genetic algorithm approaches to project scheduling under risk

    OpenAIRE

    Kılıç, Murat; Kilic, Murat

    2003-01-01

    In this thesis, project scheduling under risk is chosen as the topic of research. Project scheduling under risk is defined as a biobjective decision problem and is formulated as a 0-1 integer mathematical programming model. In this biobjective formulation, one of the objectives is taken as the expected makespan minimization and the other is taken as the expected cost minimization. As the solution approach to this biobjective formulation genetic algorithm (GA) is chosen. After carefully invest...

  18. Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese.

    Science.gov (United States)

    Lubitz, Steven A; Lunetta, Kathryn L; Lin, Honghuang; Arking, Dan E; Trompet, Stella; Li, Guo; Krijthe, Bouwe P; Chasman, Daniel I; Barnard, John; Kleber, Marcus E; Dörr, Marcus; Ozaki, Kouichi; Smith, Albert V; Müller-Nurasyid, Martina; Walter, Stefan; Agarwal, Sunil K; Bis, Joshua C; Brody, Jennifer A; Chen, Lin Y; Everett, Brendan M; Ford, Ian; Franco, Oscar H; Harris, Tamara B; Hofman, Albert; Kääb, Stefan; Mahida, Saagar; Kathiresan, Sekar; Kubo, Michiaki; Launer, Lenore J; MacFarlane, Peter W; Magnani, Jared W; McKnight, Barbara; McManus, David D; Peters, Annette; Psaty, Bruce M; Rose, Lynda M; Rotter, Jerome I; Silbernagel, Guenther; Smith, Jonathan D; Sotoodehnia, Nona; Stott, David J; Taylor, Kent D; Tomaschitz, Andreas; Tsunoda, Tatsuhiko; Uitterlinden, Andre G; Van Wagoner, David R; Völker, Uwe; Völzke, Henry; Murabito, Joanne M; Sinner, Moritz F; Gudnason, Vilmundur; Felix, Stephan B; März, Winfried; Chung, Mina; Albert, Christine M; Stricker, Bruno H; Tanaka, Toshihiro; Heckbert, Susan R; Jukema, J Wouter; Alonso, Alvaro; Benjamin, Emelia J; Ellinor, Patrick T

    2014-04-01

    This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk. AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored. We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases). We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements. The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity. Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  19. Genetic influences on incidence and case-fatality of infectious disease.

    Directory of Open Access Journals (Sweden)

    Liselotte Petersen

    Full Text Available BACKGROUND: Family, twin and adoption studies suggest that genetic susceptibility contributes to familial aggregation of infectious diseases or to death from infections. We estimated genetic and shared environmental influences separately on the risk of acquiring an infection (incidence and on dying from it (case fatality. METHODS: Genetic influences were estimated by the association between rates of hospitalization for infections and between case-fatality rates of adoptees and their biological full- and half- siblings. Familial environmental influences were investigated in adoptees and their adoptive siblings. Among 14,425 non-familial adoptions, granted in Denmark during the period 1924-47, we selected 1,603 adoptees, who had been hospitalized for infections and/or died with infection between 1977 and 1993. Their siblings were considered predisposed to infection, and compared with non-predisposed siblings of randomly selected 1,348 adoptees alive in 1993 and not hospitalized for infections in the observation period. The risk ratios presented were based on a Cox regression model. RESULTS: Among 9971 identified siblings, 2829 had been hospitalised for infections. The risk of infectious disease was increased among predisposed compared with non-predisposed in both biological (1.18; 95% confidence limits 1.03-1.36 and adoptive siblings (1.23; 0.98-1.53. The risk of a fatal outcome of the infections was strongly increased (9.36; 2.94-29.8 in biological full siblings, but such associations were not observed for the biological half siblings or for the adoptive siblings. CONCLUSION: Risk of getting infections appears to be weakly influenced by both genetically determined susceptibility to infection and by family environment, whereas there appears to be a strong non-additive genetic influence on risk of fatal outcome.

  20. Omega-3 fatty acids and the genetic risk of early onset acute coronary syndrome.

    Science.gov (United States)

    Leung Yinko, S S L; Thanassoulis, G; Stark, K D; Avgil Tsadok, M; Engert, J C; Pilote, L

    2014-11-01

    Recent gene-environment interaction studies suggest that diet may influence an individual's genetic predisposition to cardiovascular risk. We evaluated whether omega-3 fatty acid intake may influence the risk for acute coronary syndrome (ACS) conferred by genetic polymorphisms among patients with early onset ACS. Our population consisted of 705 patients of white European descent enrolled in GENESIS-PRAXY, a multicenter cohort study of patients aged 18-55 years and hospitalized with ACS. We used a case-only design to investigate interactions between the omega-3 index (a validated biomarker of omega-3 fatty acid intake) and 30 single nucleotide polymorphisms (SNPs) robustly associated with ACS. We used logistic regression to assess the interaction between each SNP and the omega-3 index. Interaction was also assessed between the omega-3 index and a genetic risk score generated from the 30 SNPs. All models were adjusted for age and sex. An interaction for increased ACS risk was found between carriers of the chromosome 9p21 variant rs4977574 and low omega-3 index (OR 1.57, 95% CI 1.07-2.32, p = 0.02), but this was not significant after correction for multiple testing. Similar results were obtained in the adjusted model (OR 1.55, 95% CI 1.05-2.29, p = 0.03). We did not observe any interaction between the genetic risk score or any of the other SNPs and the omega-3 index. Our results suggest that omega-3 fatty acid intake may modify the genetic risk conferred by chromosome 9p21 variation in the development of early onset ACS and requires independent replication. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Genetic susceptibility loci, pesticide exposure and prostate cancer risk.

    Directory of Open Access Journals (Sweden)

    Stella Koutros

    Full Text Available Uncovering SNP (single nucleotide polymorphisms-environment interactions can generate new hypotheses about the function of poorly characterized genetic variants and environmental factors, like pesticides. We evaluated SNP-environment interactions between 30 confirmed prostate cancer susceptibility loci and 45 pesticides and prostate cancer risk in 776 cases and 1,444 controls in the Agricultural Health Study. We used unconditional logistic regression to estimate odds ratios (ORs and 95% confidence intervals (CIs. Multiplicative SNP-pesticide interactions were calculated using a likelihood ratio test. After correction for multiple tests using the False Discovery Rate method, two interactions remained noteworthy. Among men carrying two T alleles at rs2710647 in EH domain binding protein 1 (EHBP1 SNP, the risk of prostate cancer in those with high malathion use was 3.43 times those with no use (95% CI: 1.44-8.15 (P-interaction= 0.003. Among men carrying two A alleles at rs7679673 in TET2, the risk of prostate cancer associated with high aldrin use was 3.67 times those with no use (95% CI: 1.43, 9.41 (P-interaction= 0.006. In contrast, associations were null for other genotypes. Although additional studies are needed and the exact mechanisms are unknown, this study suggests known genetic susceptibility loci may modify the risk between pesticide use and prostate cancer.

  2. 'A low risk is still a risk': exploring women's attitudes towards genetic testing for breast cancer susceptibility in order to target disease prevention

    NARCIS (Netherlands)

    Henneman, L.; Timmermans, D. R.; Bouwman, C. M.; Cornel, M. C.; Meijers-Heijboer, H.

    2011-01-01

    Population breast cancer screening programs by mammography are offered to women based on age. It has been suggested that a screening program based on genetic risk profile could be more effective by targeting interventions at those at higher genetic risk. This study explores women's attitudes towards

  3. Obesity during childhood and adolescence increases susceptibility to multiple sclerosis after accounting for established genetic and environmental risk factors.

    Science.gov (United States)

    Gianfrancesco, Milena A; Acuna, Brigid; Shen, Ling; Briggs, Farren B S; Quach, Hong; Bellesis, Kalliope H; Bernstein, Allan; Hedstrom, Anna K; Kockum, Ingrid; Alfredsson, Lars; Olsson, Tomas; Schaefer, Catherine; Barcellos, Lisa F

    2014-01-01

    To investigate the association between obesity and multiple sclerosis (MS) while accounting for established genetic and environmental risk factors. Participants included members of Kaiser Permanente Medical Care Plan, Northern California Region (KPNC) (1235 MS cases and 697 controls). Logistic regression models were used to estimate odds ratios (ORs) with 95% confidence intervals (95% CI). Body mass index (BMI) or body size was the primary predictor of each model. Both incident and prevalent MS cases were studied. In analyses stratified by gender, being overweight at ages 10 and 20 were associated with MS in females (pchildhood and adolescence obesity confer increased risk of MS in females beyond established heritable and environmental risk factors. Strong evidence for a dose-effect of BMI in 20s and MS was observed. The magnitude of BMI association with MS is as large as other known MS risk factors. Copyright © 2014 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

  4. The Decision-Making Process of Genetically At-Risk Couples Considering Preimplantation Genetic Diagnosis: Initial Findings from a Grounded Theory Study

    Science.gov (United States)

    Hershberger, Patricia E.; Gallo, Agatha M.; Kavanaugh, Karen; Olshansky, Ellen; Schwartz, Alan; Tur-Kaspa, Ilan

    2012-01-01

    Exponential growth in genomics has led to public and private initiatives worldwide that have dramatically increased the number of procreative couples who are aware of their ability to transmit genetic disorders to their future children. Understanding how couples process the meaning of being genetically at risk for their procreative life lags far behind the advances in genomic and reproductive sciences. Moreover, society, policy makers, and clinicians are not aware of the experiences and nuances involved when modern couples are faced with using Preimplantation Genetic Diagnosis (PGD). The purpose of this study was to discover the decision-making process of genetically at-risk couples as they decide whether to use PGD to prevent the transmission of known single-gene or sex-linked genetic disorders to their children. A qualitative, grounded theory design guided the study in which 22 couples (44 individual partners) from the USA, who were actively considering PGD, participated. Couples were recruited from June 2009 to May 2010 from the Internet and from a large PGD center and a patient newsletter. In-depth semi-structured interviews were completed with each individual partner within the couple dyad, separate from their respective partner. We discovered that couples move through four phases (Identify, Contemplate, Resolve, Engage) of a complex, dynamic, and iterative decision-making process where multiple, sequential decisions are made. In the Identify phase, couples acknowledge the meaning of their at-risk status. Parenthood and reproductive options are explored in the Contemplate phase, where 41% of couples remained for up to 36 months before moving into the Resolve phase. In Resolve, one of three decisions about PGD use is reached, including: Accepting, Declining, or Oscillating. Actualizing decisions occur in the Engage phase. Awareness of the decision-making process among genetically at-risk couples provides foundational work for understanding critical processes

  5. Genetic variants in IL-6/JAK/STAT3 pathway and the risk of CRC.

    Science.gov (United States)

    Wang, Shuwei; Zhang, Weidong

    2016-05-01

    Interleukin (IL)-6 and the downstream Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway have previously been reported to be important in the development of colorectal cancer (CRC), and several studies have shown the relationship between the polymorphisms of related genes in this pathway with the risk of CRC. However, the findings of these related studies are inconsistent. Moreover, there has no systematic review and meta-analysis to evaluate the relationship between genetic variants in IL-6/JAK/STAT3 pathway and CRC susceptibility. Hence, we conducted a meta-analysis to explore the relationship between polymorphisms in IL-6/JAK/STAT3 pathway genes and CRC risk. Eighteen eligible studies with a total of 13,795 CRC cases and 18,043 controls were identified by searching PubMed, Web of Science, Embase, and the Cochrane Library databases for the period up to September 15, 2015. Odds ratios (ORs) and their 95 % confidence intervals (CIs) were used to calculate the strength of the association. Our results indicated that IL-6 genetic variants in allele additive model (OR = 1.05, 95 % CI = 1.00, 1.09) and JAK2 genetic variants (OR = 1.40, 95 % CI = 1.15, 1.65) in genotype recessive model were significantly associated with CRC risk. Moreover, the pooled data revealed that IL-6 rs1800795 polymorphism significantly increased the risk of CRC in allele additive model in Europe (OR = 1.07, 95 % CI = 1.01, 1.14). In conclusion, the present findings indicate that IL-6 and JAK2 genetic variants are associated with the increased risk of CRC while STAT3 genetic variants not. We need more well-designed clinical studies covering more countries and population to definitively establish the association between genetic variants in IL-6/JAK/STAT3 pathway and CRC susceptibility.

  6. Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials.

    Science.gov (United States)

    Mega, J L; Stitziel, N O; Smith, J G; Chasman, D I; Caulfield, M; Devlin, J J; Nordio, F; Hyde, C; Cannon, C P; Sacks, F; Poulter, N; Sever, P; Ridker, P M; Braunwald, E; Melander, O; Kathiresan, S; Sabatine, M S

    2015-06-06

    Genetic variants have been associated with the risk of coronary heart disease. In this study, we tested whether or not a composite of these variants could ascertain the risk of both incident and recurrent coronary heart disease events and identify those individuals who derive greater clinical benefit from statin therapy. A community-based cohort study (the Malmo Diet and Cancer Study) and four randomised controlled trials of both primary prevention (JUPITER and ASCOT) and secondary prevention (CARE and PROVE IT-TIMI 22) with statin therapy, comprising a total of 48,421 individuals and 3477 events, were included in these analyses. We studied the association of a genetic risk score based on 27 genetic variants with incident or recurrent coronary heart disease, adjusting for traditional clinical risk factors. We then investigated the relative and absolute risk reductions in coronary heart disease events with statin therapy stratified by genetic risk. We combined data from the different studies using a meta-analysis. When individuals were divided into low (quintile 1), intermediate (quintiles 2-4), and high (quintile 5) genetic risk categories, a significant gradient in risk for incident or recurrent coronary heart disease was shown. Compared with the low genetic risk category, the multivariable-adjusted hazard ratio for coronary heart disease for the intermediate genetic risk category was 1·34 (95% CI 1·22-1·47, pgenetic risk category was 1·72 (1·55-1·92, pgenetic risk categories. Similarly, we noted greater absolute risk reductions in those individuals in higher genetic risk categories (p=0·0101), resulting in a roughly threefold decrease in the number needed to treat to prevent one coronary heart disease event in the primary prevention trials. Specifically, in the primary prevention trials, the number needed to treat to prevent one such event in 10 years was 66 in people at low genetic risk, 42 in those at intermediate genetic risk, and 25 in those at high

  7. Skin cancer concerns and genetic risk information-seeking in primary care.

    Science.gov (United States)

    Hay, J; Kaphingst, K A; Baser, R; Li, Y; Hensley-Alford, S; McBride, C M

    2012-01-01

    Genomic testing for common genetic variants associated with skin cancer risk could enable personalized risk feedback to motivate skin cancer screening and sun protection. In a cross-sectional study, we investigated whether skin cancer cognitions and behavioral factors, sociodemographics, family factors, and health information-seeking were related to perceived importance of learning about how (a) genes and (b) health habits affect personal health risks using classification and regression trees (CART). The sample (n = 1,772) was collected in a large health maintenance organization as part of the Multiplex Initiative, ranged in age from 25-40, was 53% female, 41% Caucasian, and 59% African-American. Most reported that they placed somewhat to very high importance on learning about how genes (79%) and health habits (88%) affect their health risks. Social influence actors were associated with information-seeking about genes and health habits. Awareness of family history was associated with importance of health habit, but not genetic, information-seeking. The investment of family and friends in health promotion may be a primary motivator for prioritizing information-seeking about how genes and health habits affect personal health risks and may contribute to the personal value, or personal utility, of risk information. Individuals who seek such risk information may be receptive to interventions aimed to maximize the social implications of healthy lifestyle change to reduce their health risks. Copyright © 2011 S. Karger AG, Basel.

  8. Prediction of breast cancer risk based on profiling with common genetic variants

    DEFF Research Database (Denmark)

    Mavaddat, Nasim; Pharoah, Paul D P; Michailidou, Kyriaki

    2015-01-01

    BACKGROUND: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking. M...

  9. Prediction of breast cancer risk based on profiling with common genetic variants

    NARCIS (Netherlands)

    N. Mavaddat (Nasim); P.D.P. Pharoah (Paul); K. Michailidou (Kyriaki); J.P. Tyrer (Jonathan); M.N. Brook (Mark N.); M.K. Bolla (Manjeet); Q. Wang (Qing); J. Dennis (Joe); A.M. Dunning (Alison); M. Shah (Mitul); R.N. Luben (Robert); J. Brown (Judith); S.E. Bojesen (Stig); B.G. Nordestgaard (Børge); S.F. Nielsen (Sune F.); H. Flyger (Henrik); K. Czene (Kamila); H. Darabi (Hatef); M. Eriksson (Mikael); J. Peto (Julian); I. dos Santos Silva (Isabel); F. Dudbridge (Frank); N. Johnson (Nichola); M.K. Schmidt (Marjanka); A. Broeks (Annegien); S. Verhoef; E.J. Rutgers (Emiel J.); A.J. Swerdlow (Anthony ); A. Ashworth (Alan); N. Orr (Nick); M. Schoemaker (Minouk); J.D. Figueroa (Jonine); S.J. Chanock (Stephen); L.A. Brinton (Louise); J. Lissowska (Jolanta); F.J. Couch (Fergus); J.E. Olson (Janet); C. Vachon (Celine); V.S. Pankratz (Shane); D. Lambrechts (Diether); H. Wildiers (Hans); C. van Ongeval (Chantal); E. van Limbergen (Erik); V. Kristensen (Vessela); G. Grenaker Alnæs (Grethe); S. Nord (Silje); A.-L. Borresen-Dale (Anne-Lise); H. Nevanlinna (Heli); T.A. Muranen (Taru); K. Aittomäki (Kristiina); C. Blomqvist (Carl); J. Chang-Claude (Jenny); A. Rudolph (Anja); P. Seibold (Petra); D. Flesch-Janys (Dieter); P.A. Fasching (Peter); L. Haeberle (Lothar); A.B. Ekici (Arif); M.W. Beckmann (Matthias); B. Burwinkel (Barbara); F. Marme (Federick); A. Schneeweiss (Andreas); C. Sohn (Christof); A. Trentham-Dietz (Amy); P. Newcomb (Polly); L. Titus (Linda); K.M. Egan (Kathleen M.); D. Hunter (David); S. Lindstrom (Stephen); R. Tamimi (Rulla); P. Kraft (Peter); N. Rahman (Nazneen); C. Turnbull (Clare); A. Renwick (Anthony); S. Seal (Sheila); J. Li (Jingmei); J. Liu (Jianjun); M.K. Humphreys (Manjeet); J. Benítez (Javier); M.P. Zamora (Pilar); J.I. Arias Pérez (José Ignacio); P. Menéndez (Primitiva); A. Jakubowska (Anna); J. Lubinski (Jan); K. Jaworska-Bieniek (Katarzyna); K. Durda (Katarzyna); N.V. Bogdanova (Natalia); N.N. Antonenkova (Natalia); T. Dörk (Thilo); H. Anton-Culver (Hoda); S.L. Neuhausen (Susan); A. Ziogas (Argyrios); L. Bernstein (Leslie); P. Devilee (Peter); R.A.E.M. Tollenaar (Rob); C.M. Seynaeve (Caroline); C.J. van Asperen (Christi); A. Cox (Angela); S.S. Cross (Simon); M.W.R. Reed (Malcolm); E.K. Khusnutdinova (Elza); M. Bermisheva (Marina); D. Prokofyeva (Darya); Z. Takhirova (Zalina); A. Meindl (Alfons); R.K. Schmutzler (Rita); C. Sutter (Christian); R. Yang (Rongxi); P. Schürmann (Peter); M. Bremer (Michael); H. Christiansen (Hans); T.-W. Park-Simon; P. Hillemanns (Peter); P. Guénel (Pascal); T. Truong (Thérèse); F. Menegaux (Florence); M. Sanchez (Marie); P. Radice (Paolo); P. Peterlongo (Paolo); S. Manoukian (Siranoush); V. Pensotti (Valeria); J. Hopper (John); H. Tsimiklis (Helen); C. Apicella (Carmel); M.C. Southey (Melissa); H. Brauch (Hiltrud); T. Brüning (Thomas); Y.-D. Ko (Yon-Dschun); A.J. Sigurdson (Alice); M.M. Doody (Michele M.); U. Hamann (Ute); D. Torres (Diana); H.U. Ulmer (Hans); A. Försti (Asta); E.J. Sawyer (Elinor); I.P. Tomlinson (Ian); M. Kerin (Michael); N. Miller (Nicola); I.L. Andrulis (Irene); J.A. Knight (Julia); G. Glendon (Gord); A. Marie Mulligan (Anna); G. Chenevix-Trench (Georgia); R. Balleine (Rosemary); G.G. Giles (Graham); R.L. Milne (Roger); C.A. McLean (Catriona Ann); A. Lindblom (Annika); S. Margolin (Sara); C.A. Haiman (Christopher); B.E. Henderson (Brian); F. Schumacher (Fredrick); L. Le Marchand (Loic); U. Eilber (Ursula); S. Wang-Gohrke (Shan); M.J. Hooning (Maartje); A. Hollestelle (Antoinette); A.M.W. van den Ouweland (Ans); L.B. Koppert (Lisa); J. Carpenter (Jane); C. Clarke (Christine); R.J. Scott (Rodney J.); A. Mannermaa (Arto); V. Kataja (Vesa); V-M. Kosma (Veli-Matti); J.M. Hartikainen (J.); H. Brenner (Hermann); V. Arndt (Volker); C. Stegmaier (Christa); A. Karina Dieffenbach (Aida); R. Winqvist (Robert); K. Pykäs (Katri); A. Jukkola-Vuorinen (Arja); M. Grip (Mervi); K. Offit (Kenneth); J. Vijai (Joseph); M. Robson (Mark); R. Rau-Murthy (Rohini); M. Dwek (Miriam); R. Swann (Ruth); K. Annie Perkins (Katherine); M.S. Goldberg (Mark); F. Labrèche (France); M. Dumont (Martine); D. Eccles (Diana); W. Tapper (William); M. Rafiq (Meena); E.M. John (Esther M.); A.S. Whittemore (Alice); S. Slager (Susan); D. Yannoukakos (Drakoulis); A.E. Toland (Amanda); S. Yao (Song); W. Zheng (Wei); S.L. Halverson (Sandra L.); A. González-Neira (Anna); G. Pita (Guillermo); M. Rosario Alonso; N. Álvarez (Nuria); D. Herrero (Daniel); D.C. Tessier (Daniel C.); D. Vincent (Daniel); F. Bacot (Francois); C. Luccarini (Craig); C. Baynes (Caroline); S. Ahmed (Shahana); M. Maranian (Melanie); S. Healey (Sue); J. Simard (Jacques); P. Hall (Per); D.F. Easton (Douglas); M. García-Closas (Montserrat)

    2015-01-01

    textabstractBackground: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is

  10. Epigenomic strategies at the interface of genetic and environmental risk factors for autism.

    Science.gov (United States)

    LaSalle, Janine M

    2013-07-01

    Autism spectrum disorders (ASD) have been increasing in prevalence over the last two decades, primarily because of increased awareness and diagnosis. However, autism is clearly a complex human genetic disorder that involves interactions between genes and environment. Epigenetic mechanisms, such as DNA methylation, act at the interface of genetic and environmental risk and protective factors. Advancements in genome-wide sequencing has broadened the view of the human methylome and revealed the organization of the human genome into large-scale methylation domains that footprint over neurologically important genes involved in embryonic development. Future integrative epigenomic analyses of genetic risk factors with environmental exposures and methylome analyses are expected to be important for understanding the complex etiology of ASD.

  11. Convergent synaptic and circuit substrates underlying autism genetic risks.

    Science.gov (United States)

    McGee, Aaron; Li, Guohui; Lu, Zhongming; Qiu, Shenfeng

    2014-02-01

    There has been a surge of diagnosis of autism spectrum disorders (ASD) over the past decade. While large, high powered genome screening studies of children with ASD have identified numerous genetic risk factors, research efforts to understanding how each of these risk factors contributes to the development autism has met with limited success. Revealing the mechanisms by which these genetic risk factors affect brain development and predispose a child to autism requires mechanistic understanding of the neurobiological changes underlying this devastating group of developmental disorders at multifaceted molecular, cellular and system levels. It has been increasingly clear that the normal trajectory of neurodevelopment is compromised in autism, in multiple domains as much as aberrant neuronal production, growth, functional maturation, patterned connectivity, and balanced excitation and inhibition of brain networks. Many autism risk factors identified in humans have been now reconstituted in experimental mouse models to allow mechanistic interrogation of the biological role of the risk gene. Studies utilizing these mouse models have revealed that underlying the enormous heterogeneity of perturbed cellular events, mechanisms directing synaptic and circuit assembly may provide a unifying explanation for the pathophysiological changes and behavioral endophenotypes seen in autism, although synaptic perturbations are far from being the only alterations relevant for ASD. In this review, we discuss synaptic and circuit abnormalities obtained from several prevalent mouse models, particularly those reflecting syndromic forms of ASD that are caused by single gene perturbations. These compiled results reveal that ASD risk genes contribute to proper signaling of the developing gene networks that maintain synaptic and circuit homeostasis, which is fundamental to normal brain development.

  12. Strong influence of El Niño Southern Oscillation on flood risk around the world

    Science.gov (United States)

    Ward, Philip J.; Jongman, Brenden; Kummu, Matti; Dettinger, Michael D.; Sperna Weiland, Frederiek C.; Winsemius, Hessel C.

    2014-01-01

    El Niño Southern Oscillation (ENSO) is the most dominant interannual signal of climate variability and has a strong influence on climate over large parts of the world. In turn, it strongly influences many natural hazards (such as hurricanes and droughts) and their resulting socioeconomic impacts, including economic damage and loss of life. However, although ENSO is known to influence hydrology in many regions of the world, little is known about its influence on the socioeconomic impacts of floods (i.e., flood risk). To address this, we developed a modeling framework to assess ENSO’s influence on flood risk at the global scale, expressed in terms of affected population and gross domestic product and economic damages. We show that ENSO exerts strong and widespread influences on both flood hazard and risk. Reliable anomalies of flood risk exist during El Niño or La Niña years, or both, in basins spanning almost half (44%) of Earth’s land surface. Our results show that climate variability, especially from ENSO, should be incorporated into disaster-risk analyses and policies. Because ENSO has some predictive skill with lead times of several seasons, the findings suggest the possibility to develop probabilistic flood-risk projections, which could be used for improved disaster planning. The findings are also relevant in the context of climate change. If the frequency and/or magnitude of ENSO events were to change in the future, this finding could imply changes in flood-risk variations across almost half of the world’s terrestrial regions. PMID:25331867

  13. Strong influence of El Niño Southern Oscillation on flood risk around the world

    Science.gov (United States)

    Ward, Philip J.; Jongman, B; Kummu, M.; Dettinger, Mike; Sperna Weiland, F.C; Winsemius, H.C

    2014-01-01

    El Niño Southern Oscillation (ENSO) is the most dominant interannual signal of climate variability and has a strong influence on climate over large parts of the world. In turn, it strongly influences many natural hazards (such as hurricanes and droughts) and their resulting socioeconomic impacts, including economic damage and loss of life. However, although ENSO is known to influence hydrology in many regions of the world, little is known about its influence on the socioeconomic impacts of floods (i.e., flood risk). To address this, we developed a modeling framework to assess ENSO’s influence on flood risk at the global scale, expressed in terms of affected population and gross domestic product and economic damages. We show that ENSO exerts strong and widespread influences on both flood hazard and risk. Reliable anomalies of flood risk exist during El Niño or La Niña years, or both, in basins spanning almost half (44%) of Earth’s land surface. Our results show that climate variability, especially from ENSO, should be incorporated into disaster-risk analyses and policies. Because ENSO has some predictive skill with lead times of several seasons, the findings suggest the possibility to develop probabilistic flood-risk projections, which could be used for improved disaster planning. The findings are also relevant in the context of climate change. If the frequency and/or magnitude of ENSO events were to change in the future, this finding could imply changes in flood-risk variations across almost half of the world’s terrestrial regions.

  14. Ethnic background and genetic variation in the evaluation of cancer risk: a systematic review.

    Science.gov (United States)

    Jing, Lijun; Su, Li; Ring, Brian Z

    2014-01-01

    The clinical use of genetic variation in the evaluation of cancer risk is expanding, and thus understanding how determinants of cancer susceptibility identified in one population can be applied to another is of growing importance. However there is considerable debate on the relevance of ethnic background in clinical genetics, reflecting both the significance and complexity of genetic heritage. We address this via a systematic review of reported associations with cancer risk for 82 markers in 68 studies across six different cancer types, comparing association results between ethnic groups and examining linkage disequilibrium between risk alleles and nearby genetic loci. We find that the relevance of ethnic background depends on the question. If asked whether the association of variants with disease risk is conserved across ethnic boundaries, we find that the answer is yes, the majority of markers show insignificant variability in association with cancer risk across ethnic groups. However if the question is whether a significant association between a variant and cancer risk is likely to reproduce, the answer is no, most markers do not validate in an ethnic group other than the discovery cohort's ancestry. This lack of reproducibility is not attributable to studies being inadequately populated due to low allele frequency in other ethnic groups. Instead, differences in local genomic structure between ethnic groups are associated with the strength of association with cancer risk and therefore confound interpretation of the implied physiologic association tracked by the disease allele. This suggest that a biological association for cancer risk alleles may be broadly consistent across ethnic boundaries, but reproduction of a clinical study in another ethnic group is uncommon, in part due to confounding genomic architecture. As clinical studies are increasingly performed globally this has important implications for how cancer risk stratifiers should be studied and employed.

  15. Ethnic Background and Genetic Variation in the Evaluation of Cancer Risk: A Systematic Review

    Science.gov (United States)

    Jing, Lijun; Su, Li; Ring, Brian Z.

    2014-01-01

    The clinical use of genetic variation in the evaluation of cancer risk is expanding, and thus understanding how determinants of cancer susceptibility identified in one population can be applied to another is of growing importance. However there is considerable debate on the relevance of ethnic background in clinical genetics, reflecting both the significance and complexity of genetic heritage. We address this via a systematic review of reported associations with cancer risk for 82 markers in 68 studies across six different cancer types, comparing association results between ethnic groups and examining linkage disequilibrium between risk alleles and nearby genetic loci. We find that the relevance of ethnic background depends on the question. If asked whether the association of variants with disease risk is conserved across ethnic boundaries, we find that the answer is yes, the majority of markers show insignificant variability in association with cancer risk across ethnic groups. However if the question is whether a significant association between a variant and cancer risk is likely to reproduce, the answer is no, most markers do not validate in an ethnic group other than the discovery cohort’s ancestry. This lack of reproducibility is not attributable to studies being inadequately populated due to low allele frequency in other ethnic groups. Instead, differences in local genomic structure between ethnic groups are associated with the strength of association with cancer risk and therefore confound interpretation of the implied physiologic association tracked by the disease allele. This suggest that a biological association for cancer risk alleles may be broadly consistent across ethnic boundaries, but reproduction of a clinical study in another ethnic group is uncommon, in part due to confounding genomic architecture. As clinical studies are increasingly performed globally this has important implications for how cancer risk stratifiers should be studied and

  16. Ethnic background and genetic variation in the evaluation of cancer risk: a systematic review.

    Directory of Open Access Journals (Sweden)

    Lijun Jing

    Full Text Available The clinical use of genetic variation in the evaluation of cancer risk is expanding, and thus understanding how determinants of cancer susceptibility identified in one population can be applied to another is of growing importance. However there is considerable debate on the relevance of ethnic background in clinical genetics, reflecting both the significance and complexity of genetic heritage. We address this via a systematic review of reported associations with cancer risk for 82 markers in 68 studies across six different cancer types, comparing association results between ethnic groups and examining linkage disequilibrium between risk alleles and nearby genetic loci. We find that the relevance of ethnic background depends on the question. If asked whether the association of variants with disease risk is conserved across ethnic boundaries, we find that the answer is yes, the majority of markers show insignificant variability in association with cancer risk across ethnic groups. However if the question is whether a significant association between a variant and cancer risk is likely to reproduce, the answer is no, most markers do not validate in an ethnic group other than the discovery cohort's ancestry. This lack of reproducibility is not attributable to studies being inadequately populated due to low allele frequency in other ethnic groups. Instead, differences in local genomic structure between ethnic groups are associated with the strength of association with cancer risk and therefore confound interpretation of the implied physiologic association tracked by the disease allele. This suggest that a biological association for cancer risk alleles may be broadly consistent across ethnic boundaries, but reproduction of a clinical study in another ethnic group is uncommon, in part due to confounding genomic architecture. As clinical studies are increasingly performed globally this has important implications for how cancer risk stratifiers should be

  17. Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis.

    OpenAIRE

    Lotta, L. A.; Scott, R. A.; Sharp, S. J.; Burgess, S.; Luan, J.; Tillin, T.; Schmidt, A. F.; Imamura, F.; Stewart, I. D.; Perry, J. R.; Marney, L.; Koulman, A.; Karoly, E. D.; Forouhi, N. G.; Sjögren, R. J.

    2016-01-01

    BACKGROUND: Higher circulating levels of the branched-chain amino acids (BCAAs; i.e., isoleucine, leucine, and valine) are strongly associated with higher type 2 diabetes risk, but it is not known whether this association is causal. We undertook large-scale human genetic analyses to address this question. METHODS AND FINDINGS: Genome-wide studies of BCAA levels in 16,596 individuals revealed five genomic regions associated at genome-wide levels of significance (p < 5 × 10-8). The strongest si...

  18. Perceptions of genetic discrimination among people at risk for Huntington’s disease: a cross sectional survey

    Science.gov (United States)

    Bombard, Yvonne; Veenstra, Gerry; Friedman, Jan M; Creighton, Susan; Currie, Lauren; Paulsen, Jane S; Bottorff, Joan L

    2009-01-01

    Objective To assess the nature and prevalence of genetic discrimination experienced by people at risk for Huntington’s disease who had undergone genetic testing or remained untested. Design Cross sectional, self reported survey. Setting Seven genetics and movement disorders clinics servicing rural and urban communities in Canada. Participants 233 genetically tested and untested asymptomatic people at risk for Huntington’s disease (response rate 80%): 167 underwent testing (83 had the Huntington’s disease mutation, 84 did not) and 66 chose not to be tested. Main outcome measures Self reported experiences of genetic discrimination and related psychological distress based on family history or genetic test results. Results Discrimination was reported by 93 respondents (39.9%). Reported experiences occurred most often in insurance (29.2%), family (15.5%), and social (12.4%) settings. There were few reports of discrimination in employment (6.9%), health care (8.6%), or public sector settings (3.9%). Although respondents who were aware that they carried the Huntington’s disease mutation reported the highest levels of discrimination, participation in genetic testing was not associated with increased levels of genetic discrimination. Family history of Huntington’s disease, rather than the result of genetic testing, was the main reason given for experiences of genetic discrimination. Psychological distress was associated with genetic discrimination (PGenetic discrimination was commonly reported by people at risk for Huntington’s disease and was a source of psychological distress. Family history, and not genetic testing, was the major reason for genetic discrimination. PMID:19509425

  19. Characterizing genetic syndromes involved in cancer and radiogenic cancer risk

    International Nuclear Information System (INIS)

    Unrau, P.; Doerffer, K.

    1998-01-01

    The COG project 2806A (1995), reviewed the On-line Mendelian Inheritance in Man (OMIM) database of genetic syndromes to identify those syndromes, genes, and DNA sequences implicated in some way in the cancer process, and especially in radiogenic cancer risk. The current report describes a recent update of the survey in light of two years of further progress in the Human Genome project, and is intended to supply a comprehensive list of those genetic syndromes, genes, DNA sequences and map locations that define genes likely to be involved in cancer risk. Of the 8203 syndromes in OMIM in 1997 June, 814 are associated, even if marginally, with cancer. Of the 814 syndromes so linked, 672 have been mapped to a chromosome, and 476 have been mapped to a chromosome and had a DNA sequence associated with their messenger RNA (or cDNA) sequences. In addition, 35 syndromes have sequences not associated with map locations, and the remaining 107 have neither been mapped nor sequenced. We supply the list of the various genetic syndromes sorted by chromosome location and by OMIM descriptor, together with all the associated but unmapped and unsequenced syndromes. (author)

  20. Characterizing genetic syndromes involved in cancer and radiogenic cancer risk

    Energy Technology Data Exchange (ETDEWEB)

    Unrau, P; Doerffer, K

    1998-01-01

    The COG project 2806A (1995), reviewed the On-line Mendelian Inheritance in Man (OMIM) database of genetic syndromes to identify those syndromes, genes, and DNA sequences implicated in some way in the cancer process, and especially in radiogenic cancer risk. The current report describes a recent update of the survey in light of two years of further progress in the Human Genome project, and is intended to supply a comprehensive list of those genetic syndromes, genes, DNA sequences and map locations that define genes likely to be involved in cancer risk. Of the 8203 syndromes in OMIM in 1997 June, 814 are associated, even if marginally, with cancer. Of the 814 syndromes so linked, 672 have been mapped to a chromosome, and 476 have been mapped to a chromosome and had a DNA sequence associated with their messenger RNA (or cDNA) sequences. In addition, 35 syndromes have sequences not associated with map locations, and the remaining 107 have neither been mapped nor sequenced. We supply the list of the various genetic syndromes sorted by chromosome location and by OMIM descriptor, together with all the associated but unmapped and unsequenced syndromes. (author) 1 tab., 4 figs.

  1. Impact of genetically modified organisms on aquatic environments: Review of available data for the risk assessment.

    Science.gov (United States)

    Pott, Antonia; Otto, Mathias; Schulz, Ralf

    2018-09-01

    The aquatic environment is strongly connected to the surrounding agricultural landscapes, which regularly serve as sources of stressors such as agrochemicals. Genetically modified crops, which are cultivated on a large scale in many countries, may also act as stressors. Despite the commercial use of genetically modified organisms (GMOs) for over 20years, their impact on the aquatic environment came into focus only 10years ago. We present the status quo of the available scientific data in order to provide an input for informed aquatic risk assessment of GMOs. We could identify only 39 publications, including 84 studies, dealing with GMOs in the aquatic environment, and our analysis shows substantial knowledge gaps. The available information is restricted to a small number of crop plants, traits, events, and test organisms. The analysis of effect studies reveals that only a narrow range of organisms has been tested and that studies on combinatorial actions of stressors are virtually absent. The analysis of fate studies shows that many aspects, such as the fate of leached toxins, degradation of plant material, and distribution of crop residues in the aquatic habitat, are insufficiently investigated. Together with these research needs, we identify standardization of test methods as an issue of high priority, both for research and risk assessment needed for GMO regulation. Copyright © 2018 Elsevier B.V. All rights reserved.

  2. Memory Resilience to Alzheimer's Genetic Risk: Sex Effects in Predictor Profiles.

    Science.gov (United States)

    McDermott, Kirstie L; McFall, G Peggy; Andrews, Shea J; Anstey, Kaarin J; Dixon, Roger A

    2017-10-01

    Apolipoprotein E (APOE) ɛ4 and Clusterin (CLU) C alleles are risk factors for Alzheimer's disease (AD) and episodic memory (EM) decline. Memory resilience occurs when genetically at-risk adults perform at high and sustained levels. We investigated whether (a) memory resilience to AD genetic risk is predicted by biological and other risk markers and (b) the prediction profiles vary by sex and AD risk variant. Using a longitudinal sample of nondemented adults (n = 642, aged 53-95) we focused on memory resilience (over 9 years) to 2 AD risk variants (APOE, CLU). Growth mixture models classified resilience. Random forest analysis, stratified by sex, tested the predictive importance of 22 nongenetic risk factors from 5 domains (n = 24-112). For both sexes, younger age, higher education, stronger grip, and everyday novel cognitive activity predicted memory resilience. For women, 9 factors from functional, health, mobility, and lifestyle domains were also predictive. For men, only fewer depressive symptoms was an additional important predictor. The prediction profiles were similar for APOE and CLU. Although several factors predicted resilience in both sexes, a greater number applied only to women. Sex-specific mechanisms and intervention targets are implied. © The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  3. Identification of a functional genetic variant at 16q12.1 for breast cancer risk: results from the Asia Breast Cancer Consortium.

    Directory of Open Access Journals (Sweden)

    Jirong Long

    2010-06-01

    Full Text Available Genetic factors play an important role in the etiology of breast cancer. We carried out a multi-stage genome-wide association (GWA study in over 28,000 cases and controls recruited from 12 studies conducted in Asian and European American women to identify genetic susceptibility loci for breast cancer. After analyzing 684,457 SNPs in 2,073 cases and 2,084 controls in Chinese women, we evaluated 53 SNPs for fast-track replication in an independent set of 4,425 cases and 1,915 controls of Chinese origin. Four replicated SNPs were further investigated in an independent set of 6,173 cases and 6,340 controls from seven other studies conducted in Asian women. SNP rs4784227 was consistently associated with breast cancer risk across all studies with adjusted odds ratios (95% confidence intervals of 1.25 (1.20-1.31 per allele (P = 3.2 x 10(-25 in the pooled analysis of samples from all Asian samples. This SNP was also associated with breast cancer risk among European Americans (per allele OR = 1.19, 95% CI = 1.09-1.31, P = 1.3 x 10(-4, 2,797 cases and 2,662 controls. SNP rs4784227 is located at 16q12.1, a region identified previously for breast cancer risk among Europeans. The association of this SNP with breast cancer risk remained highly statistically significant in Asians after adjusting for previously-reported SNPs in this region. In vitro experiments using both luciferase reporter and electrophoretic mobility shift assays demonstrated functional significance of this SNP. These results provide strong evidence implicating rs4784227 as a functional causal variant for breast cancer in the locus 16q12.1 and demonstrate the utility of conducting genetic association studies in populations with different genetic architectures.

  4. BRCA genetic counseling among at-risk Latinas in New York City: new beliefs shape new generation.

    Science.gov (United States)

    Sussner, Katarina M; Edwards, Tiffany; Villagra, Cristina; Rodriguez, M Carina; Thompson, Hayley S; Jandorf, Lina; Valdimarsdottir, Heiddis B

    2015-02-01

    Despite the life-saving information that genetic counseling can provide for women at hereditary breast and/or ovarian cancer (HBOC) risk, Latinas disproportionately underuse such services. Understanding Latinas' beliefs and attitudes about BRCA genetic counseling may be the key to better health promotion within this underserved, at-risk group. We conducted 12 focus groups (N = 54) with at-risk Latina women in New York City, followed by 30 in-depth interviews among a subset of the focus group women. Both were professionally transcribed, translated where applicable and data analysis was completed by two coders trained in qualitative methods. Results revealed personal and community knowledge about BRCA genetic counseling was relatively low, although women felt largely positive about counseling. The main motivator to undergo genetic counseling was concerns about learning family members' cancer status, while the main barrier was competing demands. Generational differences were apparent, with younger women (approximately machismo, fatalismo, destino) to undergoing genetic counseling. Participants were largely enthusiastic about educational efforts to increase awareness of genetic counseling among Latinos. Revealing the beliefs and attitudes of underserved Latinas may help shape culturally appropriate educational materials and promotion programs to increase BRCA genetic counseling uptake within this underrepresented community.

  5. The impact of genetic counselling on risk perception and mental health in women with a family history of breast cancer.

    Science.gov (United States)

    Watson, M; Lloyd, S; Davidson, J; Meyer, L; Eeles, R; Ebbs, S; Murday, V

    1999-02-01

    The present study investigated: (1) perception of genetic risk and, (2) the psychological effects of genetic counselling in women with a family history of breast cancer. Using a prospective design, with assessment pre- and post-genetic counselling at clinics and by postal follow-up at 1, 6 and 12 months, attenders at four South London genetic clinics were assessed. Participants included 282 women with a family history of breast cancer. Outcome was measured in terms of mental health, cancer-specific distress and risk perception. High levels of cancer-specific distress were found pre-genetic counselling, with 28% of participants reporting that they worried about breast cancer 'frequently or constantly' and 18% that worry about breast cancer was 'a severe or definite problem'. Following genetic counselling, levels of cancer-specific distress were unchanged. General mental health remained unchanged over time (33% psychiatric cases detected pre-genetic counselling, 27% at 12 months after genetic counselling). Prior to their genetics consultation, participants showed poor knowledge of their lifetime risk of breast cancer since there was no association between their perceived lifetime risk (when they were asked to express this as a 1 in x odds ratio) and their actual risk, when the latter was calculated by the geneticist at the clinic using the CASH model. In contrast, women were more accurate about their risk of breast cancer pre-genetic counselling when this was assessed in broad categorical terms (i.e. very much lower/very much higher than the average woman) with a significant association between this rating and the subsequently calculated CASH risk figure (P = 0.001). Genetic counselling produced a modest shift in the accuracy of perceived lifetime risk, expressed as an odds ratio, which was maintained at 12 months' follow-up. A significant minority failed to benefit from genetic counselling; 77 women continued to over-estimate their risk and maintain high levels of

  6. Genetic risk of rhegmatogenous retinal detachment a familial aggregation study

    NARCIS (Netherlands)

    S.L. Go (Sioe Lie); C. Hoyng (Carel); C.C.W. Klaver (Caroline)

    2005-01-01

    textabstractObjective: To investigate the magnitude of the genetic risk of nonsyndromic rhegmatogenous retinal detachments (RRDs) in a familial aggregation study. Design: Two hundred three consecutive patients with RRD and 461 controls without RRD were ascertained at the Department of Ophthalmology

  7. Are markers of inflammation more strongly associated with risk for fatal than for nonfatal vascular events?

    Directory of Open Access Journals (Sweden)

    Naveed Sattar

    2009-06-01

    Full Text Available BACKGROUND: Circulating inflammatory markers may more strongly relate to risk of fatal versus nonfatal cardiovascular disease (CVD events, but robust prospective evidence is lacking. We tested whether interleukin (IL-6, C-reactive protein (CRP, and fibrinogen more strongly associate with fatal compared to nonfatal myocardial infarction (MI and stroke. METHODS AND FINDINGS: In the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER, baseline inflammatory markers in up to 5,680 men and women aged 70-82 y were related to risk for endpoints; nonfatal CVD (i.e., nonfatal MI and nonfatal stroke [n = 672], fatal CVD (n = 190, death from other CV causes (n = 38, and non-CVD mortality (n = 300, over 3.2-y follow-up. Elevations in baseline IL-6 levels were significantly (p = 0.0009; competing risks model analysis more strongly associated with fatal CVD (hazard ratio [HR] for 1 log unit increase in IL-6 1.75, 95% confidence interval [CI] 1.44-2.12 than with risk of nonfatal CVD (1.17, 95% CI 1.04-1.31, in analyses adjusted for treatment allocation. The findings were consistent in a fully adjusted model. These broad trends were similar for CRP and, to a lesser extent, for fibrinogen. The results were also similar in placebo and statin recipients (i.e., no interaction. The C-statistic for fatal CVD using traditional risk factors was significantly (+0.017; p<0.0001 improved by inclusion of IL-6 but not so for nonfatal CVD events (p = 0.20. CONCLUSIONS: In PROSPER, inflammatory markers, in particular IL-6 and CRP, are more strongly associated with risk of fatal vascular events than nonfatal vascular events. These novel observations may have important implications for better understanding aetiology of CVD mortality, and have potential clinical relevance.

  8. Precision Oncology and Genetic Risk Information: Exploring Patients' Preferences and Responses

    Science.gov (United States)

    Dr. Jada Hamilton is an Assistant Member at Memorial Sloan Kettering Cancer Center, as well as an Assistant Attending Psychologist in the Behavioral Sciences Service, Department of Psychiatry and Behavioral Sciences and in the Clinical Genetics Service, Department of Medicine at Memorial Hospital in New York, New York.  She leads a program of research at the intersection of behavioral science, cancer prevention, and genomics, with the goal of translating advances in genetic and genomic medicine into improved cancer care that is of high quality, aligned with patient preferences, and ultimately improves public health.  Dr. Hamilton is also currently leading a study to assess how patients and their families respond to inherited risk information that is revealed as part of tumor sequencing (funded through a Mentored Research Scholar Grant from the American Cancer Society), as well as studies to evaluate alternative models for offering genetic counseling and testing to patients with cancer, and to examine the effects of novel breast cancer genetic risk feedback on patients’ decision-making, psychological, and behavioral outcomes. Prior to joining the faculty of Memorial Sloan Kettering, Dr. Hamilton received a BA in Genetics and Psychology from Ohio Wesleyan University (2004), an MA and PhD in Social and Health Psychology from Stony Brook University (2006, 2009), and an MPH from the Mailman School of Public Health at Columbia University (2010).  She also completed a postdoctoral fellowship as part of the National Cancer Institute’s Cancer Prevention Fellowship Program.

  9. Genetic Differences in the Immediate Transcriptome Response to Stress Predict Risk-Related Brain Function and Psychiatric Disorders

    Science.gov (United States)

    Arloth, Janine; Bogdan, Ryan; Weber, Peter; Frishman, Goar; Menke, Andreas; Wagner, Klaus V.; Balsevich, Georgia; Schmidt, Mathias V.; Karbalai, Nazanin; Czamara, Darina; Altmann, Andre; Trümbach, Dietrich; Wurst, Wolfgang; Mehta, Divya; Uhr, Manfred; Klengel, Torsten; Erhardt, Angelika; Carey, Caitlin E.; Conley, Emily Drabant; Ripke, Stephan; Wray, Naomi R.; Lewis, Cathryn M.; Hamilton, Steven P.; Weissman, Myrna M.; Breen, Gerome; Byrne, Enda M.; Blackwood, Douglas H.R.; Boomsma, Dorret I.; Cichon, Sven; Heath, Andrew C.; Holsboer, Florian; Lucae, Susanne; Madden, Pamela A.F.; Martin, Nicholas G.; McGuffin, Peter; Muglia, Pierandrea; Noethen, Markus M.; Penninx, Brenda P.; Pergadia, Michele L.; Potash, James B.; Rietschel, Marcella; Lin, Danyu; Müller-Myhsok, Bertram; Shi, Jianxin; Steinberg, Stacy; Grabe, Hans J.; Lichtenstein, Paul; Magnusson, Patrik; Perlis, Roy H.; Preisig, Martin; Smoller, Jordan W.; Stefansson, Kari; Uher, Rudolf; Kutalik, Zoltan; Tansey, Katherine E.; Teumer, Alexander; Viktorin, Alexander; Barnes, Michael R.; Bettecken, Thomas; Binder, Elisabeth B.; Breuer, René; Castro, Victor M.; Churchill, Susanne E.; Coryell, William H.; Craddock, Nick; Craig, Ian W.; Czamara, Darina; De Geus, Eco J.; Degenhardt, Franziska; Farmer, Anne E.; Fava, Maurizio; Frank, Josef; Gainer, Vivian S.; Gallagher, Patience J.; Gordon, Scott D.; Goryachev, Sergey; Gross, Magdalena; Guipponi, Michel; Henders, Anjali K.; Herms, Stefan; Hickie, Ian B.; Hoefels, Susanne; Hoogendijk, Witte; Hottenga, Jouke Jan; Iosifescu, Dan V.; Ising, Marcus; Jones, Ian; Jones, Lisa; Jung-Ying, Tzeng; Knowles, James A.; Kohane, Isaac S.; Kohli, Martin A.; Korszun, Ania; Landen, Mikael; Lawson, William B.; Lewis, Glyn; MacIntyre, Donald; Maier, Wolfgang; Mattheisen, Manuel; McGrath, Patrick J.; McIntosh, Andrew; McLean, Alan; Middeldorp, Christel M.; Middleton, Lefkos; Montgomery, Grant M.; Murphy, Shawn N.; Nauck, Matthias; Nolen, Willem A.; Nyholt, Dale R.; O’Donovan, Michael; Oskarsson, Högni; Pedersen, Nancy; Scheftner, William A.; Schulz, Andrea; Schulze, Thomas G.; Shyn, Stanley I.; Sigurdsson, Engilbert; Slager, Susan L.; Smit, Johannes H.; Stefansson, Hreinn; Steffens, Michael; Thorgeirsson, Thorgeir; Tozzi, Federica; Treutlein, Jens; Uhr, Manfred; van den Oord, Edwin J.C.G.; Van Grootheest, Gerard; Völzke, Henry; Weilburg, Jeffrey B.; Willemsen, Gonneke; Zitman, Frans G.; Neale, Benjamin; Daly, Mark; Levinson, Douglas F.; Sullivan, Patrick F.; Ruepp, Andreas; Müller-Myhsok, Bertram; Hariri, Ahmad R.; Binder, Elisabeth B.

    2015-01-01

    Summary Depression risk is exacerbated by genetic factors and stress exposure; however, the biological mechanisms through which these factors interact to confer depression risk are poorly understood. One putative biological mechanism implicates variability in the ability of cortisol, released in response to stress, to trigger a cascade of adaptive genomic and non-genomic processes through glucocorticoid receptor (GR) activation. Here, we demonstrate that common genetic variants in long-range enhancer elements modulate the immediate transcriptional response to GR activation in human blood cells. These functional genetic variants increase risk for depression and co-heritable psychiatric disorders. Moreover, these risk variants are associated with inappropriate amygdala reactivity, a transdiagnostic psychiatric endophenotype and an important stress hormone response trigger. Network modeling and animal experiments suggest that these genetic differences in GR-induced transcriptional activation may mediate the risk for depression and other psychiatric disorders by altering a network of functionally related stress-sensitive genes in blood and brain. Video Abstract PMID:26050039

  10. A genetic fuzzy system for unstable angina risk assessment.

    Science.gov (United States)

    Dong, Wei; Huang, Zhengxing; Ji, Lei; Duan, Huilong

    2014-02-18

    Unstable Angina (UA) is widely accepted as a critical phase of coronary heart disease with patients exhibiting widely varying risks. Early risk assessment of UA is at the center of the management program, which allows physicians to categorize patients according to the clinical characteristics and stratification of risk and different prognosis. Although many prognostic models have been widely used for UA risk assessment in clinical practice, a number of studies have highlighted possible shortcomings. One serious drawback is that existing models lack the ability to deal with the intrinsic uncertainty about the variables utilized. In order to help physicians refine knowledge for the stratification of UA risk with respect to vagueness in information, this paper develops an intelligent system combining genetic algorithm and fuzzy association rule mining. In detail, it models the input information's vagueness through fuzzy sets, and then applies a genetic fuzzy system on the acquired fuzzy sets to extract the fuzzy rule set for the problem of UA risk assessment. The proposed system is evaluated using a real data-set collected from the cardiology department of a Chinese hospital, which consists of 54 patient cases. 9 numerical patient features and 17 categorical patient features that appear in the data-set are selected in the experiments. The proposed system made the same decisions as the physician in 46 (out of a total of 54) tested cases (85.2%). By comparing the results that are obtained through the proposed system with those resulting from the physician's decision, it has been found that the developed model is highly reflective of reality. The proposed system could be used for educational purposes, and with further improvements, could assist and guide young physicians in their daily work.

  11. The association between a genetic risk score for allergy and the risk of developing allergies in childhood-Results of the WHISTLER cohort

    NARCIS (Netherlands)

    Arabkhazaeli, Ali; Ahmadizar, Fariba; Leusink, Maarten; Arets, Hubertus G. M.; Raaijmakers, Jan A. M.; Uiterwaal, Cuno S. P. M.; van der Ent, Cornelis K.; Maitland-van der Zee, Anke-Hilse; Vijverberg, Susanne J. H.

    2018-01-01

    Background: Several genetic variants have been associated with the susceptibility to allergic disease in adults, but it remains unclear whether these genetic variants are also associated with the onset of allergic disease early in life. The aim of this study was to develop a genetic risk score (GRS)

  12. Simulated Annealing Genetic Algorithm Based Schedule Risk Management of IT Outsourcing Project

    Directory of Open Access Journals (Sweden)

    Fuqiang Lu

    2017-01-01

    Full Text Available IT outsourcing is an effective way to enhance the core competitiveness for many enterprises. But the schedule risk of IT outsourcing project may cause enormous economic loss to enterprise. In this paper, the Distributed Decision Making (DDM theory and the principal-agent theory are used to build a model for schedule risk management of IT outsourcing project. In addition, a hybrid algorithm combining simulated annealing (SA and genetic algorithm (GA is designed, namely, simulated annealing genetic algorithm (SAGA. The effect of the proposed model on the schedule risk management problem is analyzed in the simulation experiment. Meanwhile, the simulation results of the three algorithms GA, SA, and SAGA show that SAGA is the most superior one to the other two algorithms in terms of stability and convergence. Consequently, this paper provides the scientific quantitative proposal for the decision maker who needs to manage the schedule risk of IT outsourcing project.

  13. What can be offered to couples at (possibly) increased genetic risk?

    OpenAIRE

    Read, Andrew P.; Donnai, Dian

    2012-01-01

    We review the reasons why a couple might seek specialist genetic counselling about a possible reproductive risk and the options available to them. Most commonly, the couple will be concerned about the risk of recurrence of a medical condition that has already occurred in the family. Sometimes, the increased risk may come from their ethnicity or because of a consanguineous marriage, rather than because any problem has occurred previously. The geneticist must identify the exact nature of any pr...

  14. New developments in genetics of myositis.

    Science.gov (United States)

    Rothwell, Simon; Lamb, Janine A; Chinoy, Hector

    2016-11-01

    This article reviews the advances that have been made in our understanding of the genetics of the idiopathic inflammatory myopathies (IIM) in the past 2 years, with a particular focus on polymyositis, dermatomyositis and inclusion body myositis. Two large human leukocyte antigen (HLA) imputation studies have confirmed a strong association with the 8.1 ancestral haplotype in clinical subgroups of myositis and suggest multiple independent associations on this haplotype. Risk in these genes may be due to specific amino acid positions within the peptide-binding grooves of HLA molecules. A large genetic study in 2566 IIM patients revealed associations such as PTPN22, STAT4, UBE2L3 and BLK, which overlap with risk variants reported in other seropositive autoimmune diseases. There is also evidence of different genetic architectures in clinical subgroups of IIM. Candidate gene studies in the Japanese and Chinese populations have replicated previous IIM associations which suggest common aetiology between ethnicities. International collaborations have facilitated large genetic studies in IIM that have revealed much about the genetics of this rare complex disease both within the HLA region and genome-wide. Future approaches, such as sequencing and trans-ethnic meta-analyses, will advance our knowledge of IIM genetics.

  15. Identification of Hotspots of Genetic Risk for Type 2 Diabetes Using GIS Methods

    Science.gov (United States)

    BACKGROUND: Having the ability to scan the entire country for potential "hotspots" with increased risk of developing chronic diseases due to various environmental, demographic, and genetic susceptibility factors may inform risk management decisions and enable better env...

  16. Associations between genetic risk, functional brain network organization and neuroticism

    NARCIS (Netherlands)

    Servaas, Michelle N.; Geerligs, Linda; Bastiaansen, Jojanneke A.; Renken, Remco J.; Marsman, Jan-Bernard C.; Nolte, Ilja M.; Ormel, Johan; Aleman, Andre; Riese, Harriette

    2017-01-01

    Neuroticism and genetic variation in the serotonin-transporter (SLC6A4) and catechol-O-methyltransferase (COMT) gene are risk factors for psychopathology. Alterations in the functional integration and segregation of neural circuits have recently been found in individuals scoring higher on

  17. Genetic risk of rhegmatogenous retinal detachment: a familial aggregation study.

    NARCIS (Netherlands)

    Go, S.L.; Hoyng, C.B.; Klaver, C.C.W.

    2005-01-01

    OBJECTIVE: To investigate the magnitude of the genetic risk of nonsyndromic rhegmatogenous retinal detachments (RRDs) in a familial aggregation study. DESIGN: Two hundred three consecutive patients with RRD and 461 controls without RRD were ascertained at the Department of Ophthalmology of the

  18. Genetic toxicology at the crossroads-from qualitative hazard evaluation to quantitative risk assessment.

    Science.gov (United States)

    White, Paul A; Johnson, George E

    2016-05-01

    Applied genetic toxicology is undergoing a transition from qualitative hazard identification to quantitative dose-response analysis and risk assessment. To facilitate this change, the Health and Environmental Sciences Institute (HESI) Genetic Toxicology Technical Committee (GTTC) sponsored a workshop held in Lancaster, UK on July 10-11, 2014. The event included invited speakers from several institutions and the contents was divided into three themes-1: Point-of-departure Metrics for Quantitative Dose-Response Analysis in Genetic Toxicology; 2: Measurement and Estimation of Exposures for Better Extrapolation to Humans and 3: The Use of Quantitative Approaches in Genetic Toxicology for human health risk assessment (HHRA). A host of pertinent issues were discussed relating to the use of in vitro and in vivo dose-response data, the development of methods for in vitro to in vivo extrapolation and approaches to use in vivo dose-response data to determine human exposure limits for regulatory evaluations and decision-making. This Special Issue, which was inspired by the workshop, contains a series of papers that collectively address topics related to the aforementioned themes. The Issue includes contributions that collectively evaluate, describe and discuss in silico, in vitro, in vivo and statistical approaches that are facilitating the shift from qualitative hazard evaluation to quantitative risk assessment. The use and application of the benchmark dose approach was a central theme in many of the workshop presentations and discussions, and the Special Issue includes several contributions that outline novel applications for the analysis and interpretation of genetic toxicity data. Although the contents of the Special Issue constitutes an important step towards the adoption of quantitative methods for regulatory assessment of genetic toxicity, formal acceptance of quantitative methods for HHRA and regulatory decision-making will require consensus regarding the

  19. PCSK9 genetic variants and risk of type 2 diabetes

    DEFF Research Database (Denmark)

    Schmidt, Amand F; Swerdlow, Daniel I; Holmes, Michael V

    2017-01-01

    used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using...... diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk. METHODS: In this mendelian randomisation study, we...... a standardised analysis plan, meta-analyses, and weighted gene-centric scores. FINDINGS: Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL...

  20. Association of Genetic Risk for Schizophrenia With Nonparticipation Over Time in a Population-Based Cohort Study.

    Science.gov (United States)

    Martin, Joanna; Tilling, Kate; Hubbard, Leon; Stergiakouli, Evie; Thapar, Anita; Davey Smith, George; O'Donovan, Michael C; Zammit, Stanley

    2016-06-15

    Progress has recently been made in understanding the genetic basis of schizophrenia and other psychiatric disorders. Longitudinal studies are complicated by participant dropout, which could be related to the presence of psychiatric problems and associated genetic risk. We tested whether common genetic variants implicated in schizophrenia were associated with study nonparticipation among 7,867 children and 7,850 mothers from the Avon Longitudinal Study of Parents and Children (ALSPAC; 1991-2007), a longitudinal population cohort study. Higher polygenic risk scores for schizophrenia were consistently associated with noncompletion of questionnaires by study mothers and children and nonattendance at data collection throughout childhood and adolescence (ages 1-15 years). These associations persisted after adjustment for other potential correlates of nonparticipation. Results suggest that persons at higher genetic risk for schizophrenia are likely to be underrepresented in cohort studies, which will underestimate risk of this and related psychiatric, cognitive, and behavioral phenotypes in the population. Statistical power to detect associations with these phenotypes will be reduced, while analyses of schizophrenia-related phenotypes as outcomes may be biased by the nonrandom missingness of these phenotypes, even if multiple imputation is used. Similarly, in complete-case analyses, collider bias may affect associations between genetic risk and other factors associated with missingness. © The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.

  1. Evolutionary Perspectives on Genetic and Environmental Risk Factors for Psychiatric Disorders.

    Science.gov (United States)

    Keller, Matthew C

    2018-05-07

    Evolutionary medicine uses evolutionary theory to help elucidate why humans are vulnerable to disease and disorders. I discuss two different types of evolutionary explanations that have been used to help understand human psychiatric disorders. First, a consistent finding is that psychiatric disorders are moderately to highly heritable, and many, such as schizophrenia, are also highly disabling and appear to decrease Darwinian fitness. Models used in evolutionary genetics to understand why genetic variation exists in fitness-related traits can be used to understand why risk alleles for psychiatric disorders persist in the population. The usual explanation for species-typical adaptations-natural selection-is less useful for understanding individual differences in genetic risk to disorders. Rather, two other types of models, mutation-selection-drift and balancing selection, offer frameworks for understanding why genetic variation in risk to psychiatric (and other) disorders exists, and each makes predictions that are now testable using whole-genome data. Second, species-typical capacities to mount reactions to negative events are likely to have been crafted by natural selection to minimize fitness loss. The pain reaction to tissue damage is almost certainly such an example, but it has been argued that the capacity to experience depressive symptoms such as sadness, anhedonia, crying, and fatigue in the face of adverse life situations may have been crafted by natural selection as well. I review the rationale and strength of evidence for this hypothesis. Evolutionary hypotheses of psychiatric disorders are important not only for offering explanations for why psychiatric disorders exist, but also for generating new, testable hypotheses and understanding how best to design studies and analyze data.

  2. The risk for cancer and genetic abnormalities after radioiodine treatment of hyperthyroidism

    International Nuclear Information System (INIS)

    Reiners, C.

    1997-01-01

    According to recent studies, the risk for thyroid cancer is not increased after radioiodine treatment in patients with hyperthyroidism. Only the risk of cancer of the stomach seems to be increased slightly in patents treated with I-131 because of functional autonomy. However, the risk for gastric cancer is not increased after higher activities of I-131 because of thyroid cancer. There is no increased risk for genetic abnormalities after radioiodine treatment of hyperthyroidism. (orig.) [de

  3. Association of genetic susceptibility variants for type 2 diabetes with breast cancer risk in women of European ancestry.

    Science.gov (United States)

    Zhao, Zhiguo; Wen, Wanqing; Michailidou, Kyriaki; Bolla, Manjeet K; Wang, Qin; Zhang, Ben; Long, Jirong; Shu, Xiao-Ou; Schmidt, Marjanka K; Milne, Roger L; García-Closas, Montserrat; Chang-Claude, Jenny; Lindstrom, Sara; Bojesen, Stig E; Ahsan, Habibul; Aittomäki, Kristiina; Andrulis, Irene L; Anton-Culver, Hoda; Arndt, Volker; Beckmann, Matthias W; Beeghly-Fadiel, Alicia; Benitez, Javier; Blomqvist, Carl; Bogdanova, Natalia V; Børresen-Dale, Anne-Lise; Brand, Judith; Brauch, Hiltrud; Brenner, Hermann; Burwinkel, Barbara; Cai, Qiuyin; Casey, Graham; Chenevix-Trench, Georgia; Couch, Fergus J; Cox, Angela; Cross, Simon S; Czene, Kamila; Dörk, Thilo; Dumont, Martine; Fasching, Peter A; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Flyger, Henrik; Fostira, Florentia; Gammon, Marilie; Giles, Graham G; Guénel, Pascal; Haiman, Christopher A; Hamann, Ute; Harrington, Patricia; Hartman, Mikael; Hooning, Maartje J; Hopper, John L; Jakubowska, Anna; Jasmine, Farzana; John, Esther M; Johnson, Nichola; Kabisch, Maria; Khan, Sofia; Kibriya, Muhammad; Knight, Julia A; Kosma, Veli-Matti; Kriege, Mieke; Kristensen, Vessela; Le Marchand, Loic; Lee, Eunjung; Li, Jingmei; Lindblom, Annika; Lophatananon, Artitaya; Luben, Robert; Lubinski, Jan; Malone, Kathleen E; Mannermaa, Arto; Manoukian, Siranoush; Margolin, Sara; Marme, Frederik; McLean, Catriona; Meijers-Heijboer, Hanne; Meindl, Alfons; Miao, Hui; Muir, Kenneth; Neuhausen, Susan L; Nevanlinna, Heli; Neven, Patrick; Olson, Janet E; Perkins, Barbara; Peterlongo, Paolo; Phillips, Kelly-Anne; Pylkäs, Katri; Rudolph, Anja; Santella, Regina; Sawyer, Elinor J; Schmutzler, Rita K; Schoemaker, Minouk; Shah, Mitul; Shrubsole, Martha; Southey, Melissa C; Swerdlow, Anthony J; Toland, Amanda E; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; Ursin, Giske; Van Der Luijt, Rob B; Verhoef, Senno; Wang-Gohrke, Shan; Whittemore, Alice S; Winqvist, Robert; Pilar Zamora, M; Zhao, Hui; Dunning, Alison M; Simard, Jacques; Hall, Per; Kraft, Peter; Pharoah, Paul; Hunter, David; Easton, Douglas F; Zheng, Wei

    2016-05-01

    Type 2 diabetes (T2D) has been reported to be associated with an elevated risk of breast cancer. It is unclear, however, whether this association is due to shared genetic factors. We constructed a genetic risk score (GRS) using risk variants from 33 known independent T2D susceptibility loci and evaluated its relation to breast cancer risk using the data from two consortia, including 62,328 breast cancer patients and 83,817 controls of European ancestry. Unconditional logistic regression models were used to derive adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) to measure the association of breast cancer risk with T2D GRS or T2D-associated genetic risk variants. Meta-analyses were conducted to obtain summary ORs across all studies. The T2D GRS was not found to be associated with breast cancer risk, overall, by menopausal status, or for estrogen receptor positive or negative breast cancer. Three T2D associated risk variants were individually associated with breast cancer risk after adjustment for multiple comparisons using the Bonferroni method (at p associated with the risk of both T2D and breast cancer. However, overall genetic susceptibility to T2D may not be related to breast cancer risk.

  4. Invited commentary: genetic variants and individual- and societal-level risk factors.

    Science.gov (United States)

    Coughlin, Steven S

    2010-01-01

    Over the past decade, leading epidemiologists have noted the importance of social factors in studying and understanding the distribution and determinants of disease in human populations; but to what extent are epidemiologic studies integrating genetic information and other biologic variables with information about individual-level risk factors and group-level or societal factors related to the broader residential, behavioral, or cultural context? There remains a need to consider ways to integrate genetic information with social and contextual information in epidemiologic studies, partly to combat the overemphasis on the importance of genetic factors as determinants of disease in human populations. Even in genome-wide association studies of coronary heart disease and other common complex diseases, only a small proportion of heritability is explained by the genetic variants identified to date. It is possible that familial clustering due to genetic factors has been overestimated and that important environmental or social influences (acting alone or in combination with genetic variants) have been overlooked. The accompanying article by Bressler et al. (Am J Epidemiol. 2010;171(1):14-23) highlights some of these important issues.

  5. Shared Genetic Risk Factors of Intracranial, Abdominal, and Thoracic Aneurysms

    NARCIS (Netherlands)

    van 't Hof, Femke N G; Ruigrok, Ynte M; Lee, Cue Hyunkyu; Ripke, Stephan; Anderson, Graig; de Andrade, Mariza; Baas, Annette F; Blankensteijn, Jan D; Böttinger, Erwin P; Bown, Matthew J; Broderick, Joseph; Bijlenga, Philippe; Carrell, David S; Crawford, Dana C; Crosslin, David R; Ebeling, Christian; Eriksson, Johan G; Fornage, Myriam; Foroud, Tatiana; von Und Zu Fraunberg, Mikael; Friedrich, Christoph M; Gaál, Emília I; Gottesman, Omri; Guo, Dong-Chuan; Harrison, Seamus C; Hernesniemi, Juha; Hofman, Albert; Inoue, Ituro; Jääskeläinen, Juha E; Jones, Gregory T; Kiemeney, Lambertus A L M; Kivisaari, Riku; Ko, Nerissa; Koskinen, Seppo; Kubo, Michiaki; Kullo, Iftikhar J; Kuivaniemi, Helena; Kurki, Mitja I; Laakso, Aki; Lai, Dongbing; Leal, Suzanne M; Lehto, Hanna; LeMaire, Scott A; Low, Siew-Kee; Malinowski, Jennifer; McCarty, Catherine A; Milewicz, Dianna M; Mosley, Thomas H; Nakamura, Yusuke; Nakaoka, Hirofumi; Niemelä, Mika; Pacheco, Jennifer; Peissig, Peggy L; Pera, Joanna; Rasmussen-Torvik, Laura; Ritchie, Marylyn D; Rivadeneira, Fernando; van Rij, Andre M; Santos-Cortez, Regie Lyn P; Saratzis, Athanasios; Slowik, Agnieszka; Takahashi, Atsushi; Tromp, Gerard; Uitterlinden, André G; Verma, Shefali S; Vermeulen, Sita H; Wang, Gao T; Han, Buhm; Rinkel, Gabriël J E; de Bakker, Paul I W

    2016-01-01

    BACKGROUND: Intracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (TAAs) all have a familial predisposition. Given that aneurysm types are known to co-occur, we hypothesized that there may be shared genetic risk factors for IAs, AAAs, and TAAs. METHODS AND

  6. Shared genetic risk factors of intracranial, abdominal, and thoracic aneurysms

    NARCIS (Netherlands)

    van 't Hof, Femke N G; Ruigrok, Ynte M; Lee, Cue Hyunkyu; Ripke, Stephan; Anderson, Graig; de Andrade, Mariza; Baas, Annette F; Blankensteijn, Jan D; Böttinger, Erwin P; Bown, Matthew J; Broderick, Joseph; Bijlenga, Philippe; Carrell, David S; Crawford, Dana C; Crosslin, David R; Ebeling, Christian; Eriksson, Johan G; Fornage, Myriam; Foroud, Tatiana; von Und Zu Fraunberg, Mikael; Friedrich, Christoph M; Gaál, Emília I; Gottesman, Omri; Guo, Dong-Chuan; Harrison, Seamus C; Hernesniemi, Juha; Hofman, Albert; Inoue, Ituro; Jääskeläinen, Juha E; Jones, Gregory T; Kiemeney, Lambertus A L M; Kivisaari, Riku; Ko, Nerissa; Koskinen, Seppo; Kubo, Michiaki; Kullo, Iftikhar J; Kuivaniemi, Helena; Kurki, Mitja I; Laakso, Aki; Lai, Dongbing; Leal, Suzanne M; Lehto, Hanna; LeMaire, Scott A; Low, Siew-Kee; Malinowski, Jennifer; McCarty, Catherine A; Milewicz, Dianna M; Mosley, Thomas H; Nakamura, Yusuke; Nakaoka, Hirofumi; Niemelä, Mika; Pacheco, Jennifer; Peissig, Peggy L; Pera, Joanna; Rasmussen-Torvik, Laura; Ritchie, Marylyn D; Rivadeneira, Fernando; van Rij, Andre M; Santos-Cortez, Regie Lyn P; Saratzis, Athanasios; Slowik, Agnieszka; Takahashi, Atsushi; Tromp, Gerard; Uitterlinden, André G; Verma, Shefali S; Vermeulen, Sita H; Wang, Gao T; Han, Buhm; Rinkel, Gabriël J E; de Bakker, Paul I W

    2016-01-01

    Background--Intracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (TAAs) all have a familial predisposition. Given that aneurysm types are known to co-occur, we hypothesized that there may be shared genetic risk factors for IAs, AAAs, and TAAs. Methods and

  7. Uniform risk spectra of strong earthquake ground motion: NEQRISK

    International Nuclear Information System (INIS)

    Lee, V.W.; Trifunac, M.D.

    1987-01-01

    The concept of uniform risk spectra of Anderson and Trifunac (1977) has been generalized to include (1) more refined description of earthquake source zones, (2) the uncertainties in estimating seismicity parameters a and b in log 10 N = a - bM, (3) to consider uncertainties in estimation of maximum earthquake size in each source zone, and to (4) include the most recent results on empirical scaling of strong motion amplitudes at a site. Examples of using to new NEQRISK program are presented and compared with the corresponding case studies of Anderson and Trifunac (1977). The organization of the computer program NEQRISK is also briefly described

  8. Assessment of genetic risk of exposure resulted from X-ray examination of women of the reproductive age

    International Nuclear Information System (INIS)

    Strel'nikova, N.K.

    1989-01-01

    On the basis of the available data an evaluation of genetic radiation risk during roentgenologic examination of women of the reproductive age is presented. It is demonstrated that the degree of genetic risk depends on woman's age at the moment of the roentgenologic examination and the amount of the gonadal dose. Identification of the high-risk exposed populations has been substantiated

  9. What do men understand about lifetime risk following genetic testing? The effect of context and numeracy.

    Science.gov (United States)

    Rolison, Jonathan J; Hanoch, Yaniv; Miron-Shatz, Talya

    2012-07-01

    Genetic testing for gene mutations associated with specific cancers provides an opportunity for early detection, surveillance, and intervention (Smith, Cokkinides, & Brawley, 2008). Lifetime risk estimates provided by genetic testing refer to the risk of developing a specific disease within one's lifetime, and evidence suggests that this is important for the medical choices people make, as well as their future family and financial plans. The present studies tested whether adult men understand the lifetime risks of prostate cancer informed by genetic testing. In 2 experiments, adult men were asked to interpret the lifetime risk information provided in statements about risks of prostate cancer. Statement format was manipulated such that the most appropriate interpretation of risk statements referred to an absolute risk of cancer in experiment 1 and a relative risk in experiment 2. Experiment 1 revealed that few men correctly interpreted the lifetime risks of cancer when these refer to an absolute risk of cancer, and numeracy levels positively predicted correct responding. The proportion of correct responses was greatly improved in experiment 2 when the most appropriate interpretation of risk statements referred instead to a relative rather than an absolute risk, and numeracy levels were less involved. Understanding of lifetime risk information is often poor because individuals incorrectly believe that these refer to relative rather than absolute risks of cancer.

  10. Common Genetic Variants Found in HLA and KIR Immune Genes in Autism Spectrum Disorder

    OpenAIRE

    Torres, Anthony R.; Sweeten, Thayne L.; Johnson, Randall C.; Odell, Dennis; Westover, Jonna B.; Bray-Ward, Patricia; Ward, David C.; Davies, Christopher J.; Thomas, Aaron J.; Croen, Lisa A.; Benson, Michael

    2016-01-01

    The common variant - common disease hypothesis was proposed to explain diseases with strong inheritance. This model suggests that a genetic disease is the result of the combination of several common genetic variants. Common genetic variants are described as a 5% frequency differential between diseased versus matched control populations. This theory was recently supported by an epidemiology paper stating that about 50% of genetic risk for autism resides in common variants. However, rare va...

  11. Interaction between common breast cancer susceptibility variants, genetic ancestry, and nongenetic risk factors in Hispanic women.

    Science.gov (United States)

    Fejerman, Laura; Stern, Mariana C; John, Esther M; Torres-Mejía, Gabriela; Hines, Lisa M; Wolff, Roger K; Baumgartner, Kathy B; Giuliano, Anna R; Ziv, Elad; Pérez-Stable, Eliseo J; Slattery, Martha L

    2015-11-01

    Most genetic variants associated with breast cancer risk have been discovered in women of European ancestry, and only a few genome-wide association studies (GWAS) have been conducted in minority groups. This research disparity persists in post-GWAS gene-environment interaction analyses. We tested the interaction between hormonal and lifestyle risk factors for breast cancer, and ten GWAS-identified SNPs among 2,107 Hispanic women with breast cancer and 2,587 unaffected controls, to gain insight into a previously reported gene by ancestry interaction in this population. We estimated genetic ancestry with a set of 104 ancestry-informative markers selected to discriminate between Indigenous American and European ancestry. We used logistic regression models to evaluate main effects and interactions. We found that the rs13387042-2q35(G/A) SNP was associated with breast cancer risk only among postmenopausal women who never used hormone therapy [per A allele OR: 0.94 (95% confidence intervals, 0.74-1.20), 1.20 (0.94-1.53), and 1.49 (1.28-1.75) for current, former, and never hormone therapy users, respectively, Pinteraction 0.002] and premenopausal women who breastfed >12 months [OR: 1.01 (0.72-1.42), 1.19 (0.98-1.45), and 1.69 (1.26-2.26) for never, 12 months breastfeeding, respectively, Pinteraction 0.014]. The correlation between genetic ancestry, hormone replacement therapy use, and breastfeeding behavior partially explained a previously reported interaction between a breast cancer risk variant and genetic ancestry in Hispanic women. These results highlight the importance of understanding the interplay between genetic ancestry, genetics, and nongenetic risk factors and their contribution to breast cancer risk. ©2015 American Association for Cancer Research.

  12. Genetic risks associated with radiation exposures during space flight

    International Nuclear Information System (INIS)

    Grahn, D.

    1983-01-01

    Although the genetic risks of space radiation do not pose a significant hazard to the general population, the risks may be very important to the individual astronaut. The present paper summarizes some experimental results on the induction of dominant lethal mutations and chromosomal damage in the first generation which may be used in the prediction of the genetic risks of radiation exposures of space crews. Young adult male mice were exposed to single, weekly and continuous doses of gamma rays, neutrons in single doses and weekly exposures and continuous doses of Pu-239 alpha particles. Evaluation of fetal survival rates in females mated to the exposed males shows the mutation rate in individuals exposed to gamma rays to decline as the exposure period is prolonged and the dose rate is reduced, while the response to neutrons is in the opposite direction. Cytological determinations show the rate of balanced chromosomal translocations to drop as gamma ray exposures change from one-time to continuous, however little or no dose rate effect is seen with neutron radiation and alpha particle exposure shows no regular dose-response. Based on the above results, it is predicted that the rate of dominant mutations and transmissible chromosome aberrations in astronauts on a 100-day mission will increase by 4.5 to 41.25 percent over the spontaneous rate. 35 references

  13. Genetic characteristics of Japanese clinical Listeria monocytogenes isolates.

    Directory of Open Access Journals (Sweden)

    Satoko Miya

    Full Text Available Listeria monocytogenes causes foodborne illnesses through consumption of ready-to-eat foods. Although 135-201annual listeriosis cases have been estimated in Japan, the details regarding the clinical isolates such as infection source, virulence level, and other genetic characteristics, are not known. In order to uncover the trends of listeriosis in Japan and use the knowledge for prevention measures to be taken, the genetic characteristics of the past human clinical isolates needs to be elucidated. For this purpose, multilocus tandem-repeat sequence analysis (MLTSA and multi-virulence-locus sequence typing (MVLST were used in this study. The clinical isolates showed a variety of genetically distant genotypes, indicating they were from sporadic cases. However, the MVLST profiles of 7 clinical isolates were identical to those of epidemic clone (EC I isolates, which have caused several serious outbreaks in other countries, suggesting the possibility that they have strong virulence potential and originated from a single outbreak. Moreover, 6 Japanese food isolates shared their genotypes with ECI isolates, indicating that there may be risks for listeriosis outbreak in Japan. This is the first investigational study on genetic characteristics of Japanese listeriosis isolates. The listeriosis cases happened in the past are presumably sporadic, but it is still possible that some isolates with strong virulence potential have caused listeriosis outbreaks, and future listeriosis risks also exist.

  14. Understanding your colon cancer risk

    Science.gov (United States)

    ... for women and 2 drinks per day for men DO NOT smoke You can also have genetic testing done to assess your risk for colon cancer. If you have a strong family history of the disease, talk with your ...

  15. A counselee-oriented perspective on risk communication in genetic counseling : Explaining the inaccuracy of the counselees' risk perception shortly after BRCA1/2 test result disclosure

    NARCIS (Netherlands)

    Vos, Joel; Stiggelbout, Anne M.; Oosterwijk, Jan; Gomez-Garcia, Encarna; Menko, Fred; Collee, J. Margriet; van Asperen, Christi J.; Tibben, Aad

    Purpose: Genetic counseling may help counselees understand their genetic risk of developing breast/ovarian cancer. However, many studies have shown that their perception of their risks is inaccurate. Information-oriented variables often predicted the level of accuracy, focusing on specific processes

  16. Strong Signature of Natural Selection within an FHIT Intron Implicated in Prostate Cancer Risk

    Science.gov (United States)

    Ding, Yan; Larson, Garrett; Rivas, Guillermo; Lundberg, Cathryn; Geller, Louis; Ouyang, Ching; Weitzel, Jeffrey; Archambeau, John; Slater, Jerry; Daly, Mary B.; Benson, Al B.; Kirkwood, John M.; O'Dwyer, Peter J.; Sutphen, Rebecca; Stewart, James A.; Johnson, David; Nordborg, Magnus; Krontiris, Theodore G.

    2008-01-01

    Previously, a candidate gene linkage approach on brother pairs affected with prostate cancer identified a locus of prostate cancer susceptibility at D3S1234 within the fragile histidine triad gene (FHIT), a tumor suppressor that induces apoptosis. Subsequent association tests on 16 SNPs spanning approximately 381 kb surrounding D3S1234 in Americans of European descent revealed significant evidence of association for a single SNP within intron 5 of FHIT. In the current study, re-sequencing and genotyping within a 28.5 kb region surrounding this SNP further delineated the association with prostate cancer risk to a 15 kb region. Multiple SNPs in sequences under evolutionary constraint within intron 5 of FHIT defined several related haplotypes with an increased risk of prostate cancer in European-Americans. Strong associations were detected for a risk haplotype defined by SNPs 138543, 142413, and 152494 in all cases (Pearson's χ2 = 12.34, df 1, P = 0.00045) and for the homozygous risk haplotype defined by SNPs 144716, 142413, and 148444 in cases that shared 2 alleles identical by descent with their affected brothers (Pearson's χ2 = 11.50, df 1, P = 0.00070). In addition to highly conserved sequences encompassing SNPs 148444 and 152413, population studies revealed strong signatures of natural selection for a 1 kb window covering the SNP 144716 in two human populations, the European American (π = 0.0072, Tajima's D = 3.31, 14 SNPs) and the Japanese (π = 0.0049, Fay & Wu's H = 8.05, 14 SNPs), as well as in chimpanzees (Fay & Wu's H = 8.62, 12 SNPs). These results strongly support the involvement of the FHIT intronic region in an increased risk of prostate cancer. PMID:18953408

  17. Association of genetic susceptibility variants for type 2 diabetes with breast cancer risk in women of European ancestry

    DEFF Research Database (Denmark)

    Zhao, Zhiguo; Wen, Wanqing; Michailidou, Kyriaki

    2016-01-01

    PURPOSE: Type 2 diabetes (T2D) has been reported to be associated with an elevated risk of breast cancer. It is unclear, however, whether this association is due to shared genetic factors. METHODS: We constructed a genetic risk score (GRS) using risk variants from 33 known independent T2D suscept...

  18. Barriers and Facilitators for Utilization of Genetic Counseling and Risk Assessment Services in Young Female Breast Cancer Survivors

    Directory of Open Access Journals (Sweden)

    Beth Anderson

    2012-01-01

    Full Text Available Introduction. Women diagnosed with breast cancer at a young age are more likely to carry a cancer predisposing genetic mutation. Per the current NCCN recommendations, women diagnosed under age 50 should be referred to cancer genetic counseling for further risk evaluation. This study seeks to assess patient-reported barriers and facilitators to receiving genetic counseling and risk assessment among a community-based population of young breast cancer survivors (YBCS. Methods. Through the Michigan Cancer Surveillance Program, a state-based cancer registry, 488 women diagnosed with breast cancer before age 50 in 2006-2007 were identified. They received a mail survey regarding family history and facilitators and barriers to receiving genetic counseling and risk assessment. Results. Responses were received from 289 women (59.2%. One hundred twenty-two (42.2% reported having received cancer genetic counseling. The most frequent reason identified for receiving services was to benefit their family's future. The top reasons for not attending were “no one recommended it” and “medical insurance coverage issues.” Discussion. This study is the first published report using a state cancer registry to determine facilitators and barriers to receiving genetic counseling and risk assessment among YBCS. These findings demonstrate the need for additional awareness and education about appropriate indications for genetic services.

  19. Barriers and Facilitators for Utilization of Genetic Counseling and Risk Assessment Services in Young Female Breast Cancer Survivors

    International Nuclear Information System (INIS)

    Anderson, B.; McLosky, J.; Wasilevich, E.; Callo, S. L.; Duquette, D.; Copeland, G.

    2012-01-01

    Introduction. Women diagnosed with breast cancer at a young age are more likely to carry a cancer predisposing genetic mutation. Per the current NCCN recommendations, women diagnosed under age 50 should be referred to cancer genetic counseling for further risk evaluation. This study seeks to assess patient-reported barriers and facilitators to receiving genetic counseling and risk assessment among a community-based population of young breast cancer survivors (YBCS). Methods. Through the Michigan Cancer Surveillance Program, a state-based cancer registry, 488 women diagnosed with breast cancer before age 50 in 2006-2007 were identified. They received a mail survey regarding family history and facilitators and barriers to receiving genetic counseling and risk assessment. Results. Responses were received from 289 women (59.2%). One hundred twenty-two (42.2%) reported having received cancer genetic counseling. The most frequent reason identified for receiving services was to benefit their family's future. The top reasons for not attending were “no one recommended it” and “medical insurance coverage issues.” Discussion. This study is the first published report using a state cancer registry to determine facilitators and barriers to receiving genetic counseling and risk assessment among YBCS. These findings demonstrate the need for additional awareness and education about appropriate indications for genetic services.

  20. Meat, vegetables and genetic polymorphisms and the risk of colorectal carcinomas and adenomas

    International Nuclear Information System (INIS)

    Skjelbred, Camilla F; Sæbø, Mona; Hjartåker, Anette; Grotmol, Tom; Hansteen, Inger-Lise; Tveit, Kjell M; Hoff, Geir; Kure, Elin H

    2007-01-01

    The risk of sporadic colorectal cancer (CRC) is mainly associated with lifestyle factors, particularly dietary factors. Diets high in red meat and fat and low in fruit and vegetables are associated with an increased risk of CRC. The dietary effects may be modulated by genetic polymorphisms in biotransformation genes. In this study we aimed to evaluate the role of dietary factors in combination with genetic factors in the different stages of colorectal carcinogenesis in a Norwegian population. We used a case-control study design (234 carcinomas, 229 high-risk adenomas, 762 low-risk adenomas and 400 controls) to test the association between dietary factors (meat versus fruit, berries and vegetables) genetic polymorphisms in biotransformation genes (GSTM1, GSTT1, GSTP1 Ile 105 Val, EPHX1 Tyr 113 His and EPHX1 His 139 Arg), and risk of colorectal carcinomas and adenomas. Odds ratio (OR) and 95% confidence interval (95% CI) were estimated by binary logistic regression. A higher ratio of total meat to total fruit, berry and vegetable intake was positively associated with both high and low-risk adenomas, with approximately twice the higher risk in the 2 nd quartile compared to the lowest quartile. For the high-risk adenomas this positive association was more obvious for the common allele (Tyr allele) of the EPHX1 codon 113 polymorphism. An association was also observed for the EPHX1 codon 113 polymorphism in the low-risk adenomas, although not as obvious. Although, the majority of the comparison groups are not significant, our results suggest an increased risk of colorectal adenomas in individuals for some of the higher ratios of total meat to total fruit, berry and vegetable intake. In addition the study supports the notion that the biotransformation enzymes GSTM1, GSTP1 and EPHX1 may modify the effect of dietary factors on the risk of developing colorectal carcinoma and adenoma

  1. "Well, good luck with that": reactions to learning of increased genetic risk for Alzheimer disease.

    Science.gov (United States)

    Zallen, Doris T

    2018-03-08

    PurposeApolipoprotein-E (APOE) genetic testing to estimate risk for developing late-onset Alzheimer disease is increasingly being offered without prior genetic counseling or preparation. Consumer interest continues to grow, raising the question of how best to conduct such testing.MethodsTwenty-six semistructured interviews were carried out to study the reactions of individuals who had already learned of their higher risk after APOE testing had been done because of a family history of Alzheimer disease, or from genetic tests done for other health-related or general-interest reasons.ResultsAdverse psychological reactions were reported by a substantial fraction of the participants, including those who had specifically sought testing, those for whom the information came as a surprise, those with a family history, and those with no known history. Still, nearly all of those interviewed said that they had benefited in the long term from lifestyle changes, often learned from online sources, that they subsequently made.ConclusionThe results show that people should be prepared prior to any genetic testing and allowed to opt out of particular tests. If testing is carried out and a higher risk is revealed, they should be actively assisted in deciding how to proceed.GENETICS in MEDICINE advance online publication, 8 March 2018; doi:10.1038/gim.2018.13.

  2. Communicating genetic risk information for common disorders in the era of genomic medicine.

    Science.gov (United States)

    Lautenbach, Denise M; Christensen, Kurt D; Sparks, Jeffrey A; Green, Robert C

    2013-01-01

    Communicating genetic risk information in ways that maximize understanding and promote health is increasingly important given the rapidly expanding availability and capabilities of genomic technologies. A well-developed literature on risk communication in general provides guidance for best practices, including presentation of information in multiple formats, attention to framing effects, use of graphics, sensitivity to the way numbers are presented, parsimony of information, attentiveness to emotions, and interactivity as part of the communication process. Challenges to communicating genetic risk information include deciding how best to tailor it, streamlining the process, deciding what information to disclose, accepting that communications may have limited influence, and understanding the impact of context. Meeting these challenges has great potential for empowering individuals to adopt healthier lifestyles and improve public health, but will require multidisciplinary approaches and collaboration.

  3. Lifestyle modifies obesity-associated risk of cardiovascular disease in a genetically homogeneous population

    DEFF Research Database (Denmark)

    Jørgensen, Marit E; Borch-Johnsen, Knut; Bjerregaard, Peter

    2006-01-01

    BACKGROUND: The association between obesity and cardiovascular disease risk differs across populations. Whether such differences in obesity-related risk factors exist within population groups of the same genetic origin but with differences in lifestyle remains to be determined. OBJECTIVE: The aim...... was to analyze whether obesity was associated with the same degree of metabolic disturbances in 2 groups of genetically homogeneous Inuit who were exposed to considerable differences in lifestyle. DESIGN: We studied obesity and cardiovascular disease risk factors in a cross-sectional population survey of 2311...... Inuit living in Denmark (n = 995) or Greenland (n = 1316). The participants received an oral-glucose-tolerance test. Blood tests were supplemented by structured interviews and anthropometric and blood pressure measurements. RESULTS: The trend in the association between obesity and metabolic effects...

  4. Genetic variation in DNA repair pathways and risk of non-Hodgkin's lymphoma.

    Directory of Open Access Journals (Sweden)

    Justin Rendleman

    Full Text Available Molecular and genetic evidence suggests that DNA repair pathways may contribute to lymphoma susceptibility. Several studies have examined the association of DNA repair genes with lymphoma risk, but the findings from these reports have been inconsistent. Here we provide the results of a focused analysis of genetic variation in DNA repair genes and their association with the risk of non-Hodgkin's lymphoma (NHL. With a population of 1,297 NHL cases and 1,946 controls, we have performed a two-stage case/control association analysis of 446 single nucleotide polymorphisms (SNPs tagging the genetic variation in 81 DNA repair genes. We found the most significant association with NHL risk in the ATM locus for rs227060 (OR = 1.27, 95% CI: 1.13-1.43, p = 6.77×10(-5, which remained significant after adjustment for multiple testing. In a subtype-specific analysis, associations were also observed for the ATM locus among both diffuse large B-cell lymphomas (DLBCL and small lymphocytic lymphomas (SLL, however there was no association observed among follicular lymphomas (FL. In addition, our study provides suggestive evidence of an interaction between SNPs in MRE11A and NBS1 associated with NHL risk (OR = 0.51, 95% CI: 0.34-0.77, p = 0.0002. Finally, an imputation analysis using the 1,000 Genomes Project data combined with a functional prediction analysis revealed the presence of biologically relevant variants that correlate with the observed association signals. While the findings generated here warrant independent validation, the results of our large study suggest that ATM may be a novel locus associated with the risk of multiple subtypes of NHL.

  5. The relevance of animal experimental results for the assessment of radiation genetic risks in man

    International Nuclear Information System (INIS)

    Stephan, G.

    1981-01-01

    No suitable data are available from man for the quantitative assessment of genetic radiation risk. Therefore, the results from experiments on animals must be utilized. Two hypotheses are presented here in drawing analogical conclusions from one species to another. Although the extrapolation of results from animal experiments remains an open question, the use of experimental results from mice seems to be justified for an assessment of the genetic radiation risk in man. (orig.) [de

  6. Anorexia nervosa and major depression: shared genetic and environmental risk factors.

    Science.gov (United States)

    Wade, T D; Bulik, C M; Neale, M; Kendler, K S

    2000-03-01

    The authors sought to derive heritability estimates for anorexia nervosa and to explore the etiology of the comorbid relationship between anorexia nervosa and major depression. They applied bivariate structural equation modeling to a broad definition of anorexia nervosa and lifetime major depression as assessed in a population-based sample of 2,163 female twins. Anorexia nervosa was estimated to have a heritability of 58% (95% confidence interval=33%-84%). The authors were unable to completely rule out a contribution of shared environment. The comorbidity between anorexia nervosa and major depression is likely due to genetic factors that influence the risk for both disorders. Although the study was limited by the small number of affected twins, the results suggest that genetic factors significantly influence the risk for anorexia nervosa and substantially contribute to the observed comorbidity between anorexia nervosa and major depression.

  7. Human papillomavirus 33 worldwide genetic variation and associated risk of cervical cancer

    Science.gov (United States)

    Chen, Alyce A.; Heideman, Daniëlle A.M.; Boon, Debby; Chen, Zigui; Burk, Robert D.; De Vuyst, Hugo; Gheit, Tarik; Snijders, Peter J.F.; Tommasino, Massimo; Franceschi, Silvia; Clifford, Gary M.

    2014-01-01

    Human papillomavirus (HPV) 33, a member of the HPV16-related alpha-9 species group, is found in approximately 5% of cervical cancers worldwide. The current study aimed to characterize the genetic diversity of HPV33 and to explore the association of HPV33 variants with the risk for cervical cancer. Taking advantage of the International Agency for Research on Cancer biobank, we sequenced the entire E6 and E7 open reading frames of 213 HPV33-positive cervical samples from 30 countries. We identified 28 HPV33 variants that formed 5 phylogenetic groups: the previously identified A1, A2, and B (sub) lineages and the novel A3 and C (sub)lineages. The A1 sublineage was strongly over-represented in cervical cases compared to controls in both Africa and Europe. In conclusion, we provide a classification system for HPV33 variants based on the sequence of E6 and E7 and suggest that the association of HPV33 with cervical cancer may differ by variant (sub)lineage. PMID:24314666

  8. Association of TP53 codon 72 and CDH1 genetic polymorphisms with colorectal cancer risk in Bangladeshi population.

    Science.gov (United States)

    Rivu, Sanzana Fareen; Apu, Mohd Nazmul Hasan; Shabnaz, Samia; Nahid, Noor Ahmed; Islam, Md Reazul; Al-Mamun, Mir Md Abdullah; Nahar, Zabun; Rabbi, Sikder Nahidul Islam; Ahmed, Maizbha Uddin; Islam, Mohammad Safiqul; Hasnat, Abul

    2017-08-01

    Till now no pharmacogenetic study of TP53 codon 72 (Arg72Pro) and CDH1 rs16260 (-160Ccolorectal cancer. So the aim of the study is to determine whether there is an elevated risk of colorectal cancer development with TP53 codon 72 and CDH1 rs16260 genetic polymorphism in Bangladeshi population for the first time. To investigate the association of these two SNPs, we conducted a case-control study with 288 colorectal cancer patients and 295 healthy volunteers by using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. We found an increased risk of association between Arg/Pro heterozygosity (adjusted OR=2.58, 95% CI=1.77-3.77, pcolorectal cancer predisposition. In case of CDH1 rs16260 polymorphism, C/A heterozygous and A/A mutant homozygous are significantly (pcolorectal cancer risk with adjusted OR of 1.94 and 2.63, respectively. The combined genotype of C/A and A/A was also found to be strongly associated with colorectal cancer risk compared to C/C genotype (adjusted OR=2.02, 95% CI=1.42-2.87, pcolorectal cancer development in Bangladeshi population. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. The genetic validation of heterogeneity in schizophrenia.

    Science.gov (United States)

    Tsutsumi, Atsushi; Glatt, Stephen J; Kanazawa, Tetsufumi; Kawashige, Seiya; Uenishi, Hiroyuki; Hokyo, Akira; Kaneko, Takao; Moritani, Makiko; Kikuyama, Hiroki; Koh, Jun; Matsumura, Hitoshi; Yoneda, Hiroshi

    2011-10-07

    Schizophrenia is a heritable disorder, however clear genetic architecture has not been detected. To overcome this state of uncertainty, the SZGene database has been established by including all published case-control genetic association studies appearing in peer-reviewed journals. In the current study, we aimed to determine if genetic variants strongly suggested by SZGene are associated with risk of schizophrenia in our case-control samples of Japanese ancestry. In addition, by employing the additive model for aggregating the effect of seven variants, we aimed to verify the genetic heterogeneity of schizophrenia diagnosed by an operative diagnostic manual, the DSM-IV. Each positively suggested genetic polymorphism was ranked according to its p-value, then the seven top-ranked variants (p Japanese population. It is also important to aggregate the updated positive variants in the SZGene database when the replication work is conducted.

  10. Association of Genetic Susceptibility Variants for Type 2 Diabetes with Breast Cancer Risk in Women of European Ancestry

    Science.gov (United States)

    Zhao, Zhiguo; Wen, Wanqing; Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Zhang, Ben; Long, Jirong; Shu, Xiao-Ou; Schmidt, Marjanka K.; Milne, Roger L.; García-Closas, Montserrat; Chang-Claude, Jenny; Lindstrom, Sara; Bojesen, Stig E.; Ahsan, Habibul; Aittomäki, Kristiina; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker; Beckmann, Matthias W.; Beeghly-Fadiel, Alicia; Benitez, Javier; Blomqvist, Carl; Bogdanova, Natalia V.; Børresen-Dale, Anne-Lise; Brand, Judith; Brauch, Hiltrud; Brenner, Hermann; Burwinkel, Barbara; Cai, Qiuyin; Casey, Graham; Chenevix-Trench, Georgia; Couch, Fergus J.; Cox, Angela; Cross, Simon S.; Czene, Kamila; Dörk, Thilo; Dumont, Martine; Fasching, Peter A.; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Flyger, Henrik; Fostira, Florentia; Gammon, Marilie; Giles, Graham G.; Guénel, Pascal; Haiman, Christopher A.; Hamann, Ute; Harrington, Patricia; Hartman, Mikael; Hooning, Maartje J.; Hopper, John L.; Jakubowska, Anna; Jasmine, Farzana; John, Esther M.; Johnson, Nichola; Kabisch, Maria; Khan, Sofia; Kibriya, Muhammad; Knight, Julia A.; Kosma, Veli-Matti; Kriege, Mieke; Kristensen, Vessela; Le Marchand, Loic; Lee, Eunjung; Li, Jingmei; Lindblom, Annika; Lophatananon, Artitaya; Luben, Robert; Lubinski, Jan; Malone, Kathleen E.; Mannermaa, Arto; Manoukian, Siranoush; Margolin, Sara; Marme, Frederik; McLean, Catriona; Meijers-Heijboer, Hanne; Meindl, Alfons; Miao, Hui; Muir, Kenneth; Neuhausen, Susan L.; Nevanlinna, Heli; Neven, Patrick; Olson, Janet E.; Perkins, Barbara; Peterlongo, Paolo; Phillips, Kelly-Anne; Pylkäs, Katri; Rudolph, Anja; Santella, Regina; Sawyer, Elinor J.; Schmutzler, Rita K.; Schoemaker, Minouk; Shah, Mitul; Shrubsole, Martha; Southey, Melissa C.; Swerdlow, Anthony J; Toland, Amanda E.; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; Ursin, Giske; Van Der Luijt, Rob B.; Verhoef, Senno; Wang-Gohrke, Shan; Whittemore, Alice S.; Winqvist, Robert; Zamora, M. Pilar; Zhao, Hui; Dunning, Alison M.; Simard, Jacques; Hall, Per; Kraft, Peter; Pharoah, Paul; Hunter, David; Easton, Douglas F.; Zheng, Wei

    2016-01-01

    Purpose Type 2 diabetes (T2D) has been reported to be associated with an elevated risk of breast cancer. It is unclear, however, whether this association is due to shared genetic factors. Methods We constructed a genetic risk score (GRS) using risk variants from 33 known independent T2D susceptibility loci and evaluated its relation to breast cancer risk using the data from two consortia, including 62,328 breast cancer patients and 83,817 controls of European ancestry. Unconditional logistic regression models were used to derive adjusted odds ratios (OR) and 95% confidence intervals (CI) to measure the association of breast cancer risk with T2D GRS or T2D-associated genetic risk variants. Meta-analyses were conducted to obtain summary ORs across all studies. Results The T2D GRS was not found to be associated with breast cancer risk, overall, by menopausal status, or for estrogen receptor positive or negative breast cancer. Three T2D associated risk variants were individually associated with breast cancer risk after adjustment for multiple comparisons using the Bonferroni method (at P < 0.001), rs9939609 (FTO) (OR = 0.94, 95% CI = 0.92 – 0.95, P = 4.13E-13), rs7903146 (TCF7L2) (OR = 1.04, 95% CI = 1.02 – 1.06, P = 1.26E-05), and rs8042680 (PRC1) (OR = 0.97, 95% CI = 0.95 – 0.99, P = 8.05E-04). Conclusions We have shown that several genetic risk variants were associated with the risk of both T2D and breast cancer. However, overall genetic susceptibility to T2D may not be related to breast cancer risk. PMID:27053251

  11. Circulating Fetuin-A and Risk of Type 2 Diabetes

    DEFF Research Database (Denmark)

    Kröger, Janine; Meidtner, Karina; Stefan, Norbert

    2018-01-01

    with those from the Diabetes Genetics Replication And Meta-analysis (DIAGRAM) consortium (12,171 cases) also did not suggest a clear significant relation of fetuin-A with diabetes risk. In conclusion, although there is mechanistical evidence for an effect of fetuin-A on insulin sensitivity and secretion......Fetuin-A, a hepatic-origin protein, is strongly positively associated with risk of type 2 diabetes in human observational studies, but it is unknown whether this association is causal. We aimed to study the potential causal relation of circulating fetuin-A to risk of type 2 diabetes in a Mendelian...... score of theAHSGSNPs was strongly associated with fetuin-A (28% explained variation). Using the genetic score as instrumental variable of fetuin-A, we observed no significant association of a 50 µg/ml higher fetuin-A concentration with diabetes risk (HR 1.02 [95%-CI 0.97, 1.07]). Combining our results...

  12. Risk adjustment model of credit life insurance using a genetic algorithm

    Science.gov (United States)

    Saputra, A.; Sukono; Rusyaman, E.

    2018-03-01

    In managing the risk of credit life insurance, insurance company should acknowledge the character of the risks to predict future losses. Risk characteristics can be learned in a claim distribution model. There are two standard approaches in designing the distribution model of claims over the insurance period i.e, collective risk model and individual risk model. In the collective risk model, the claim arises when risk occurs is called individual claim, accumulation of individual claim during a period of insurance is called an aggregate claim. The aggregate claim model may be formed by large model and a number of individual claims. How the measurement of insurance risk with the premium model approach and whether this approach is appropriate for estimating the potential losses occur in the future. In order to solve the problem Genetic Algorithm with Roulette Wheel Selection is used.

  13. Are markers of inflammation more strongly associated with risk for fatal than for nonfatal vascular events?

    LENUS (Irish Health Repository)

    Sattar, Naveed

    2009-06-23

    Circulating inflammatory markers may more strongly relate to risk of fatal versus nonfatal cardiovascular disease (CVD) events, but robust prospective evidence is lacking. We tested whether interleukin (IL)-6, C-reactive protein (CRP), and fibrinogen more strongly associate with fatal compared to nonfatal myocardial infarction (MI) and stroke.

  14. The genetics of hyperuricaemia and gout.

    Science.gov (United States)

    Reginato, Anthony M; Mount, David B; Yang, Irene; Choi, Hyon K

    2012-10-01

    Gout is a common and very painful inflammatory arthritis caused by hyperuricaemia. This review provides an update on the genetics of hyperuricaemia and gout, including findings from genome-wide association studies. Most of the genes that associated with serum uric acid levels or gout are involved in the renal urate-transport system. For example, the urate transporter genes SLC2A9, ABCG2 and SLC22A12 modulate serum uric acid levels and gout risk. The net balance between renal urate absorption and secretion is a major determinant of serum uric acid concentration and loss-of-function mutations in SLC2A9 and SLC22A12 cause hereditary hypouricaemia due to reduced urate absorption and unopposed urate secretion. However, the variance in serum uric acid explained by genetic variants is small and their clinical utility for gout risk prediction seems limited because serum uric acid levels effectively predict gout risk. Urate-associated genes and genetically determined serum uric acid levels were largely unassociated with cardiovascular-metabolic outcomes, challenging the hypothesis of a causal role of serum uric acid in the development of cardiovascular disease. Strong pharmacogenetic associations between HLA-B*5801 alleles and severe allopurinol-hypersensitivity reactions were shown in Asian and European populations. Genetic testing for HLA-B*5801 alleles could be used to predict these potentially fatal adverse effects.

  15. Probability Model of Allele Frequency of Alzheimer’s Disease Genetic Risk Factor

    Directory of Open Access Journals (Sweden)

    Afshin Fayyaz-Movaghar

    2016-06-01

    Full Text Available Background and Purpose: The identification of genetics risk factors of human diseases is very important. This study is conducted to model the allele frequencies (AFs of Alzheimer’s disease. Materials and Methods: In this study, several candidate probability distributions are fitted on a data set of Alzheimer’s disease genetic risk factor. Unknown parameters of the considered distributions are estimated, and some criterions of goodness-of-fit are calculated for the sake of comparison. Results: Based on some statistical criterions, the beta distribution gives the best fit on AFs. However, the estimate values of the parameters of beta distribution lead us to the standard uniform distribution. Conclusion: The AFs of Alzheimer’s disease follow the standard uniform distribution.

  16. Robust symptom networks in recurrent major depression across different levels of genetic and environmental risk

    NARCIS (Netherlands)

    van Loo, H.M.; Van Borkulo, C.D.; Peterson, R.E.; Fried, E.I.; Aggen, S.H.; Borsboom, D.; Kendler, K.S.

    BACKGROUND: Genetic risk and environmental adversity-both important risk factors for major depression (MD)-are thought to differentially impact on depressive symptom types and associations. Does heterogeneity in these risk factors result in different depressive symptom networks in patients with MD?

  17. Decoding the non-coding genome: elucidating genetic risk outside the coding genome.

    Science.gov (United States)

    Barr, C L; Misener, V L

    2016-01-01

    Current evidence emerging from genome-wide association studies indicates that the genetic underpinnings of complex traits are likely attributable to genetic variation that changes gene expression, rather than (or in combination with) variation that changes protein-coding sequences. This is particularly compelling with respect to psychiatric disorders, as genetic changes in regulatory regions may result in differential transcriptional responses to developmental cues and environmental/psychosocial stressors. Until recently, however, the link between transcriptional regulation and psychiatric genetic risk has been understudied. Multiple obstacles have contributed to the paucity of research in this area, including challenges in identifying the positions of remote (distal from the promoter) regulatory elements (e.g. enhancers) and their target genes and the underrepresentation of neural cell types and brain tissues in epigenome projects - the availability of high-quality brain tissues for epigenetic and transcriptome profiling, particularly for the adolescent and developing brain, has been limited. Further challenges have arisen in the prediction and testing of the functional impact of DNA variation with respect to multiple aspects of transcriptional control, including regulatory-element interaction (e.g. between enhancers and promoters), transcription factor binding and DNA methylation. Further, the brain has uncommon DNA-methylation marks with unique genomic distributions not found in other tissues - current evidence suggests the involvement of non-CG methylation and 5-hydroxymethylation in neurodevelopmental processes but much remains unknown. We review here knowledge gaps as well as both technological and resource obstacles that will need to be overcome in order to elucidate the involvement of brain-relevant gene-regulatory variants in genetic risk for psychiatric disorders. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  18. Genetic regulation of serum phytosterol levels and risk of coronary artery disease.

    Science.gov (United States)

    Teupser, Daniel; Baber, Ronny; Ceglarek, Uta; Scholz, Markus; Illig, Thomas; Gieger, Christian; Holdt, Lesca M; Leichtle, Alexander; Greiser, Karin H; Huster, Dominik; Linsel-Nitschke, Patrick; Schäfer, Arne; Braund, Peter S; Tiret, Laurence; Stark, Klaus; Raaz-Schrauder, Dorette; Fiedler, Georg M; Wilfert, Wolfgang; Beutner, Frank; Gielen, Stephan; Grosshennig, Anika; König, Inke R; Lichtner, Peter; Heid, Iris M; Kluttig, Alexander; El Mokhtari, Nour E; Rubin, Diana; Ekici, Arif B; Reis, André; Garlichs, Christoph D; Hall, Alistair S; Matthes, Gert; Wittekind, Christian; Hengstenberg, Christian; Cambien, Francois; Schreiber, Stefan; Werdan, Karl; Meitinger, Thomas; Loeffler, Markus; Samani, Nilesh J; Erdmann, Jeanette; Wichmann, H-Erich; Schunkert, Heribert; Thiery, Joachim

    2010-08-01

    Phytosterols are plant-derived sterols that are taken up from food and can serve as biomarkers of cholesterol uptake. Serum levels are under tight genetic control. We used a genomic approach to study the molecular regulation of serum phytosterol levels and potential links to coronary artery disease (CAD). A genome-wide association study for serum phytosterols (campesterol, sitosterol, brassicasterol) was conducted in a population-based sample from KORA (Cooperative Research in the Region of Augsburg) (n=1495) with subsequent replication in 2 additional samples (n=1157 and n=1760). Replicated single-nucleotide polymorphisms (SNPs) were tested for association with premature CAD in a metaanalysis of 11 different samples comprising 13 764 CAD cases and 13 630 healthy controls. Genetic variants in the ATP-binding hemitransporter ABCG8 and at the blood group ABO locus were significantly associated with serum phytosterols. Effects in ABCG8 were independently related to SNPs rs4245791 and rs41360247 (combined P=1.6 x 10(-50) and 6.2 x 10(-25), respectively; n=4412). Serum campesterol was elevated 12% for each rs4245791 T-allele. The same allele was associated with 40% decreased hepatic ABCG8 mRNA expression (P=0.009). Effects at the ABO locus were related to SNP rs657152 (combined P=9.4x10(-13)). Alleles of ABCG8 and ABO associated with elevated phytosterol levels displayed significant associations with increased CAD risk (rs4245791 odds ratio, 1.10; 95% CI, 1.06 to 1.14; P=2.2 x 10(-6); rs657152 odds ratio, 1.13; 95% CI, 1.07 to 1.19; P=9.4 x 10(-6)), whereas alleles at ABCG8 associated with reduced phytosterol levels were associated with reduced CAD risk (rs41360247 odds ratio, 0.84; 95% CI, 0.78 to 0.91; P=1.3 x 10(-5)). Common variants in ABCG8 and ABO are strongly associated with serum phytosterol levels and show concordant and previously unknown associations with CAD.

  19. Intrauterine and genetic factors in early childhood sensitization

    DEFF Research Database (Denmark)

    Bønnelykke, Klaus

    2010-01-01

    The allergy-associated (atopic) diseases; asthma, eczema and rhinoconjunctivitis, are the most common chronic diseases in childhood. A large number of environmental and genetic risk factors have been suggested, but still our understanding of the underlying disease mechanisms and etiologies...... with production of specific IgE-antibodies against allergens. Sensitization may cause allergic symptoms, and sensitization early in life is a strong risk factor for later disease. Fetal and early postnatal life seems to be a critical period for development of atopic disease and may be an important “window...... of opportunity” for prevention. The aim of this thesis was to increase the understanding of sensitization in early life. We studied indicators of sensitization in the newborn, and early development of sensitization and disease associated with a newly discovered genetic risk factor. Such insight may increase our...

  20. Genetic variation in liver x receptor alpha and risk of ischemic vascular disease in the general population

    DEFF Research Database (Denmark)

    Stender, Stefan; Frikke-Schmidt, Ruth; Anestis, Aristomenis

    2011-01-01

    Although animal studies indicate that liver X receptor alpha (LXRα) might influence risk of atherosclerosis, data in humans remain scarce. We tested the hypothesis that genetic variation in LXRα associates with risk of ischemic vascular disease and/or plasma lipid and lipoprotein levels in the ge......Although animal studies indicate that liver X receptor alpha (LXRα) might influence risk of atherosclerosis, data in humans remain scarce. We tested the hypothesis that genetic variation in LXRα associates with risk of ischemic vascular disease and/or plasma lipid and lipoprotein levels...... in the general population....

  1. Genetic variation in liver x receptor alpha and risk of ischemic vascular disease in the general population

    DEFF Research Database (Denmark)

    Stender, Stefan; Frikke-Schmidt, Ruth; Anestis, Aristomenis

    2011-01-01

    Although animal studies indicate that liver X receptor alpha (LXRa) might influence risk of atherosclerosis, data in humans remain scarce. We tested the hypothesis that genetic variation in LXRa associates with risk of ischemic vascular disease and/or plasma lipid and lipoprotein levels in the ge......Although animal studies indicate that liver X receptor alpha (LXRa) might influence risk of atherosclerosis, data in humans remain scarce. We tested the hypothesis that genetic variation in LXRa associates with risk of ischemic vascular disease and/or plasma lipid and lipoprotein levels...... in the general population....

  2. Effect of genetic testing for risk of type 2 diabetes mellitus on health behaviors and outcomes: study rationale, development and design

    Directory of Open Access Journals (Sweden)

    Cho Alex H

    2012-01-01

    Full Text Available Abstract Background Type 2 diabetes is a prevalent chronic condition globally that results in extensive morbidity, decreased quality of life, and increased health services utilization. Lifestyle changes can prevent the development of diabetes, but require patient engagement. Genetic risk testing might represent a new tool to increase patients' motivation for lifestyle changes. Here we describe the rationale, development, and design of a randomized controlled trial (RCT assessing the clinical and personal utility of incorporating type 2 diabetes genetic risk testing into comprehensive diabetes risk assessments performed in a primary care setting. Methods/Design Patients are recruited in the laboratory waiting areas of two primary care clinics and enrolled into one of three study arms. Those interested in genetic risk testing are randomized to receive either a standard risk assessment (SRA for type 2 diabetes incorporating conventional risk factors plus upfront disclosure of the results of genetic risk testing ("SRA+G" arm, or the SRA alone ("SRA" arm. Participants not interested in genetic risk testing will not receive the test, but will receive SRA (forming a third, "no-test" arm. Risk counseling is provided by clinic staff (not study staff external to the clinic. Fasting plasma glucose, insulin levels, body mass index (BMI, and waist circumference are measured at baseline and 12 months, as are patients' self-reported behavioral and emotional responses to diabetes risk information. Primary outcomes are changes in insulin resistance and BMI after 12 months; secondary outcomes include changes in diet patterns, physical activity, waist circumference, and perceived risk of developing diabetes. Discussion The utility, feasibility, and efficacy of providing patients with genetic risk information for common chronic diseases in primary care remain unknown. The study described here will help to establish whether providing type 2 diabetes genetic risk

  3. Genetic association study identifies HSPB7 as a risk gene for idiopathic dilated cardiomyopathy.

    Directory of Open Access Journals (Sweden)

    Klaus Stark

    2010-10-01

    Full Text Available Dilated cardiomyopathy (DCM is a structural heart disease with strong genetic background. Monogenic forms of DCM are observed in families with mutations located mostly in genes encoding structural and sarcomeric proteins. However, strong evidence suggests that genetic factors also affect the susceptibility to idiopathic DCM. To identify risk alleles for non-familial forms of DCM, we carried out a case-control association study, genotyping 664 DCM cases and 1,874 population-based healthy controls from Germany using a 50K human cardiovascular disease bead chip covering more than 2,000 genes pre-selected for cardiovascular relevance. After quality control, 30,920 single nucleotide polymorphisms (SNP were tested for association with the disease by logistic regression adjusted for gender, and results were genomic-control corrected. The analysis revealed a significant association between a SNP in HSPB7 gene (rs1739843, minor allele frequency 39% and idiopathic DCM (p = 1.06 × 10⁻⁶, OR  = 0.67 [95% CI 0.57-0.79] for the minor allele T. Three more SNPs showed p < 2.21 × 10⁻⁵. De novo genotyping of these four SNPs was done in three independent case-control studies of idiopathic DCM. Association between SNP rs1739843 and DCM was significant in all replication samples: Germany (n =564, n = 981 controls, p = 2.07 × 10⁻³, OR = 0.79 [95% CI 0.67-0.92], France 1 (n = 433 cases, n = 395 controls, p =3.73 × 10⁻³, OR  = 0.74 [95% CI 0.60-0.91], and France 2 (n = 249 cases, n = 380 controls, p = 2.26 × 10⁻⁴, OR  = 0.63 [95% CI 0.50-0.81]. The combined analysis of all four studies including a total of n = 1,910 cases and n = 3,630 controls showed highly significant evidence for association between rs1739843 and idiopathic DCM (p = 5.28 × 10⁻¹³, OR= 0.72 [95% CI 0.65-0.78]. None of the other three SNPs showed significant results in the replication stage.This finding of the HSPB7 gene from a genetic search for idiopathic DCM using

  4. Association analysis identifies 65 new breast cancer risk loci

    DEFF Research Database (Denmark)

    Michailidou, Kyriaki; Lindström, Sara; Dennis, Joe

    2017-01-01

    Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast...... cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P risk single-nucleotide polymorphisms in these loci fall......-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores...

  5. Genetic liability, prenatal health, stress and family environment: risk factors in the Harvard Adolescent Family High Risk for schizophrenia study.

    Science.gov (United States)

    Walder, Deborah J; Faraone, Stephen V; Glatt, Stephen J; Tsuang, Ming T; Seidman, Larry J

    2014-08-01

    The familial ("genetic") high-risk (FHR) paradigm enables assessment of individuals at risk for schizophrenia based on a positive family history of schizophrenia in first-degree, biological relatives. This strategy presumes genetic transmission of abnormal traits given high heritability of the illness. It is plausible, however, that adverse environmental factors are also transmitted in these families. Few studies have evaluated both biological and environmental factors within a FHR study of adolescents. We conceptualize four precursors to psychosis pathogenesis: two biological (genetic predisposition, prenatal health issues (PHIs)) and two environmental (family environment, stressful life events (SLEs)). Participants assessed between 1998 and 2007 (ages 13-25) included 40 (20F/20M) adolescents at FHR for schizophrenia (FHRs) and 55 (31F/24M) community controls. 'Genetic load' indexed number of affected family members relative to pedigree size. PHI was significantly greater among FHRs, and family cohesion and expressiveness were less (and family conflict was higher) among FHRs; however, groups did not significantly differ in SLE indices. Among FHRs, genetic liability was significantly associated with PHI and family expressiveness. Prenatal and family environmental disruptions are elevated in families with a first-degree relative with schizophrenia. Findings support our proposed 'polygenic neurodevelopmental diathesis-stress model' whereby psychosis susceptibility (and resilience) involves the independent and synergistic confluence of (temporally-sensitive) biological and environmental factors across development. Recognition of biological and social environmental influences across critical developmental periods points to key issues relevant for enhanced identification of psychosis susceptibility, facilitation of more precise models of illness risk, and development of novel prevention strategies. Copyright © 2014 Elsevier B.V. All rights reserved.

  6. Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression.

    Science.gov (United States)

    Wray, Naomi R; Ripke, Stephan; Mattheisen, Manuel; Trzaskowski, Maciej; Byrne, Enda M; Abdellaoui, Abdel; Adams, Mark J; Agerbo, Esben; Air, Tracy M; Andlauer, Till M F; Bacanu, Silviu-Alin; Bækvad-Hansen, Marie; Beekman, Aartjan F T; Bigdeli, Tim B; Binder, Elisabeth B; Blackwood, Douglas R H; Bryois, Julien; Buttenschøn, Henriette N; Bybjerg-Grauholm, Jonas; Cai, Na; Castelao, Enrique; Christensen, Jane Hvarregaard; Clarke, Toni-Kim; Coleman, Jonathan I R; Colodro-Conde, Lucía; Couvy-Duchesne, Baptiste; Craddock, Nick; Crawford, Gregory E; Crowley, Cheynna A; Dashti, Hassan S; Davies, Gail; Deary, Ian J; Degenhardt, Franziska; Derks, Eske M; Direk, Nese; Dolan, Conor V; Dunn, Erin C; Eley, Thalia C; Eriksson, Nicholas; Escott-Price, Valentina; Kiadeh, Farnush Hassan Farhadi; Finucane, Hilary K; Forstner, Andreas J; Frank, Josef; Gaspar, Héléna A; Gill, Michael; Giusti-Rodríguez, Paola; Goes, Fernando S; Gordon, Scott D; Grove, Jakob; Hall, Lynsey S; Hannon, Eilis; Hansen, Christine Søholm; Hansen, Thomas F; Herms, Stefan; Hickie, Ian B; Hoffmann, Per; Homuth, Georg; Horn, Carsten; Hottenga, Jouke-Jan; Hougaard, David M; Hu, Ming; Hyde, Craig L; Ising, Marcus; Jansen, Rick; Jin, Fulai; Jorgenson, Eric; Knowles, James A; Kohane, Isaac S; Kraft, Julia; Kretzschmar, Warren W; Krogh, Jesper; Kutalik, Zoltán; Lane, Jacqueline M; Li, Yihan; Li, Yun; Lind, Penelope A; Liu, Xiaoxiao; Lu, Leina; MacIntyre, Donald J; MacKinnon, Dean F; Maier, Robert M; Maier, Wolfgang; Marchini, Jonathan; Mbarek, Hamdi; McGrath, Patrick; McGuffin, Peter; Medland, Sarah E; Mehta, Divya; Middeldorp, Christel M; Mihailov, Evelin; Milaneschi, Yuri; Milani, Lili; Mill, Jonathan; Mondimore, Francis M; Montgomery, Grant W; Mostafavi, Sara; Mullins, Niamh; Nauck, Matthias; Ng, Bernard; Nivard, Michel G; Nyholt, Dale R; O'Reilly, Paul F; Oskarsson, Hogni; Owen, Michael J; Painter, Jodie N; Pedersen, Carsten Bøcker; Pedersen, Marianne Giørtz; Peterson, Roseann E; Pettersson, Erik; Peyrot, Wouter J; Pistis, Giorgio; Posthuma, Danielle; Purcell, Shaun M; Quiroz, Jorge A; Qvist, Per; Rice, John P; Riley, Brien P; Rivera, Margarita; Saeed Mirza, Saira; Saxena, Richa; Schoevers, Robert; Schulte, Eva C; Shen, Ling; Shi, Jianxin; Shyn, Stanley I; Sigurdsson, Engilbert; Sinnamon, Grant B C; Smit, Johannes H; Smith, Daniel J; Stefansson, Hreinn; Steinberg, Stacy; Stockmeier, Craig A; Streit, Fabian; Strohmaier, Jana; Tansey, Katherine E; Teismann, Henning; Teumer, Alexander; Thompson, Wesley; Thomson, Pippa A; Thorgeirsson, Thorgeir E; Tian, Chao; Traylor, Matthew; Treutlein, Jens; Trubetskoy, Vassily; Uitterlinden, André G; Umbricht, Daniel; Van der Auwera, Sandra; van Hemert, Albert M; Viktorin, Alexander; Visscher, Peter M; Wang, Yunpeng; Webb, Bradley T; Weinsheimer, Shantel Marie; Wellmann, Jürgen; Willemsen, Gonneke; Witt, Stephanie H; Wu, Yang; Xi, Hualin S; Yang, Jian; Zhang, Futao; Arolt, Volker; Baune, Bernhard T; Berger, Klaus; Boomsma, Dorret I; Cichon, Sven; Dannlowski, Udo; de Geus, E C J; DePaulo, J Raymond; Domenici, Enrico; Domschke, Katharina; Esko, Tõnu; Grabe, Hans J; Hamilton, Steven P; Hayward, Caroline; Heath, Andrew C; Hinds, David A; Kendler, Kenneth S; Kloiber, Stefan; Lewis, Glyn; Li, Qingqin S; Lucae, Susanne; Madden, Pamela F A; Magnusson, Patrik K; Martin, Nicholas G; McIntosh, Andrew M; Metspalu, Andres; Mors, Ole; Mortensen, Preben Bo; Müller-Myhsok, Bertram; Nordentoft, Merete; Nöthen, Markus M; O'Donovan, Michael C; Paciga, Sara A; Pedersen, Nancy L; Penninx, Brenda W J H; Perlis, Roy H; Porteous, David J; Potash, James B; Preisig, Martin; Rietschel, Marcella; Schaefer, Catherine; Schulze, Thomas G; Smoller, Jordan W; Stefansson, Kari; Tiemeier, Henning; Uher, Rudolf; Völzke, Henry; Weissman, Myrna M; Werge, Thomas; Winslow, Ashley R; Lewis, Cathryn M; Levinson, Douglas F; Breen, Gerome; Børglum, Anders D; Sullivan, Patrick F

    2018-05-01

    Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype.

  7. Factors influencing parents' decision to donate their healthy infant's DNA for minimal-risk genetic research.

    Science.gov (United States)

    Hatfield, Linda A; Pearce, Margaret M

    2014-11-01

    To examine factors that influence a parent's decision to donate their healthy infant's DNA for minimal-risk genetic research. Grounded theory, using semi-structured interviews conducted with 35 postpartum mother or mother-father dyads in an urban teaching hospital. Data were collected from July 2011 to January 2012. Audiorecorded semistructured interviews were conducted in private rooms with mothers or mother-father dyads 24 to 48 hr after the birth of their healthy, full-term infant. Data-driven content analysis using selected principles of grounded theory was performed. Parents' willingness to donate their healthy infant's DNA for minimal-risk pediatric genetic research emerged as a process involving three interacting components: the parents, the scientist, and the comfort of the child embedded within the context of benefit to the child. The purpose of the study and parents' perception of their commitment of time and resources determined their willingness to participate. The scientist's ability to communicate trust in the research process influenced parents' decisions. Physical discomfort of the child shaped parents' decision to donate DNA. Parental perception of a direct benefit to their child affected their willingness to discuss genetic research and its outcomes. Significant gaps and misunderstandings in parental knowledge of pediatric genetic research may affect parental willingness to donate their healthy child's DNA. Nurses knowledgeable about the decision-making process parents utilize to donate their healthy infant's DNA for minimal-risk genetic research and the factors influencing that decision are well positioned to educate parents about the role of genetics in health and illness and reassure potential research participants of the value and safeguards in pediatric genetic research. © 2014 Sigma Theta Tau International.

  8. Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study.

    Science.gov (United States)

    Cleynen, Isabelle; Boucher, Gabrielle; Jostins, Luke; Schumm, L Philip; Zeissig, Sebastian; Ahmad, Tariq; Andersen, Vibeke; Andrews, Jane M; Annese, Vito; Brand, Stephan; Brant, Steven R; Cho, Judy H; Daly, Mark J; Dubinsky, Marla; Duerr, Richard H; Ferguson, Lynnette R; Franke, Andre; Gearry, Richard B; Goyette, Philippe; Hakonarson, Hakon; Halfvarson, Jonas; Hov, Johannes R; Huang, Hailang; Kennedy, Nicholas A; Kupcinskas, Limas; Lawrance, Ian C; Lee, James C; Satsangi, Jack; Schreiber, Stephan; Théâtre, Emilie; van der Meulen-de Jong, Andrea E; Weersma, Rinse K; Wilson, David C; Parkes, Miles; Vermeire, Severine; Rioux, John D; Mansfield, John; Silverberg, Mark S; Radford-Smith, Graham; McGovern, Dermot P B; Barrett, Jeffrey C; Lees, Charlie W

    2016-01-09

    Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases. This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34,819 patients (19,713 with Crohn's disease, 14,683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype-phenotype associations across 156,154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile. After quality control, the primary analysis included 29,838 patients (16,902 with Crohn's disease, 12,597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with

  9. Association analysis identifies 65 new breast cancer risk loci.

    Science.gov (United States)

    Michailidou, Kyriaki; Lindström, Sara; Dennis, Joe; Beesley, Jonathan; Hui, Shirley; Kar, Siddhartha; Lemaçon, Audrey; Soucy, Penny; Glubb, Dylan; Rostamianfar, Asha; Bolla, Manjeet K; Wang, Qin; Tyrer, Jonathan; Dicks, Ed; Lee, Andrew; Wang, Zhaoming; Allen, Jamie; Keeman, Renske; Eilber, Ursula; French, Juliet D; Qing Chen, Xiao; Fachal, Laura; McCue, Karen; McCart Reed, Amy E; Ghoussaini, Maya; Carroll, Jason S; Jiang, Xia; Finucane, Hilary; Adams, Marcia; Adank, Muriel A; Ahsan, Habibul; Aittomäki, Kristiina; Anton-Culver, Hoda; Antonenkova, Natalia N; Arndt, Volker; Aronson, Kristan J; Arun, Banu; Auer, Paul L; Bacot, François; Barrdahl, Myrto; Baynes, Caroline; Beckmann, Matthias W; Behrens, Sabine; Benitez, Javier; Bermisheva, Marina; Bernstein, Leslie; Blomqvist, Carl; Bogdanova, Natalia V; Bojesen, Stig E; Bonanni, Bernardo; Børresen-Dale, Anne-Lise; Brand, Judith S; Brauch, Hiltrud; Brennan, Paul; Brenner, Hermann; Brinton, Louise; Broberg, Per; Brock, Ian W; Broeks, Annegien; Brooks-Wilson, Angela; Brucker, Sara Y; Brüning, Thomas; Burwinkel, Barbara; Butterbach, Katja; Cai, Qiuyin; Cai, Hui; Caldés, Trinidad; Canzian, Federico; Carracedo, Angel; Carter, Brian D; Castelao, Jose E; Chan, Tsun L; David Cheng, Ting-Yuan; Seng Chia, Kee; Choi, Ji-Yeob; Christiansen, Hans; Clarke, Christine L; Collée, Margriet; Conroy, Don M; Cordina-Duverger, Emilie; Cornelissen, Sten; Cox, David G; Cox, Angela; Cross, Simon S; Cunningham, Julie M; Czene, Kamila; Daly, Mary B; Devilee, Peter; Doheny, Kimberly F; Dörk, Thilo; Dos-Santos-Silva, Isabel; Dumont, Martine; Durcan, Lorraine; Dwek, Miriam; Eccles, Diana M; Ekici, Arif B; Eliassen, A Heather; Ellberg, Carolina; Elvira, Mingajeva; Engel, Christoph; Eriksson, Mikael; Fasching, Peter A; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Flyger, Henrik; Fritschi, Lin; Gaborieau, Valerie; Gabrielson, Marike; Gago-Dominguez, Manuela; Gao, Yu-Tang; Gapstur, Susan M; García-Sáenz, José A; Gaudet, Mia M; Georgoulias, Vassilios; Giles, Graham G; Glendon, Gord; Goldberg, Mark S; Goldgar, David E; González-Neira, Anna; Grenaker Alnæs, Grethe I; Grip, Mervi; Gronwald, Jacek; Grundy, Anne; Guénel, Pascal; Haeberle, Lothar; Hahnen, Eric; Haiman, Christopher A; Håkansson, Niclas; Hamann, Ute; Hamel, Nathalie; Hankinson, Susan; Harrington, Patricia; Hart, Steven N; Hartikainen, Jaana M; Hartman, Mikael; Hein, Alexander; Heyworth, Jane; Hicks, Belynda; Hillemanns, Peter; Ho, Dona N; Hollestelle, Antoinette; Hooning, Maartje J; Hoover, Robert N; Hopper, John L; Hou, Ming-Feng; Hsiung, Chia-Ni; Huang, Guanmengqian; Humphreys, Keith; Ishiguro, Junko; Ito, Hidemi; Iwasaki, Motoki; Iwata, Hiroji; Jakubowska, Anna; Janni, Wolfgang; John, Esther M; Johnson, Nichola; Jones, Kristine; Jones, Michael; Jukkola-Vuorinen, Arja; Kaaks, Rudolf; Kabisch, Maria; Kaczmarek, Katarzyna; Kang, Daehee; Kasuga, Yoshio; Kerin, Michael J; Khan, Sofia; Khusnutdinova, Elza; Kiiski, Johanna I; Kim, Sung-Won; Knight, Julia A; Kosma, Veli-Matti; Kristensen, Vessela N; Krüger, Ute; Kwong, Ava; Lambrechts, Diether; Le Marchand, Loic; Lee, Eunjung; Lee, Min Hyuk; Lee, Jong Won; Neng Lee, Chuen; Lejbkowicz, Flavio; Li, Jingmei; Lilyquist, Jenna; Lindblom, Annika; Lissowska, Jolanta; Lo, Wing-Yee; Loibl, Sibylle; Long, Jirong; Lophatananon, Artitaya; Lubinski, Jan; Luccarini, Craig; Lux, Michael P; Ma, Edmond S K; MacInnis, Robert J; Maishman, Tom; Makalic, Enes; Malone, Kathleen E; Kostovska, Ivana Maleva; Mannermaa, Arto; Manoukian, Siranoush; Manson, JoAnn E; Margolin, Sara; Mariapun, Shivaani; Martinez, Maria Elena; Matsuo, Keitaro; Mavroudis, Dimitrios; McKay, James; McLean, Catriona; Meijers-Heijboer, Hanne; Meindl, Alfons; Menéndez, Primitiva; Menon, Usha; Meyer, Jeffery; Miao, Hui; Miller, Nicola; Taib, Nur Aishah Mohd; Muir, Kenneth; Mulligan, Anna Marie; Mulot, Claire; Neuhausen, Susan L; Nevanlinna, Heli; Neven, Patrick; Nielsen, Sune F; Noh, Dong-Young; Nordestgaard, Børge G; Norman, Aaron; Olopade, Olufunmilayo I; Olson, Janet E; Olsson, Håkan; Olswold, Curtis; Orr, Nick; Pankratz, V Shane; Park, Sue K; Park-Simon, Tjoung-Won; Lloyd, Rachel; Perez, Jose I A; Peterlongo, Paolo; Peto, Julian; Phillips, Kelly-Anne; Pinchev, Mila; Plaseska-Karanfilska, Dijana; Prentice, Ross; Presneau, Nadege; Prokofyeva, Darya; Pugh, Elizabeth; Pylkäs, Katri; Rack, Brigitte; Radice, Paolo; Rahman, Nazneen; Rennert, Gadi; Rennert, Hedy S; Rhenius, Valerie; Romero, Atocha; Romm, Jane; Ruddy, Kathryn J; Rüdiger, Thomas; Rudolph, Anja; Ruebner, Matthias; Rutgers, Emiel J T; Saloustros, Emmanouil; Sandler, Dale P; Sangrajrang, Suleeporn; Sawyer, Elinor J; Schmidt, Daniel F; Schmutzler, Rita K; Schneeweiss, Andreas; Schoemaker, Minouk J; Schumacher, Fredrick; Schürmann, Peter; Scott, Rodney J; Scott, Christopher; Seal, Sheila; Seynaeve, Caroline; Shah, Mitul; Sharma, Priyanka; Shen, Chen-Yang; Sheng, Grace; Sherman, Mark E; Shrubsole, Martha J; Shu, Xiao-Ou; Smeets, Ann; Sohn, Christof; Southey, Melissa C; Spinelli, John J; Stegmaier, Christa; Stewart-Brown, Sarah; Stone, Jennifer; Stram, Daniel O; Surowy, Harald; Swerdlow, Anthony; Tamimi, Rulla; Taylor, Jack A; Tengström, Maria; Teo, Soo H; Beth Terry, Mary; Tessier, Daniel C; Thanasitthichai, Somchai; Thöne, Kathrin; Tollenaar, Rob A E M; Tomlinson, Ian; Tong, Ling; Torres, Diana; Truong, Thérèse; Tseng, Chiu-Chen; Tsugane, Shoichiro; Ulmer, Hans-Ulrich; Ursin, Giske; Untch, Michael; Vachon, Celine; van Asperen, Christi J; Van Den Berg, David; van den Ouweland, Ans M W; van der Kolk, Lizet; van der Luijt, Rob B; Vincent, Daniel; Vollenweider, Jason; Waisfisz, Quinten; Wang-Gohrke, Shan; Weinberg, Clarice R; Wendt, Camilla; Whittemore, Alice S; Wildiers, Hans; Willett, Walter; Winqvist, Robert; Wolk, Alicja; Wu, Anna H; Xia, Lucy; Yamaji, Taiki; Yang, Xiaohong R; Har Yip, Cheng; Yoo, Keun-Young; Yu, Jyh-Cherng; Zheng, Wei; Zheng, Ying; Zhu, Bin; Ziogas, Argyrios; Ziv, Elad; Lakhani, Sunil R; Antoniou, Antonis C; Droit, Arnaud; Andrulis, Irene L; Amos, Christopher I; Couch, Fergus J; Pharoah, Paul D P; Chang-Claude, Jenny; Hall, Per; Hunter, David J; Milne, Roger L; García-Closas, Montserrat; Schmidt, Marjanka K; Chanock, Stephen J; Dunning, Alison M; Edwards, Stacey L; Bader, Gary D; Chenevix-Trench, Georgia; Simard, Jacques; Kraft, Peter; Easton, Douglas F

    2017-11-02

    Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10 -8 . The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

  10. Genetic and Environmental Risk for Chronic Pain and the Contribution of Risk Variants for Major Depressive Disorder: A Family-Based Mixed-Model Analysis.

    Science.gov (United States)

    McIntosh, Andrew M; Hall, Lynsey S; Zeng, Yanni; Adams, Mark J; Gibson, Jude; Wigmore, Eleanor; Hagenaars, Saskia P; Davies, Gail; Fernandez-Pujals, Ana Maria; Campbell, Archie I; Clarke, Toni-Kim; Hayward, Caroline; Haley, Chris S; Porteous, David J; Deary, Ian J; Smith, Daniel J; Nicholl, Barbara I; Hinds, David A; Jones, Amy V; Scollen, Serena; Meng, Weihua; Smith, Blair H; Hocking, Lynne J

    2016-08-01

    Chronic pain is highly prevalent and a significant source of disability, yet its genetic and environmental risk factors are poorly understood. Its relationship with major depressive disorder (MDD) is of particular importance. We sought to test the contribution of genetic factors and shared and unique environment to risk of chronic pain and its correlation with MDD in Generation Scotland: Scottish Family Health Study (GS:SFHS). We then sought to replicate any significant findings in the United Kingdom Biobank study. Using family-based mixed-model analyses, we examined the contribution of genetics and shared family environment to chronic pain by spouse, sibling, and household relationships. These analyses were conducted in GS:SFHS (n = 23,960), a family- and population-based study of individuals recruited from the Scottish population through their general practitioners. We then examined and partitioned the correlation between chronic pain and MDD and estimated the contribution of genetic factors and shared environment in GS:SFHS. Finally, we used data from two independent genome-wide association studies to test whether chronic pain has a polygenic architecture and examine whether genomic risk of psychiatric disorder predicted chronic pain and whether genomic risk of chronic pain predicted MDD. These analyses were conducted in GS:SFHS and repeated in UK Biobank, a study of 500,000 from the UK population, of whom 112,151 had genotyping and phenotypic data. Chronic pain is a moderately heritable trait (heritability = 38.4%, 95% CI 33.6% to 43.9%) that is significantly concordant in spouses (variance explained 18.7%, 95% CI 9.5% to 25.1%). Chronic pain is positively correlated with depression (ρ = 0.13, 95% CI 0.11 to 0.15, p = 2.72x10-68) and shows a tendency to cluster within families for genetic reasons (genetic correlation = 0.51, 95%CI 0.40 to 0.62, p = 8.24x10-19). Polygenic risk profiles for pain, generated using independent GWAS data, were associated with

  11. Genetic and Environmental Risk for Chronic Pain and the Contribution of Risk Variants for Major Depressive Disorder: A Family-Based Mixed-Model Analysis.

    Directory of Open Access Journals (Sweden)

    Andrew M McIntosh

    2016-08-01

    Full Text Available Chronic pain is highly prevalent and a significant source of disability, yet its genetic and environmental risk factors are poorly understood. Its relationship with major depressive disorder (MDD is of particular importance. We sought to test the contribution of genetic factors and shared and unique environment to risk of chronic pain and its correlation with MDD in Generation Scotland: Scottish Family Health Study (GS:SFHS. We then sought to replicate any significant findings in the United Kingdom Biobank study.Using family-based mixed-model analyses, we examined the contribution of genetics and shared family environment to chronic pain by spouse, sibling, and household relationships. These analyses were conducted in GS:SFHS (n = 23,960, a family- and population-based study of individuals recruited from the Scottish population through their general practitioners. We then examined and partitioned the correlation between chronic pain and MDD and estimated the contribution of genetic factors and shared environment in GS:SFHS. Finally, we used data from two independent genome-wide association studies to test whether chronic pain has a polygenic architecture and examine whether genomic risk of psychiatric disorder predicted chronic pain and whether genomic risk of chronic pain predicted MDD. These analyses were conducted in GS:SFHS and repeated in UK Biobank, a study of 500,000 from the UK population, of whom 112,151 had genotyping and phenotypic data. Chronic pain is a moderately heritable trait (heritability = 38.4%, 95% CI 33.6% to 43.9% that is significantly concordant in spouses (variance explained 18.7%, 95% CI 9.5% to 25.1%. Chronic pain is positively correlated with depression (ρ = 0.13, 95% CI 0.11 to 0.15, p = 2.72x10-68 and shows a tendency to cluster within families for genetic reasons (genetic correlation = 0.51, 95%CI 0.40 to 0.62, p = 8.24x10-19. Polygenic risk profiles for pain, generated using independent GWAS data, were associated

  12. Associations of Fitness, Physical Activity, Strength, and Genetic Risk With Cardiovascular Disease: Longitudinal Analyses in the UK Biobank Study.

    Science.gov (United States)

    Tikkanen, Emmi; Gustafsson, Stefan; Ingelsson, Erik

    2018-04-09

    Background -Observational studies have shown inverse associations among fitness, physical activity, and cardiovascular disease. However, little is known about these associations in individuals with elevated genetic susceptibility for these diseases. Methods -We estimated associations of grip strength, objective and subjective physical activity, and cardiorespiratory fitness with cardiovascular events and all-cause death in a large cohort of 502635 individuals from the UK Biobank (median follow-up, 6.1 years; interquartile range, 5.4-6.8 years). Then we further examined these associations in individuals with different genetic burden by stratifying individuals based on their genetic risk scores for coronary heart disease and atrial fibrillation. We compared disease risk among individuals in different tertiles of fitness, physical activity, and genetic risk using lowest tertiles as reference. Results -Grip strength, physical activity, and cardiorespiratory fitness showed inverse associations with incident cardiovascular events (coronary heart disease: hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.77- 0.81; HR, 0.95; 95% CI, 0.93-0.97; and HR, 0.68; 95% CI, 0.63-0.74, per SD change, respectively; atrial fibrillation: HR, 0.75; 95% CI, 0.73- 0.76; HR, 0.93; 95% CI, 0.91-0.95; and HR, 0.60; 95% CI, 0.56-0.65, per SD change, respectively). Higher grip strength and cardiorespiratory fitness were associated with lower risk of incident coronary heart disease and atrial fibrillation in each genetic risk score group ( P trend fitness were associated with 49% lower risk for coronary heart disease (HR, 0.51; 95% CI, 0.38-0.69) and 60% lower risk for atrial fibrillation (HR, 0.40; 95%, CI 0.30-0.55) among individuals at high genetic risk for these diseases. Conclusions - Fitness and physical activity demonstrated inverse associations with incident cardiovascular disease in the general population, as well as in individuals with elevated genetic risk for these diseases.

  13. The effectiveness of argumentation in tutorial dialogues with an Intelligent Tutoring System for genetic risk of breast cancer

    Science.gov (United States)

    Cedillos-Whynott, Elizabeth M.; Wolfe, Christopher R.; Widmer, Colin L.; Brust-Renck, Priscila G.; Weil, Audrey; Reyna, Valerie F.

    2017-01-01

    BRCA Gist is an Intelligent Tutoring System that helps women understand issues related to genetic testing and breast cancer risk. In two laboratory experiments and a field experiment with community and web-based samples, an avatar asked 120 participants to produce arguments for and against genetic testing for breast cancer risk. Two raters assessed the number of argumentation elements (claim, reason, backing, etc.) found in response to prompts soliciting arguments for and against genetic testing for breast cancer risk (IRR=.85). When asked to argue for genetic testing, 53.3 % failed to meet the minimum operational definition of making an argument, a claim supported by one or more reasons. When asked to argue against genetic testing, 59.3 % failed to do so. Of those who failed to generate arguments most simply listed disconnected reasons. However, participants who provided arguments against testing (40.7 %) performed significantly higher on a posttest of declarative knowledge. In each study we found positive correlations between the quality of arguments against genetic testing (i.e., number of argumentation elements) and genetic risk categorization scores. Although most interactions did not contain two or more argument elements, when more elements of arguments were included in the argument against genetic testing interaction, participants had greater learning outcomes. Apparently, many participants lack skills in making coherent arguments. These results suggest an association between argumentation ability (knowing how to make complex arguments) and subsequent learning. Better education in developing arguments may be necessary for people to learn from generating arguments within Intelligent Tutoring Systems and other settings. PMID:26511370

  14. Night Shift Work, Genetic Risk, and Type 2 Diabetes in the UK Biobank.

    Science.gov (United States)

    Vetter, Céline; Dashti, Hassan S; Lane, Jacqueline M; Anderson, Simon G; Schernhammer, Eva S; Rutter, Martin K; Saxena, Richa; Scheer, Frank A J L

    2018-04-01

    To examine the effects of past and current night shift work and genetic type 2 diabetes vulnerability on type 2 diabetes odds. In the UK Biobank, we examined associations of current ( N = 272,214) and lifetime ( N = 70,480) night shift work exposure with type 2 diabetes risk (6,770 and 1,191 prevalent cases, respectively). For 180,704 and 44,141 unrelated participants of European ancestry (4,002 and 726 cases, respectively) with genetic data, we assessed whether shift work exposure modified the relationship between a genetic risk score (comprising 110 single-nucleotide polymorphisms) for type 2 diabetes and prevalent diabetes. Compared with day workers, all current night shift workers were at higher multivariable-adjusted odds for type 2 diabetes (none or rare night shifts: odds ratio [OR] 1.15 [95% CI 1.05-1.26]; some nights: OR 1.18 [95% CI 1.05-1.32]; and usual nights: OR 1.44 [95% CI 1.19-1.73]), except current permanent night shift workers (OR 1.09 [95% CI 0.93-1.27]). Considering a person's lifetime work schedule and compared with never shift workers, working more night shifts per month was associated with higher type 2 diabetes odds (8/month: OR 1.36 [95% CI 1.14-1.62]; P trend = 0.001). The association between genetic type 2 diabetes predisposition and type 2 diabetes odds was not modified by shift work exposure. Our findings show that night shift work, especially rotating shift work including night shifts, is associated with higher type 2 diabetes odds and that the number of night shifts worked per month appears most relevant for type 2 diabetes odds. Also, shift work exposure does not modify genetic risk for type 2 diabetes, a novel finding that warrants replication. © 2018 by the American Diabetes Association.

  15. The Association between Infants' Attention Control and Social Inhibition Is Moderated by Genetic and Environmental Risk for Anxiety

    Science.gov (United States)

    Brooker, Rebecca J.; Neiderhiser, Jenae M.; Kiel, Elizabeth J.; Leve, Leslie D.; Shaw, Daniel S.; Reiss, David

    2011-01-01

    Infant social inhibition is associated with increased risk for anxiety later in life. Although both genetic and environmental factors are associated with anxiety, little empirical work has addressed how developing regulatory abilities work with genetic and environmental risk to exacerbate or mitigate problem behaviors. The current study was aimed…

  16. Who is at risk for compassion fatigue? An investigation of genetic counselor demographics, anxiety, compassion satisfaction, and burnout.

    Science.gov (United States)

    Lee, Whiwon; Veach, Patricia McCarthy; MacFarlane, Ian M; LeRoy, Bonnie S

    2015-04-01

    Compassion fatigue is a state of detachment and isolation experienced when healthcare providers repeatedly engage with patients in distress. Compassion fatigue can hinder empathy and cause extreme tension. Prior research suggests 73.8 % of genetic counselors are at moderate to high risk for compassion fatigue and approximately 1 in 4 have considered leaving the field as a result Injeyan et al. (Journal of Genetic Counseling, 20, 526-540, 2011). Empirical data to establish a reliable profile of genetic counselors at risk for compassion fatigue are limited. Thus the purpose of this study was to establish a profile by assessing relationships between state and trait anxiety, burnout, compassion satisfaction, selected demographics and compassion fatigue risk in practicing genetic counselors. Practicing genetic counselors (n = 402) completed an anonymous, online survey containing demographic questions, the State-Trait Anxiety Inventory, and the Professional Quality of Life scale. Multiple regression analysis yielded four significant predictors which increase compassion fatigue risk (accounting for 48 % of the variance): higher levels of trait anxiety, burnout, and compassion satisfaction, and ethnicity other than Caucasian. Additional findings, study limitations, practice implications, and research recommendations are provided.

  17. Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis

    NARCIS (Netherlands)

    Manousaki, Despoina; Dudding, Tom; Haworth, Simon; Hsu, Yi Hsiang; Liu, Ching Ti; Medina-Gómez, Carolina; Voortman, Trudy; Velde, Van Der Nathalie; Melhus, Håkan; Vandenput, Liesbeth; Noordam, Raymond; Forgetta, Vincenzo; Greenwood, Celia M.T.; Biggs, Mary L.; Psaty, Bruce M.; Rotter, Jerome I.; Zemel, Babette S.; Mitchell, Jonathan A.; Taylor, Bruce; Lorentzon, Mattias; Karlsson, Magnus; Jaddoe, Vincent W.V.; Tiemeier, Henning; Campos-Obando, Natalia; Franco, Oscar H.; Utterlinden, Andre G.; Broer, Linda; Schoor, van Natasja M.; Ham, Annelies C.; Ikram, Arfan M.A.; Karasik, David; Mutsert, De Renée; Rosendaal, Frits R.; Heijer, den Martin; Wang, Thomas J.; Lind, Lars; Orwoll, Eric S.; Mook-Kanamori, Dennis O.; Michaëlsson, Karl; Kestenbaum, Bryan; Ohlsson, Claes; Mellström, Dan; Groot, de Lisette C.P.G.M.; Grant, Struan F.A.; Kiel, Douglas P.; Zillikens, M.C.; Rivadeneira, Fernando; Sawcer, Stephen; Timpson, Nicholas J.; Richards, J.B.

    2017-01-01

    Vitamin D insufficiency is common, correctable, and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that strongly increase the risk of vitamin D insufficiency and tested their effect on risk of multiple

  18. Benefits and risks associated with genetically modified food products.

    Science.gov (United States)

    Kramkowska, Marta; Grzelak, Teresa; Czyżewska, Krystyna

    2013-01-01

    Scientists employing methods of genetic engineering have developed a new group of living organisms, termed 'modified organisms', which found application in, among others, medicine, the pharmaceutical industry and food distribution. The introduction of transgenic products to the food market resulted in them becoming a controversial topic, with their proponents and contestants. The presented study aims to systematize objective data on the potential benefits and risks resulting from the consumption of transgenic food. Genetic modifications of plants and animals are justified by the potential for improvement of the food situation worldwide, an increase in yield crops, an increase in the nutritional value of food, and the development of pharmaceutical preparations of proven clinical significance. In the opinions of critics, however, transgenic food may unfavourably affect the health of consumers. Therefore, particular attention was devoted to the short- and long-lasting undesirable effects, such as alimentary allergies, synthesis of toxic agents or resistance to antibiotics. Examples arguing for the justified character of genetic modifications and cases proving that their use can be dangerous are innumerable. In view of the presented facts, however, complex studies are indispensable which, in a reliable way, evaluate effects linked to the consumption of food produced with the application of genetic engineering techniques. Whether one backs up or negates transgenic products, the choice between traditional and non-conventional food remains to be decided exclusively by the consumers.

  19. Classification of rare missense substitutions, using risk surfaces, with genetic- and molecular-epidemiology applications.

    Science.gov (United States)

    Tavtigian, Sean V; Byrnes, Graham B; Goldgar, David E; Thomas, Alun

    2008-11-01

    Many individually rare missense substitutions are encountered during deep resequencing of candidate susceptibility genes and clinical mutation screening of known susceptibility genes. BRCA1 and BRCA2 are among the most resequenced of all genes, and clinical mutation screening of these genes provides an extensive data set for analysis of rare missense substitutions. Align-GVGD is a mathematically simple missense substitution analysis algorithm, based on the Grantham difference, which has already contributed to classification of missense substitutions in BRCA1, BRCA2, and CHEK2. However, the distribution of genetic risk as a function of Align-GVGD's output variables Grantham variation (GV) and Grantham deviation (GD) has not been well characterized. Here, we used data from the Myriad Genetic Laboratories database of nearly 70,000 full-sequence tests plus two risk estimates, one approximating the odds ratio and the other reflecting strength of selection, to display the distribution of risk in the GV-GD plane as a series of surfaces. We abstracted contours from the surfaces and used the contours to define a sequence of missense substitution grades ordered from greatest risk to least risk. The grades were validated internally using a third, personal and family history-based, measure of risk. The Align-GVGD grades defined here are applicable to both the genetic epidemiology problem of classifying rare missense substitutions observed in known susceptibility genes and the molecular epidemiology problem of analyzing rare missense substitutions observed during case-control mutation screening studies of candidate susceptibility genes. (c) 2008 Wiley-Liss, Inc.

  20. Characterization of clinical and genetic risk factors associated with dyslipidemia after kidney transplantation.

    Science.gov (United States)

    Numakura, Kazuyuki; Kagaya, Hideaki; Yamamoto, Ryohei; Komine, Naoki; Saito, Mitsuru; Hiroshi, Tsuruta; Akihama, Susumu; Inoue, Takamitsu; Narita, Shintaro; Tsuchiya, Norihiko; Habuchi, Tomonori; Niioka, Takenori; Miura, Masatomo; Satoh, Shigeru

    2015-01-01

    We determined the prevalence of dyslipidemia in a Japanese cohort of renal allograft recipients and investigated clinical and genetic characteristics associated with having the disease. In total, 126 patients that received renal allograft transplants between February 2002 and August 2011 were studied, of which 44 recipients (34.9%) were diagnosed with dyslipidemia at 1 year after transplantation. Three clinical factors were associated with a risk of having dyslipidemia: a higher prevalence of disease observed among female than male patients (P = 0.021) and treatment with high mycophenolate mofetil (P = 0.012) and prednisolone (P = 0.023) doses per body weight at 28 days after transplantation. The genetic association between dyslipidemia and 60 previously described genetic polymorphisms in 38 putative disease-associated genes was analyzed. The frequency of dyslipidemia was significantly higher in patients with the glucocorticoid receptor (NR3C1) Bcl1 G allele than in those with the CC genotype (P = 0.001). A multivariate analysis revealed that the NR3C1 Bcl1 G allele was a significant risk factor for the prevalence of dyslipidemia (odds ratio = 4.6; 95% confidence interval = 1.8-12.2). These findings may aid in predicting a patient's risk of developing dyslipidemia.

  1. Characterization of Clinical and Genetic Risk Factors Associated with Dyslipidemia after Kidney Transplantation

    Science.gov (United States)

    Numakura, Kazuyuki; Kagaya, Hideaki; Yamamoto, Ryohei; Komine, Naoki; Saito, Mitsuru; Hiroshi, Tsuruta; Akihama, Susumu; Narita, Shintaro; Tsuchiya, Norihiko; Habuchi, Tomonori; Niioka, Takenori; Miura, Masatomo; Satoh, Shigeru

    2015-01-01

    We determined the prevalence of dyslipidemia in a Japanese cohort of renal allograft recipients and investigated clinical and genetic characteristics associated with having the disease. In total, 126 patients that received renal allograft transplants between February 2002 and August 2011 were studied, of which 44 recipients (34.9%) were diagnosed with dyslipidemia at 1 year after transplantation. Three clinical factors were associated with a risk of having dyslipidemia: a higher prevalence of disease observed among female than male patients (P = 0.021) and treatment with high mycophenolate mofetil (P = 0.012) and prednisolone (P = 0.023) doses per body weight at 28 days after transplantation. The genetic association between dyslipidemia and 60 previously described genetic polymorphisms in 38 putative disease-associated genes was analyzed. The frequency of dyslipidemia was significantly higher in patients with the glucocorticoid receptor (NR3C1) Bcl1 G allele than in those with the CC genotype (P = 0.001). A multivariate analysis revealed that the NR3C1 Bcl1 G allele was a significant risk factor for the prevalence of dyslipidemia (odds ratio = 4.6; 95% confidence interval = 1.8–12.2). These findings may aid in predicting a patient's risk of developing dyslipidemia. PMID:25944971

  2. Octodon Degus: A Strong Attractor for Alzheimer Research

    Directory of Open Access Journals (Sweden)

    Rafael Castro-Fuentes

    2013-01-01

    Full Text Available   The most popular animal models of Alzheimer’s disease (AD are transgenic mice expressing human genes with known mutations which do not represent the most abundant sporadic form of the disease. An increasing number of genetic, vascular and psychosocial data strongly support that the Octodon degus, a moderate-sized and diurnal precocial rodent, provides a naturalistic model for the study of the early neurodegenerative process associated with sporadic AD. In this minireview we describe and analyze the risk factors that contribute to Alzheimer-like characteristics in the degus, following recent publications, and establish some guidelines for future studies in this model of natural aging associated with the disease. Given the heterogeneity of current data derived from the diverse transgenic animal models of AD, now may be the time for the degus to become a strong attractor for academic research labs and companies involved with AD. This may help to understand the mechanisms responsible for the early neurodegenerative process associated with this devastating disease.

  3. Octodon Degus: A Strong Attractor for Alzheimer Research

    Directory of Open Access Journals (Sweden)

    Rafael Castro-Fuentes

    2013-02-01

    Full Text Available The most popular animal models of Alzheimer’s disease (AD are transgenic mice expressing human genes with known mutations which do not represent the most abundant sporadic form of the disease. An increasing number of genetic, vascular and psychosocial data strongly support that the Octodon degus, a moderate-sized and diurnal precocial rodent, provides a naturalistic model for the study of the early neurodegenerative process associated with sporadic AD. In this minireview we describe and analyze the risk factors that contribute to Alzheimer-like characteristics in the degus, following recent publications, and establish some guidelines for future studies in this model of natural aging associated with the disease. Given the heterogeneity of current data derived from the diverse transgenic animal models of AD, now may be the time for the degus to become a strong attractor for academic research labs and companies involved with AD. This may help to understand the mechanisms responsible for the early neurodegenerative process associated with this devastating disease.

  4. Do species conservation assessments capture genetic diversity?

    Directory of Open Access Journals (Sweden)

    Malin C. Rivers

    2014-12-01

    Full Text Available The best known system for classifying threat status of species, the IUCN Red List, currently lacks explicit considerations of genetic diversity, and consequently may not account for potential adaptation of species to future environmental change. To address this gap, we integrate range-wide genetic analysis with IUCN Red List assessments.We calculated the loss of genetic diversity under simulated range loss for species of Delonix (Leguminosae. Simulated range loss involved random loss of populations and was intended to model ongoing habitat destruction. We found a strong relationship between loss of genetic diversity and range. Moreover, we found correspondence between levels of genetic diversity and thresholds for ‘non-threatened’ versus ‘threatened’ IUCN Red List categories.Our results support the view that current threat thresholds of the IUCN Red List criteria reflect genetic diversity, and hence evolutionary potential; although the genetic diversity distinction between threatened categories was less evident. Thus, by supplementing conventional conservation assessments with genetic data, new insights into the biological robustness of IUCN Red List assessments for targeted conservation initiatives can be achieved. Keywords: Conservation assessment, Conservation genetics, Extinction risk, Genetic diversity, IUCN Red List, Range

  5. Diabetes-specific genetic effects on obesity traits in American Indian populations: the Strong Heart Family Study

    Directory of Open Access Journals (Sweden)

    Howard Barbara V

    2008-10-01

    Full Text Available Abstract Background Body fat mass distribution and deposition are determined by multiple environmental and genetic factors. Obesity is associated with insulin resistance, hyperinsulinemia, and type 2 diabetes. We previously identified evidence for genotype-by-diabetes interaction on obesity traits in Strong Heart Family Study (SHFS participants. To localize these genetic effects, we conducted genome-wide linkage scans of obesity traits in individuals with and without type 2 diabetes, and in the combined sample while modeling interaction with diabetes using maximum likelihood methods (SOLAR 2.1.4. Methods SHFS recruited American Indians from Arizona, North and South Dakota, and Oklahoma. Anthropometric measures and diabetes status were obtained during a clinic visit. Marker allele frequencies were derived using maximum likelihood methods estimated from all individuals and multipoint identity by descent sharing was estimated using Loki. We used variance component linkage analysis to localize quantitative trait loci (QTLs influencing obesity traits. We tested for evidence of additive and QTL-specific genotype-by-diabetes interactions using the regions identified in the diabetes-stratified analyses. Results Among 245 diabetic and 704 non-diabetic American Indian individuals, we detected significant additive gene-by-diabetes interaction for weight and BMI (P P Conclusion These results suggest distinct genetic effects on body mass in individuals with diabetes compared to those without diabetes, and a possible role for one or more genes on chromosome 1 in the pathogenesis of obesity.

  6. The downside of strong emotional memories: how human memory-related genes influence the risk for posttraumatic stress disorder--a selective review.

    Science.gov (United States)

    Wilker, Sarah; Elbert, Thomas; Kolassa, Iris-Tatjana

    2014-07-01

    A good memory for emotionally arousing experiences may be intrinsically adaptive, as it helps the organisms to predict safety and danger and to choose appropriate responses to prevent potential harm. However, under conditions of repeated exposure to traumatic stressors, strong emotional memories of these experiences can lead to the development of trauma-related disorders such as posttraumatic stress disorder (PTSD). This syndrome is characterized by distressing intrusive memories that can be so intense that the survivor is unable to discriminate past from present experiences. This selective review on the role of memory-related genes in PTSD etiology is divided in three sections. First, we summarize studies indicating that the likelihood to develop PTSD depends on the cumulative exposure to traumatic stressors and on individual predisposing risk factors, including a substantial genetic contribution to PTSD risk. Second, we focus on memory processes supposed to be involved in PTSD etiology and present evidence for PTSD-associated alterations in both implicit (fear conditioning, fear extinction) and explicit memory for emotional material. This is supplemented by a brief description of structural and functional alterations in memory-relevant brain regions in PTSD. Finally, we summarize a selection of studies indicating that genetic variations found to be associated with enhanced fear conditioning, reduced fear extinction or better episodic memory in human experimental studies can have clinical implications in the case of trauma exposure and influence the risk of PTSD development. Here, we focus on genes involved in noradrenergic (ADRA2B), serotonergic (SLC6A4), and dopaminergic signaling (COMT) as well as in the molecular cascades of memory formation (PRKCA and WWC1). This is supplemented by initial evidence that such memory-related genes might also influence the response rates of exposure-based psychotherapy or pharmacological treatment of PTSD, which underscores the

  7. Evaluation of type 2 diabetes genetic risk variants in Chinese adults

    DEFF Research Database (Denmark)

    Gan, Wei; Walters, Robin G; Holmes, Michael V

    2016-01-01

    : Association signals were directionally consistent between CKB and the original discovery GWAS: of 56 variants passing quality control, 48 showed the same direction of effect (binomial test, p = 2.3 × 10(-8)). We observed a consistent overall trend towards lower risk variant effect sizes in CKB than in case......-control samples of GWAS meta-analyses (mean 19-22% decrease in log odds, p ≤ 0.0048), likely to reflect correction of both 'winner's curse' and spectrum bias effects. The association with risk of diabetes of a genetic risk score, based on lead variants at 25 loci considered to act through beta cell function...

  8. Genetic risk prediction and neurobiological understanding of alcoholism.

    Science.gov (United States)

    Levey, D F; Le-Niculescu, H; Frank, J; Ayalew, M; Jain, N; Kirlin, B; Learman, R; Winiger, E; Rodd, Z; Shekhar, A; Schork, N; Kiefer, F; Kiefe, F; Wodarz, N; Müller-Myhsok, B; Dahmen, N; Nöthen, M; Sherva, R; Farrer, L; Smith, A H; Kranzler, H R; Rietschel, M; Gelernter, J; Niculescu, A B

    2014-05-20

    We have used a translational Convergent Functional Genomics (CFG) approach to discover genes involved in alcoholism, by gene-level integration of genome-wide association study (GWAS) data from a German alcohol dependence cohort with other genetic and gene expression data, from human and animal model studies, similar to our previous work in bipolar disorder and schizophrenia. A panel of all the nominally significant P-value SNPs in the top candidate genes discovered by CFG  (n=135 genes, 713 SNPs) was used to generate a genetic  risk prediction score (GRPS), which showed a trend towards significance (P=0.053) in separating  alcohol dependent individuals from controls in an independent German test cohort. We then validated and prioritized our top findings from this discovery work, and subsequently tested them in three independent cohorts, from two continents. A panel of all the nominally significant P-value single-nucleotide length polymorphisms (SNPs) in the top candidate genes discovered by CFG (n=135 genes, 713 SNPs) were used to generate a Genetic Risk Prediction Score (GRPS), which showed a trend towards significance (P=0.053) in separating alcohol-dependent individuals from controls in an independent German test cohort. In order to validate and prioritize the key genes that drive behavior without some of the pleiotropic environmental confounds present in humans, we used a stress-reactive animal model of alcoholism developed by our group, the D-box binding protein (DBP) knockout mouse, consistent with the surfeit of stress theory of addiction proposed by Koob and colleagues. A much smaller panel (n=11 genes, 66 SNPs) of the top CFG-discovered genes for alcoholism, cross-validated and prioritized by this stress-reactive animal model showed better predictive ability in the independent German test cohort (P=0.041). The top CFG scoring gene for alcoholism from the initial discovery step, synuclein alpha (SNCA) remained the top gene after the stress

  9. Whole-genome sequencing of monozygotic twins discordant for schizophrenia indicates multiple genetic risk factors for schizophrenia.

    Science.gov (United States)

    Tang, Jinsong; Fan, Yu; Li, Hong; Xiang, Qun; Zhang, Deng-Feng; Li, Zongchang; He, Ying; Liao, Yanhui; Wang, Ya; He, Fan; Zhang, Fengyu; Shugart, Yin Yao; Liu, Chunyu; Tang, Yanqing; Chan, Raymond C K; Wang, Chuan-Yue; Yao, Yong-Gang; Chen, Xiaogang

    2017-06-20

    Schizophrenia is a common disorder with a high heritability, but its genetic architecture is still elusive. We implemented whole-genome sequencing (WGS) analysis of 8 families with monozygotic (MZ) twin pairs discordant for schizophrenia to assess potential association of de novo mutations (DNMs) or inherited variants with susceptibility to schizophrenia. Eight non-synonymous DNMs (including one splicing site) were identified and shared by twins, which were either located in previously reported schizophrenia risk genes (p.V24689I mutation in TTN, p.S2506T mutation in GCN1L1, IVS3+1G > T in DOCK1) or had a benign to damaging effect according to in silico prediction analysis. By searching the inherited rare damaging or loss-of-function (LOF) variants and common susceptible alleles from three classes of schizophrenia candidate genes, we were able to distill genetic alterations in several schizophrenia risk genes, including GAD1, PLXNA2, RELN and FEZ1. Four inherited copy number variations (CNVs; including a large deletion at 16p13.11) implicated for schizophrenia were identified in four families, respectively. Most of families carried both missense DNMs and inherited risk variants, which might suggest that DNMs, inherited rare damaging variants and common risk alleles together conferred to schizophrenia susceptibility. Our results support that schizophrenia is caused by a combination of multiple genetic factors, with each DNM/variant showing a relatively small effect size. Copyright © 2017 Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. All rights reserved.

  10. Interest in and reactions to genetic risk information: The role of implicit theories and self-affirmation.

    Science.gov (United States)

    Taber, Jennifer M; Klein, William M P; Persky, Susan; Ferrer, Rebecca A; Kaufman, Annette R; Thai, Chan L; Harris, Peter R

    2017-10-01

    Implicit theories reflect core assumptions about whether human attributes are malleable or fixed: Incremental theorists believe a characteristic is malleable whereas entity theorists believe it is fixed. People with entity theories about health may be less likely to engage in risk-mitigating behavior. Spontaneous self-affirmation (e.g., reflecting on one's values when threatened) may lessen defensiveness and unhealthy behaviors associated with fixed beliefs, and reduce the likelihood of responding to health risk information with fixed beliefs. Across two studies conducted in the US from 2012 to 2015, we investigated how self-affirmation and implicit theories about health and body weight were linked to engagement with genetic risk information. In Study 1, participants in a genome sequencing trial (n = 511) completed cross-sectional assessments of implicit theories, self-affirmation, and intentions to learn, share, and use genetic information. In Study 2, overweight women (n = 197) were randomized to receive genetic or behavioral explanations for weight; participants completed surveys assessing implicit theories, self-affirmation, self-efficacy, motivation, and intentions. Fixed beliefs about weight were infrequently endorsed across studies (10.8-15.2%). In Study 1, participants with stronger fixed theories were less interested in learning and using genetic risk information about medically actionable disease; these associations were weaker among participants higher in self-affirmation. In Study 2, among participants given behavioral explanations for weight, stronger fixed theories about weight were associated with lower motivation and intentions to eat a healthy diet. Among participants given genetic explanations, being higher in self-affirmation was associated with less fixed beliefs. Stronger health-related fixed theories may decrease the likelihood of benefiting from genetic information, but less so for people who self-affirm. Published by Elsevier Ltd.

  11. Performance of genetic risk factors in prediction of trichloroethylene induced hypersensitivity syndrome.

    Science.gov (United States)

    Dai, Yufei; Chen, Ying; Huang, Hanlin; Zhou, Wei; Niu, Yong; Zhang, Mingrong; Bin, Ping; Dong, Haiyan; Jia, Qiang; Huang, Jianxun; Yi, Juan; Liao, Qijun; Li, Haishan; Teng, Yanxia; Zang, Dan; Zhai, Qingfeng; Duan, Huawei; Shen, Juan; He, Jiaxi; Meng, Tao; Sha, Yan; Shen, Meili; Ye, Meng; Jia, Xiaowei; Xiang, Yingping; Huang, Huiping; Wu, Qifeng; Shi, Mingming; Huang, Xianqing; Yang, Huanming; Luo, Longhai; Li, Sai; Li, Lin; Zhao, Jinyang; Li, Laiyu; Wang, Jun; Zheng, Yuxin

    2015-07-20

    Trichloroethylene induced hypersensitivity syndrome is dose-independent and potentially life threatening disease, which has become one of the serious occupational health issues and requires intensive treatment. To discover the genetic risk factors and evaluate the performance of risk prediction model for the disease, we conducted genomewide association study and replication study with total of 174 cases and 1761 trichloroethylene-tolerant controls. Fifty seven SNPs that exceeded the threshold for genome-wide significance (P < 5 × 10(-8)) were screened to relate with the disease, among which two independent SNPs were identified, that is rs2857281 at MICA (odds ratio, 11.92; P meta = 1.33 × 10(-37)) and rs2523557 between HLA-B and MICA (odds ratio, 7.33; P meta = 8.79 × 10(-35)). The genetic risk score with these two SNPs explains at least 20.9% of the disease variance and up to 32.5-fold variation in inter-individual risk. Combining of two SNPs as predictors for the disease would have accuracy of 80.73%, the area under receiver operator characteristic curves (AUC) scores was 0.82 with sensitivity of 74% and specificity of 85%, which was considered to have excellent discrimination for the disease, and could be considered for translational application for screening employees before exposure.

  12. Nature Versus Nurture: Does Proteostasis Imbalance Underlie the Genetic, Environmental, and Age-Related Risk Factors for Alzheimer's Disease?

    Science.gov (United States)

    Kikis, Elise A

    2017-08-22

    Aging is a risk factor for a number of "age-related diseases", including Alzheimer's disease (AD). AD affects more than a third of all people over the age of 85, and is the leading cause of dementia worldwide. Symptoms include forgetfulness, memory loss, and cognitive decline, ultimately resulting in the need for full-time care. While there is no cure for AD, pharmacological approaches to alleviate symptoms and target underlying causes of the disease have been developed, albeit with limited success. This review presents the age-related, genetic, and environmental risk factors for AD and proposes a hypothesis for the mechanistic link between genetics and the environment. In short, much is known about the genetics of early-onset familial AD (EO-FAD) and the central role played by the Aβ peptide and protein misfolding, but late-onset AD (LOAD) is not thought to have direct genetic causes. Nonetheless, genetic risk factors such as isoforms of the protein ApoE have been identified. Additional findings suggest that air pollution caused by the combustion of fossil fuels may be an important environmental risk factor for AD. A hypothesis suggesting that poor air quality might act by disrupting protein folding homeostasis (proteostasis) is presented.

  13. IQ and schizophrenia in a Swedish national sample: their causal relationship and the interaction of IQ with genetic risk.

    Science.gov (United States)

    Kendler, Kenneth S; Ohlsson, Henrik; Sundquist, Jan; Sundquist, Kristina

    2015-03-01

    The authors sought to clarify the relationship between IQ and subsequent risk for schizophrenia. IQ was assessed at ages 18-20 in 1,204,983 Swedish males born between 1951 and 1975. Schizophrenia was assessed by hospital diagnosis through 2010. Cox proportional hazards models were used to investigate future risk for schizophrenia in individuals as a function of their IQ score, and then stratified models using pairs of relatives were used to adjust for familial cluster. Finally, regression models were used to examine the interaction between IQ and genetic liability on risk for schizophrenia. IQ had a monotonic relationship with schizophrenia risk across the IQ range, with a mean increase in risk of 3.8% per 1-point decrease in IQ; this association was stronger in the lower than the higher IQ range. Co-relative control analyses showed a similar association between IQ and schizophrenia in the general population and in cousin, half-sibling, and full-sibling pairs. A robust interaction was seen between genetic liability to schizophrenia and IQ in predicting schizophrenia risk. Genetic susceptibility for schizophrenia had a much stronger impact on risk of illness for those with low than high intelligence. The IQ-genetic liability interaction arose largely from IQ differences between close relatives. IQ assessed in late adolescence is a robust risk factor for subsequent onset of schizophrenia. This association is not the result of a declining IQ associated with insidious onset. In this large, representative sample, we found no evidence for a link between genius and schizophrenia. Co-relative control analyses showed that the association between lower IQ and schizophrenia is not the result of shared familial risk factors and may be causal. The strongest effect was seen with IQ differences within families. High intelligence substantially attenuates the impact of genetic liability on the risk for schizophrenia.

  14. Molecular genetics and livestock selection. Approaches, opportunities and risks

    International Nuclear Information System (INIS)

    Williams, J.L.

    2005-01-01

    Following domestication, livestock were selected both naturally through adaptation to their environments and by man so that they would fulfil a particular use. As selection methods have become more sophisticated, rapid progress has been made in improving those traits that are easily measured. However, selection has also resulted in decreased diversity. In some cases, improved breeds have replaced local breeds, risking the loss of important survival traits. The advent of molecular genetics provides the opportunity to identify the genes that control particular traits by a gene mapping approach. However, as with selection, the early mapping studies focused on traits that are easy to measure. Where molecular genetics can play a valuable role in livestock production is by providing the means to select effectively for traits that are difficult to measure. Identifying the genes underpinning particular traits requires a population in which these traits are segregating. Fortunately, several experimental populations have been created that have allowed a wide range of traits to be studied. Gene mapping work in these populations has shown that the role of particular genes in controlling variation in a given trait can depend on the genetic background. A second finding is that the most favourable alleles for a trait may in fact. be present in animals that perform poorly for the trait. In the long term, knowledge of -the genes controlling particular traits, and the way they interact with the genetic background, will allow introgression between breeds and the assembly of genotypes that are best suited to particular environments, producing animals with the desired characteristics. If used wisely, this approach will maintain genetic diversity while improving performance over a wide range of desired traits. (author)

  15. How Should Clinicians Counsel a Woman with a Strong Family History of Early-Onset Alzheimer's Disease about Her Pregnancy?

    Science.gov (United States)

    Mapes, Marianna V; O'Brien, Barbara M; King, Louise P

    2017-07-01

    Counseling patients regarding the benefits, harms, and dilemmas of genetic testing is one of the greatest ethical challenges facing reproductive medicine today. With or without test results, clinicians grapple with how to communicate potential genetic risks as patients weigh their reproductive options. Here, we consider a case of a woman with a strong family history of early-onset Alzheimer's disease (EOAD). She is early in her pregnancy and unsure about learning her own genetic status. We address the ethical ramifications of each of her options, which include genetic testing, genetic counseling, and termination versus continuation of the pregnancy. Our analysis foregrounds clinicians' role in helping to ensure autonomous decision making as the patient reflects on these clinical options in light of her goals and values. © 2017 American Medical Association. All Rights Reserved.

  16. Beyond the patient: the broader impact of genetic discrimination among individuals at risk of Huntington disease.

    Science.gov (United States)

    Bombard, Yvonne; Palin, JoAnne; Friedman, Jan M; Veenstra, Gerry; Creighton, Susan; Bottorff, Joan L; Hayden, Michael R

    2012-03-01

    We aimed to address gaps in current understanding of the scope and impact of discrimination, by examining a cohort of individuals at-risk for Huntington disease (HD), to describe the prevalence of concern for oneself and one's family in multiple domains; strategies used to mitigate discrimination; and the extent to which concerns relate to experiences. We conducted a cross-sectional survey of 293 individuals at-risk for HD (80% response rate); 167 respondents were genetically tested and 66 were not. Fear of discrimination was widespread (86%), particularly in the insurance, family and social settings. Approximately half of concerned individuals experienced discrimination (40-62%, depending on genetic status). Concern was associated with "keeping quiet" about one's risk of HD or "taking action to avoid" discrimination. Importantly, concern was highly distressing for some respondents (21% for oneself; 32% for relatives). Overall, concerned respondents with high education levels, who discovered their family history at a younger age, and those who were mutation-positive were more likely to report experiences of discrimination than others who were concerned. Concerns were rarely attributed to genetic test results alone. Concern about genetic discrimination is frequent among individuals at-risk of HD and spans many settings. It influences behavioral patterns and can result in high levels of self-rated distress, highlighting the need for practice and policy interventions. © 2012 Wiley Periodicals, Inc. Copyright © 2012 Wiley Periodicals, Inc.

  17. Genetic and environmental influences on last-year major depression in adulthood: a highly heritable stable liability but strong environmental effects on 1-year prevalence.

    Science.gov (United States)

    Kendler, K S; Gardner, C O

    2017-07-01

    This study seeks to clarify the contribution of temporally stable and occasion-specific genetic and environmental influences on risk for major depression (MD). Our sample was 2153 members of female-female twin pairs from the Virginia Twin Registry. We examined four personal interview waves conducted over an 8-year period with MD in the last year defined by DSM-IV criteria. We fitted a structural equation model to the data using classic Mx. The model included genetic and environmental risk factors for a latent, stable vulnerability to MD and for episodes in each of the four waves. The best-fit model was simple and included genetic and unique environmental influences on the latent liability to MD and unique wave-specific environmental effects. The path from latent liability to MD in the last year was constant over time, moderate in magnitude (+0.65) and weaker than the impact of occasion-specific environmental effects (+0.76). Heritability of the latent stable liability to MD was much higher (78%) than that estimated for last-year MD (32%). Of the total unique environmental influences on MD, 13% reflected enduring consequences of earlier environmental insults, 17% diagnostic error and 70% wave-specific short-lived environmental stressors. Both genetic influences on MD and MD heritability are stable over middle adulthood. However, the largest influence on last-year MD is short-lived environmental effects. As predicted by genetic theory, the heritability of MD is increased substantially by measurement at multiple time points largely through the reduction of the effects of measurement error and short-term environmental risk factors.

  18. Benefits and risks associated with genetically modified food products

    Directory of Open Access Journals (Sweden)

    Marta Kramkowska

    2013-09-01

    Full Text Available Scientists employing methods of genetic engineering have developed a new group of living organisms, termed ‘modified organisms’, which found application in, among others, medicine, the pharmaceutical industry and food distribution. The introduction of transgenic products to the food market resulted in them becoming a controversial topic, with their proponents and contestants. The presented study aims to systematize objective data on the potential benefits and risks resulting from the consumption of transgenic food. Genetic modifications of plants and animals are justified by the potential for improvement of the food situation worldwide, an increase in yield crops, an increase in the nutritional value of food, and the development of pharmaceutical preparations of proven clinical significance. In the opinions of critics, however, transgenic food may unfavourably affect the health of consumers. Therefore, particular attention was devoted to the short- and long-lasting undesirable effects, such as alimentary allergies, synthesis of toxic agents or resistance to antibiotics. Examples arguing for the justified character of genetic modifications and cases proving that their use can be dangerous are innumerable. In view of the presented facts, however, complex studies are indispensable which, in a reliable way, evaluate effects linked to the consumption of food produced with the application of genetic engineering techniques. Whether one backs up or negates transgenic products, the choice between traditional and non-conventional food remains to be decided exclusively by the consumers.

  19. Primary prevention in patients with a strong family history of coronary heart disease.

    Science.gov (United States)

    Burke, Lora A

    2003-01-01

    The interplay of genetic and environmental factors places first-degree relatives of individuals with premature coronary heart disease at greater risk of developing the disease than the general population. Disease processes, such as dyslipidemia, hypertension, and glucose and insulin metabolism, and lifestyle habits, such as eating and exercise patterns, as well as socioeconomic status aggregate in families with coronary heart disease. The degree of risk associated with a family history varies with the degree of relationship and the age at onset of disease. All individuals with a family history of premature heart disease should have a thorough coronary risk assessment performed, which can be initiated in an office visit. Absolute risk for coronary heart disease determination will predict the intensity of preventive interventions. This article reviews the components of risk determination and primary prevention in individuals with a strong family history of coronary heart disease.

  20. Polygenic risk scores for smoking: predictors for alcohol and cannabis use?

    NARCIS (Netherlands)

    Vink, J.M.; de Geus, E.J.C.; Willemsen, G.; Neale, M.C.; Furberg, H.; Boomsma, D.I.

    2014-01-01

    Background and Aims: A strong correlation exists between smoking and the use of alcohol and cannabis. This paper uses polygenic risk scores to explore the possibility of overlapping genetic factors. Those scores reflect a combined effect of selected risk alleles for smoking. Methods: Summary-level

  1. The Relationship Between the Genetic and Environmental Influences on Common Externalizing Psychopathology and Mental Wellbeing

    Science.gov (United States)

    Kendler, Kenneth S.; Myers, John M.; Keyes, Corey L. M.

    2012-01-01

    To determine the relationship between the genetic and environmental risk factors for externalizing psychopathology and mental wellbeing, we examined detailed measures of emotional, social and psychological wellbeing, and a history of alcohol-related problems and smoking behavior in the last year in 1,386 individual twins from same-sex pairs from the MIDUS national US sample assessed in 1995. Cholesky decomposition analyses were performed with the Mx program. The best fit model contained one highly heritable common externalizing psychopathology factor for both substance use/abuse measures, and one strongly heritable common factor for the three wellbeing measures. Genetic and environmental risk factors for externalizing psychopathology were both negatively associated with levels of mental wellbeing and accounted for, respectively, 7% and 21% of its genetic and environmental influences. Adding internalizing psychopathology assessed in the last year to the model, genetic risk factors unique for externalizing psychopathology were now positively related to levels of mental wellbeing, although accounting for only 5% of the genetic variance. Environmental risk factors unique to externalizing psychopathology continued to be negatively associated with mental wellbeing, accounting for 26% of the environmental variance. When both internalizing psychopathology and externalizing psychopathology are associated with mental wellbeing, the strongest risk factors for low mental wellbeing are genetic factors that impact on both internalizing psychopathology and externalizing psychopathology, and environmental factors unique to externalizing psychopathology. In this model, genetic risk factors for externalizing psychopathology predict, albeit weakly, higher levels of mental wellbeing. PMID:22506307

  2. Genetic Risk Can Be Decreased: Quitting Smoking Decreases and Delays Lung Cancer for Smokers With High and Low CHRNA5 Risk Genotypes — A Meta-Analysis

    Directory of Open Access Journals (Sweden)

    Li-Shiun Chen

    2016-09-01

    Conclusion: We demonstrate that quitting smoking is highly beneficial in reducing lung cancer risks for smokers regardless of their CHRNA5 rs16969968 genetic risk status. Smokers with high-risk CHRNA5 genotypes, on average, can largely eliminate their elevated genetic risk for lung cancer by quitting smoking- cutting their risk of lung cancer in half and delaying its onset by 7 years for those who develop it. These results: 1 underscore the potential value of smoking cessation for all smokers, 2 suggest that CHRNA5 rs16969968 genotype affects lung cancer diagnosis through its effects on smoking, and 3 have potential value for framing preventive interventions for those who smoke.

  3. Awareness, knowledge, perceptions, and attitudes towards genetic testing for cancer risk among ethnic minority groups: a systematic review.

    Science.gov (United States)

    Hann, Katie E J; Freeman, Madeleine; Fraser, Lindsay; Waller, Jo; Sanderson, Saskia C; Rahman, Belinda; Side, Lucy; Gessler, Sue; Lanceley, Anne

    2017-05-25

    Genetic testing for risk of hereditary cancer can help patients to make important decisions about prevention or early detection. US and UK studies show that people from ethnic minority groups are less likely to receive genetic testing. It is important to understand various groups' awareness of genetic testing and its acceptability to avoid further disparities in health care. This review aims to identify and detail awareness, knowledge, perceptions, and attitudes towards genetic counselling/testing for cancer risk prediction in ethnic minority groups. A search was carried out in PsycInfo, CINAHL, Embase and MEDLINE. Search terms referred to ethnicity, genetic testing/counselling, cancer, awareness, knowledge, attitudes, and perceptions. Quantitative and qualitative studies, written in English, and published between 2000 and 2015, were included. Forty-one studies were selected for review: 39 from the US, and two from Australia. Results revealed low awareness and knowledge of genetic counselling/testing for cancer susceptibility amongst ethnic minority groups including African Americans, Asian Americans, and Hispanics. Attitudes towards genetic testing were generally positive; perceived benefits included positive implications for personal health and being able to inform family. However, negative attitudes were also evident, particularly the anticipated emotional impact of test results, and concerns about confidentiality, stigma, and discrimination. Chinese Australian groups were less studied, but of interest was a finding from qualitative research indicating that different views of who close family members are could impact on reported family history of cancer, which could in turn impact a risk assessment. Interventions are needed to increase awareness and knowledge of genetic testing for cancer risk and to reduce the perceived stigma and taboo surrounding the topic of cancer in ethnic minority groups. More detailed research is needed in countries other than the US and

  4. Prediction of individual genetic risk to prostate cancer using a polygenic score

    DEFF Research Database (Denmark)

    Szulkin, Robert; Whitington, Thomas; Eklund, Martin

    2015-01-01

    BACKGROUND: Polygenic risk scores comprising established susceptibility variants have shown to be informative classifiers for several complex diseases including prostate cancer. For prostate cancer it is unknown if inclusion of genetic markers that have so far not been associated with prostate ca...

  5. Genetic determinants of LDL, lipoprotein(a), triglyceride-rich lipoproteins and HDL: concordance and discordance with cardiovascular disease risk

    DEFF Research Database (Denmark)

    Nordestgaard, Børge G; Tybjærg-Hansen, Anne

    2011-01-01

    To evaluate whether new and known genetic determinants of plasma levels of LDL cholesterol, lipoprotein(a), triglyceride-rich lipoproteins, and HDL cholesterol associate with the risk of cardiovascular disease expected from the effect on lipoprotein levels. Concordance or discordance...... of such genetic determinants with cardiovascular disease risk will either favor or disfavor that these lipoproteins are causally related to cardiovascular disease....

  6. Joint association of nicotinic acetylcholine receptor variants with abdominal obesity in American Indians: the Strong Heart Family Study.

    Science.gov (United States)

    Zhu, Yun; Yang, Jingyun; Yeh, Fawn; Cole, Shelley A; Haack, Karin; Lee, Elisa T; Howard, Barbara V; Zhao, Jinying

    2014-01-01

    Cigarette smoke is a strong risk factor for obesity and cardiovascular disease. The effect of genetic variants involved in nicotine metabolism on obesity or body composition has not been well studied. Though many genetic variants have previously been associated with adiposity or body fat distribution, a single variant usually confers a minimal individual risk. The goal of this study is to evaluate the joint association of multiple variants involved in cigarette smoke or nicotine dependence with obesity-related phenotypes in American Indians. To achieve this goal, we genotyped 61 tagSNPs in seven genes encoding nicotine acetylcholine receptors (nAChRs) in 3,665 American Indians participating in the Strong Heart Family Study. Single SNP association with obesity-related traits was tested using family-based association, adjusting for traditional risk factors including smoking. Joint association of all SNPs in the seven nAChRs genes were examined by gene-family analysis based on weighted truncated product method (TPM). Multiple testing was controlled by false discovery rate (FDR). Results demonstrate that multiple SNPs showed weak individual association with one or more measures of obesity, but none survived correction for multiple testing. However, gene-family analysis revealed significant associations with waist circumference (p = 0.0001) and waist-to-hip ratio (p = 0.0001), but not body mass index (p = 0.20) and percent body fat (p = 0.29), indicating that genetic variants are jointly associated with abdominal, but not general, obesity among American Indians. The observed combined genetic effect is independent of cigarette smoking per se. In conclusion, multiple variants in the nAChR gene family are jointly associated with abdominal obesity in American Indians, independent of general obesity and cigarette smoking per se.

  7. DTREEv2, a computer-based support system for the risk assessment of genetically modified plants

    NARCIS (Netherlands)

    Pertry, I.; Nothegger, C.; Sweet, J.; Kuiper, H.A.; Davies, H.; Iserentant, D.; Hull, R.; Mezzetti, B.; Messens, K.; Loose, De M.; Oliveira, de D.; Burssens, S.; Gheysen, G.; Tzotzos, G.

    2014-01-01

    Risk assessment of genetically modified organisms (GMOs) remains a contentious area and a major factor influencing the adoption of agricultural biotech. Methodologically, in many countries, risk assessment is conducted by expert committees with little or no recourse to databases and expert systems

  8. Can genetic pleiotropy replicate common clinical constellations of cardiovascular disease and risk?

    Directory of Open Access Journals (Sweden)

    Omri Gottesman

    Full Text Available The relationship between obesity, diabetes, hyperlipidemia, hypertension, kidney disease and cardiovascular disease (CVD is established when looked at from a clinical, epidemiological or pathophysiological perspective. Yet, when viewed from a genetic perspective, there is comparatively little data synthesis that these conditions have an underlying relationship. We sought to investigate the overlap of genetic variants independently associated with each of these commonly co-existing conditions from the NHGRI genome-wide association study (GWAS catalog, in an attempt to replicate the established notion of shared pathophysiology and risk. We used pathway-based analyses to detect subsets of pleiotropic genes involved in similar biological processes. We identified 107 eligible GWAS studies related to CVD and its established comorbidities and risk factors and assigned genes that correspond to the associated signals based on their position. We found 44 positional genes shared across at least two CVD-related phenotypes that independently recreated the established relationship between the six phenotypes, but only if studies representing non-European populations were included. Seven genes revealed pleiotropy across three or more phenotypes, mostly related to lipid transport and metabolism. Yet, many genes had no relationship to each other or to genes with established functional connection. Whilst we successfully reproduced established relationships between CVD risk factors using GWAS findings, interpretation of biological pathways involved in the observed pleiotropy was limited. Further studies linking genetic variation to gene expression, as well as describing novel biological pathways will be needed to take full advantage of GWAS results.

  9. Genetic modifiers of CHEK2*1100delC-associated breast cancer risk

    DEFF Research Database (Denmark)

    Muranen, Taru A; Greco, Dario; Blomqvist, Carl

    2017-01-01

    PURPOSE: CHEK2*1100delC is a founder variant in European populations that confers a two- to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2*1100delC is modified by other genetic factors in a multiplicative fashion....... We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC). METHODS: Using genotype data from 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2*1100delC and 77...

  10. The structure of genetic and environmental risk factors for fears and phobias.

    Science.gov (United States)

    Loken, E K; Hettema, J M; Aggen, S H; Kendler, K S

    2014-08-01

    Although prior genetic studies of interview-assessed fears and phobias have shown that genetic factors predispose individuals to fears and phobias, they have been restricted to the DSM-III to DSM-IV aggregated subtypes of phobias rather than to individual fearful and phobic stimuli. We examined the lifetime history of fears and/or phobias in response to 21 individual phobic stimuli in 4067 personally interviewed twins from same-sex pairs from the Virginia Adult Twin Study of Psychiatric and Substance Abuse Disorders (VATSPSUD). We performed multivariate statistical analyses using Mx and Mplus. The best-fitting model for the 21 phobic stimuli included four genetic factors (agora-social-acrophobia, animal phobia, blood-injection-illness phobia and claustrophobia) and three environmental factors (agora-social-hospital phobia, animal phobia, and situational phobia). This study provides the first view of the architecture of genetic and environmental risk factors for phobic disorders and their subtypes. The genetic factors of the phobias support the DSM-IV and DSM-5 constructs of animal and blood-injection-injury phobias but do not support the separation of agoraphobia from social phobia. The results also do not show a coherent genetic factor for the DSM-IV and DSM-5 situational phobia. Finally, the patterns of co-morbidity across individual fears and phobias produced by genetic and environmental influences differ appreciably.

  11. Genetically modified foods and allergy.

    Science.gov (United States)

    Lee, T H; Ho, H K; Leung, T F

    2017-06-01

    2015 marked the 25th anniversary of the commercial use and availability of genetically modified crops. The area of planted biotech crops cultivated globally occupies a cumulative two billion hectares, equivalent to twice the land size of China or the United States. Foods derived from genetically modified plants are widely consumed in many countries and genetically modified soybean protein is extensively used in processed foods throughout the industrialised countries. Genetically modified food technology offers a possible solution to meet current and future challenges in food and medicine. Yet there is a strong undercurrent of anxiety that genetically modified foods are unsafe for human consumption, sometimes fuelled by criticisms based on little or no firm evidence. This has resulted in some countries turning away food destined for famine relief because of the perceived health risks of genetically modified foods. The major concerns include their possible allergenicity and toxicity despite the vigorous testing of genetically modified foods prior to marketing approval. It is imperative that scientists engage the public in a constructive evidence-based dialogue to address these concerns. At the same time, improved validated ways to test the safety of new foods should be developed. A post-launch strategy should be established routinely to allay concerns. Mandatory labelling of genetically modified ingredients should be adopted for the sake of transparency. Such ingredient listing and information facilitate tracing and recall if required.

  12. Association of substance use disorders with childhood trauma but not African genetic heritage in an African American cohort.

    Science.gov (United States)

    Ducci, Francesca; Roy, Alec; Shen, Pei-Hong; Yuan, Qiaoping; Yuan, Nicole P; Hodgkinson, Colin A; Goldman, Lynn R; Goldman, David

    2009-09-01

    Genetic variation influences differential vulnerability to addiction within populations. However, it remains unclear whether differences in frequencies of vulnerability alleles contribute to disparities between populations and to what extent ancestry correlates with differential exposure to environmental risk factors, including poverty and trauma. The authors used 186 ancestry-informative markers to measure African ancestry in 407 addicts and 457 comparison subjects self-identified as African Americans. The reference group was 1,051 individuals from the Human Genome Diversity Cell Line Panel, which includes 51 diverse populations representing most worldwide genetic diversity. African Americans varied in degrees of African, European, Middle Eastern, and Central Asian genetic heritage. The overall level of African ancestry was actually smaller among cocaine, opiate, and alcohol addicts (proportion=0.76-0.78) than nonaddicted African American comparison subjects (proportion=0.81). African ancestry was associated with living in impoverished neighborhoods, a factor previously associated with risk. There was no association between African ancestry and exposure to childhood abuse or neglect, a factor that strongly predicted all types of addictions. These results suggest that African genetic heritage does not increase the likelihood of genetic risk for addictions. They highlight the complex interrelation between genetic ancestry and social, economic, and environmental conditions and the strong relation of those factors to addiction. Studies of epidemiological samples characterized for genetic ancestry and social, psychological, demographic, economic, cultural, and historical factors are needed to better disentangle the effects of genetic and environmental factors underlying interpopulation differences in vulnerability to addiction and other health disparities.

  13. A risk-based classification scheme for genetically modified foods. I: Conceptual development.

    Science.gov (United States)

    Chao, Eunice; Krewski, Daniel

    2008-12-01

    The predominant paradigm for the premarket assessment of genetically modified (GM) foods reflects heightened public concern by focusing on foods modified by recombinant deoxyribonucleic acid (rDNA) techniques, while foods modified by other methods of genetic modification are generally not assessed for safety. To determine whether a GM product requires less or more regulatory oversight and testing, we developed and evaluated a risk-based classification scheme (RBCS) for crop-derived GM foods. The results of this research are presented in three papers. This paper describes the conceptual development of the proposed RBCS that focuses on two categories of adverse health effects: (1) toxic and antinutritional effects, and (2) allergenic effects. The factors that may affect the level of potential health risks of GM foods are identified. For each factor identified, criteria for differentiating health risk potential are developed. The extent to which a GM food satisfies applicable criteria for each factor is rated separately. A concern level for each category of health effects is then determined by aggregating the ratings for the factors using predetermined aggregation rules. An overview of the proposed scheme is presented, as well as the application of the scheme to a hypothetical GM food.

  14. Genetic risk scores and number of autoantibodies in patients with rheumatoid arthritis

    NARCIS (Netherlands)

    Maehlen, Marthe T.; Olsen, Inge C.; Andreassen, Bettina K.; Viken, Marte K.; Jiang, Xia; Alfredsson, Lars; Kallberg, Henrik; Brynedal, Boel; Kurreeman, Fina; Daha, Nina; Toes, Rene; Zhernakova, Alexandra; Gutierrez-Achury, Javier; de Bakker, Paul I. W.; Martin, Javier; Teruel, Maria; Gonzalez-Gay, Miguel A.; Rodriguez-Rodriguez, Luis; Balsa, Alejandro; Uhlig, Till; Kvien, Tore K.; Lie, Benedicte A.

    Objective Certain HLA-DRB1 alleles and single-nucleotide polymorphisms (SNPs) are associated with rheumatoid arthritis (RA). Our objective was to examine the combined effect of these associated variants, calculated as a cumulative genetic risk score (GRS) on RA predisposition, as well as the number

  15. Genetic risk scores and number of autoantibodies in patients with rheumatoid arthritis

    NARCIS (Netherlands)

    Maehlen, Marthe T; Olsen, Inge C; Andreassen, Bettina K; Viken, Marte K; Jiang, Xia; Alfredsson, Lars; Källberg, Henrik; Brynedal, Boel; Kurreeman, Fina; Daha, Nina; Toes, Rene; Zhernakova, Alexandra; Gutierrez-Achury, Javier; de Bakker, Paul I W; Martin, Javier; Teruel, María; Gonzalez-Gay, Miguel A; Rodríguez-Rodríguez, Luis; Balsa, Alejandro; Uhlig, Till; Kvien, Tore K; Lie, Benedicte A

    OBJECTIVE: Certain HLA-DRB1 alleles and single-nucleotide polymorphisms (SNPs) are associated with rheumatoid arthritis (RA). Our objective was to examine the combined effect of these associated variants, calculated as a cumulative genetic risk score (GRS) on RA predisposition, as well as the number

  16. Genetic Determinants of Thrombin Generation and Their Relation to Venous Thrombosis: Results from the GAIT-2 Project

    Science.gov (United States)

    Martin-Fernandez, Laura; Ziyatdinov, Andrey; Carrasco, Marina; Millon, Juan Antonio; Martinez-Perez, Angel; Vilalta, Noelia; Brunel, Helena; Font, Montserrat; Hamsten, Anders; Souto, Juan Carlos; Soria, José Manuel

    2016-01-01

    Background Venous thromboembolism (VTE) is a common disease where known genetic risk factors explain only a small portion of the genetic variance. Then, the analysis of intermediate phenotypes, such as thrombin generation assay, can be used to identify novel genetic risk factors that contribute to VTE. Objectives To investigate the genetic basis of distinct quantitative phenotypes of thrombin generation and its relationship to the risk of VTE. Patients/Methods Lag time, thrombin peak and endogenous thrombin potential (ETP) were measured in the families of the Genetic Analysis of Idiopathic Thrombophilia 2 (GAIT-2) Project. This sample consisted of 935 individuals in 35 extended families selected through a proband with idiopathic thrombophilia. We performed also genome wide association studies (GWAS) with thrombin generation phenotypes. Results The results showed that 67% of the variation in the risk of VTE is attributable to genetic factors. The heritabilities of lag time, thrombin peak and ETP were 49%, 54% and 52%, respectively. More importantly, we demonstrated also the existence of positive genetic correlations between thrombin peak or ETP and the risk of VTE. Moreover, the major genetic determinant of thrombin generation was the F2 gene. However, other suggestive signals were observed. Conclusions The thrombin generation phenotypes are strongly genetically determined. The thrombin peak and ETP are significantly genetically correlated with the risk of VTE. In addition, F2 was identified as a major determinant of thrombin generation. We reported suggestive signals that might increase our knowledge to explain the variability of this important phenotype. Validation and functional studies are required to confirm GWAS results. PMID:26784699

  17. Abnormal temporal lobe white matter as a biomarker for genetic risk of bipolar disorder.

    Science.gov (United States)

    Mahon, Katie; Burdick, Katherine E; Ikuta, Toshikazu; Braga, Raphael J; Gruner, Patricia; Malhotra, Anil K; Szeszko, Philip R

    2013-01-15

    Brain white matter (WM) abnormalities have been hypothesized to play an important role in the neurobiology of bipolar disorder (BD). The nature of these abnormalities is not well-characterized, however, and it is unknown whether they occur after disease onset or represent potential markers of genetic risk. We examined WM integrity (assessed via fractional anisotropy [FA]) with diffusion tensor imaging in patients with BD (n=26), unaffected siblings of patients with BD (n=15), and healthy volunteers (n=27) to identify WM biomarkers of genetic risk. The FA differed significantly (punaffected siblings>BD). Moreover, FA values in this region correlated negatively and significantly with trait impulsivity in unaffected siblings. Probabilistic tractography indicated that the regional abnormality lies along the inferior fronto-occipital fasciculus, a large intrahemispheric association pathway. Our results suggest that lower WM integrity in the right temporal lobe might be a biomarker for genetic risk of BD. It is conceivable that the attenuated nature of these WM abnormalities present in unaffected siblings allows for some preservation of adaptive emotional regulation, whereas more pronounced alterations observed in patients is related to the marked emotional dysregulation characteristic of BD. Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  18. Evidence that hippocampal-parahippocampal dysfunction is related to genetic risk for schizophrenia.

    Science.gov (United States)

    Di Giorgio, A; Gelao, B; Caforio, G; Romano, R; Andriola, I; D'Ambrosio, E; Papazacharias, A; Elifani, F; Bianco, L Lo; Taurisano, P; Fazio, L; Popolizio, T; Blasi, G; Bertolino, A

    2013-08-01

    Abnormalities in hippocampal-parahippocampal (H-PH) function are prominent features of schizophrenia and have been associated with deficits in episodic memory. However, it remains unclear whether these abnormalities represent a phenotype related to genetic risk for schizophrenia or whether they are related to disease state. We investigated H-PH-mediated behavior and physiology, using blood oxygenation level-dependent functional magnetic resonance imaging (BOLD fMRI), during episodic memory in a sample of patients with schizophrenia, clinically unaffected siblings and healthy subjects. Patients with schizophrenia and unaffected siblings displayed abnormalities in episodic memory performance. During an fMRI memory encoding task, both patients and siblings demonstrated a similar pattern of reduced H-PH engagement compared with healthy subjects. Our findings suggest that the pathophysiological mechanism underlying the inability of patients with schizophrenia to properly engage the H-PH during episodic memory is related to genetic risk for the disorder. Therefore, H-PH dysfunction can be assumed as a schizophrenia susceptibility-related phenotype.

  19. Prospective associations of C-reactive protein (CRP) levels and CRP genetic risk scores with risk of total knee and hip replacement for osteoarthritis in a diverse cohort.

    Science.gov (United States)

    Shadyab, A H; Terkeltaub, R; Kooperberg, C; Reiner, A; Eaton, C B; Jackson, R D; Krok-Schoen, J L; Salem, R M; LaCroix, A Z

    2018-05-22

    To examine associations of high-sensitivity C-reactive protein (CRP) levels and polygenic CRP genetic risk scores (GRS) with risk of end-stage hip or knee osteoarthritis (OA), defined as incident total hip (THR) or knee replacement (TKR) for OA. This study included a cohort of postmenopausal white, African American, and Hispanic women from the Women's Health Initiative. Women were followed from baseline to date of THR or TKR, death, or December 31, 2014. Medicare claims data identified THR and TKR. Hs-CRP and genotyping data were collected at baseline. Three CRP GRS were constructed: 1) a 4-SNP GRS comprised of genetic variants representing variation in the CRP gene among European populations; 2) a multilocus 18-SNP GRS of genetic variants significantly associated with CRP levels in a meta-analysis of genome-wide association studies; and 3) a 5-SNP GRS of genetic variants significantly associated with CRP levels among African American women. In analyses conducted separately among each race and ethnic group, there were no significant associations of ln hs-CRP with risk of THR or TKR, after adjusting for age, body mass index, lifestyle characteristics, chronic diseases, hormone therapy use, and non-steroidal anti-inflammatory drug use. CRP GRS were not associated with risk of THR or TKR in any ethnic group. Serum levels of ln hs-CRP and genetically-predicted CRP levels were not associated with risk of THR or TKR for OA among a diverse cohort of women. Copyright © 2018 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

  20. Genetically meaningful phenotypic subgroups in autism spectrum disorders.

    Science.gov (United States)

    Veatch, O J; Veenstra-Vanderweele, J; Potter, M; Pericak-Vance, M A; Haines, J L

    2014-03-01

    Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with strong evidence for genetic susceptibility. However, the effect sizes for implicated chromosomal loci are small, hard to replicate and current evidence does not explain the majority of the estimated heritability. Phenotypic heterogeneity could be one phenomenon complicating identification of genetic factors. We used data from the Autism Diagnostic Interview-Revised, Autism Diagnostic Observation Schedule, Vineland Adaptive Behavior Scales, head circumferences, and ages at exams as classifying variables to identify more clinically similar subgroups of individuals with ASD. We identified two distinct subgroups of cases within the Autism Genetic Resource Exchange dataset, primarily defined by the overall severity of evaluated traits. In addition, there was significant familial clustering within subgroups (odds ratio, OR ≈ 1.38-1.42, P definition that should increase power to detect genetic factors influencing risk for ASD. © 2013 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  1. Association analysis identifies 65 new breast cancer risk loci

    Science.gov (United States)

    Lemaçon, Audrey; Soucy, Penny; Glubb, Dylan; Rostamianfar, Asha; Bolla, Manjeet K.; Wang, Qin; Tyrer, Jonathan; Dicks, Ed; Lee, Andrew; Wang, Zhaoming; Allen, Jamie; Keeman, Renske; Eilber, Ursula; French, Juliet D.; Chen, Xiao Qing; Fachal, Laura; McCue, Karen; McCart Reed, Amy E.; Ghoussaini, Maya; Carroll, Jason; Jiang, Xia; Finucane, Hilary; Adams, Marcia; Adank, Muriel A.; Ahsan, Habibul; Aittomäki, Kristiina; Anton-Culver, Hoda; Antonenkova, Natalia N.; Arndt, Volker; Aronson, Kristan J.; Arun, Banu; Auer, Paul L.; Bacot, François; Barrdahl, Myrto; Baynes, Caroline; Beckmann, Matthias W.; Behrens, Sabine; Benitez, Javier; Bermisheva, Marina; Bernstein, Leslie; Blomqvist, Carl; Bogdanova, Natalia V.; Bojesen, Stig E.; Bonanni, Bernardo; Børresen-Dale, Anne-Lise; Brand, Judith S.; Brauch, Hiltrud; Brennan, Paul; Brenner, Hermann; Brinton, Louise; Broberg, Per; Brock, Ian W.; Broeks, Annegien; Brooks-Wilson, Angela; Brucker, Sara Y.; Brüning, Thomas; Burwinkel, Barbara; Butterbach, Katja; Cai, Qiuyin; Cai, Hui; Caldés, Trinidad; Canzian, Federico; Carracedo, Angel; Carter, Brian D.; Castelao, Jose E.; Chan, Tsun L.; Cheng, Ting-Yuan David; Chia, Kee Seng; Choi, Ji-Yeob; Christiansen, Hans; Clarke, Christine L.; Collée, Margriet; Conroy, Don M.; Cordina-Duverger, Emilie; Cornelissen, Sten; Cox, David G; Cox, Angela; Cross, Simon S.; Cunningham, Julie M.; Czene, Kamila; Daly, Mary B.; Devilee, Peter; Doheny, Kimberly F.; Dörk, Thilo; dos-Santos-Silva, Isabel; Dumont, Martine; Durcan, Lorraine; Dwek, Miriam; Eccles, Diana M.; Ekici, Arif B.; Eliassen, A. Heather; Ellberg, Carolina; Elvira, Mingajeva; Engel, Christoph; Eriksson, Mikael; Fasching, Peter A.; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Flyger, Henrik; Fritschi, Lin; Gaborieau, Valerie; Gabrielson, Marike; Gago-Dominguez, Manuela; Gao, Yu-Tang; Gapstur, Susan M.; García-Sáenz, José A.; Gaudet, Mia M.; Georgoulias, Vassilios; Giles, Graham G.; Glendon, Gord; Goldberg, Mark S.; Goldgar, David E.; González-Neira, Anna; Grenaker Alnæs, Grethe I.; Grip, Mervi; Gronwald, Jacek; Grundy, Anne; Guénel, Pascal; Haeberle, Lothar; Hahnen, Eric; Haiman, Christopher A.; Håkansson, Niclas; Hamann, Ute; Hamel, Nathalie; Hankinson, Susan; Harrington, Patricia; Hart, Steven N.; Hartikainen, Jaana M.; Hartman, Mikael; Hein, Alexander; Heyworth, Jane; Hicks, Belynda; Hillemanns, Peter; Ho, Dona N.; Hollestelle, Antoinette; Hooning, Maartje J.; Hoover, Robert N.; Hopper, John L.; Hou, Ming-Feng; Hsiung, Chia-Ni; Huang, Guanmengqian; Humphreys, Keith; Ishiguro, Junko; Ito, Hidemi; Iwasaki, Motoki; Iwata, Hiroji; Jakubowska, Anna; Janni, Wolfgang; John, Esther M.; Johnson, Nichola; Jones, Kristine; Jones, Michael; Jukkola-Vuorinen, Arja; Kaaks, Rudolf; Kabisch, Maria; Kaczmarek, Katarzyna; Kang, Daehee; Kasuga, Yoshio; Kerin, Michael J.; Khan, Sofia; Khusnutdinova, Elza; Kiiski, Johanna I.; Kim, Sung-Won; Knight, Julia A.; Kosma, Veli-Matti; Kristensen, Vessela N.; Krüger, Ute; Kwong, Ava; Lambrechts, Diether; Marchand, Loic Le; Lee, Eunjung; Lee, Min Hyuk; Lee, Jong Won; Lee, Chuen Neng; Lejbkowicz, Flavio; Li, Jingmei; Lilyquist, Jenna; Lindblom, Annika; Lissowska, Jolanta; Lo, Wing-Yee; Loibl, Sibylle; Long, Jirong; Lophatananon, Artitaya; Lubinski, Jan; Luccarini, Craig; Lux, Michael P.; Ma, Edmond S.K.; MacInnis, Robert J.; Maishman, Tom; Makalic, Enes; Malone, Kathleen E; Kostovska, Ivana Maleva; Mannermaa, Arto; Manoukian, Siranoush; Manson, JoAnn E.; Margolin, Sara; Mariapun, Shivaani; Martinez, Maria Elena; Matsuo, Keitaro; Mavroudis, Dimitrios; McKay, James; McLean, Catriona; Meijers-Heijboer, Hanne; Meindl, Alfons; Menéndez, Primitiva; Menon, Usha; Meyer, Jeffery; Miao, Hui; Miller, Nicola; Mohd Taib, Nur Aishah; Muir, Kenneth; Mulligan, Anna Marie; Mulot, Claire; Neuhausen, Susan L.; Nevanlinna, Heli; Neven, Patrick; Nielsen, Sune F.; Noh, Dong-Young; Nordestgaard, Børge G.; Norman, Aaron; Olopade, Olufunmilayo I.; Olson, Janet E.; Olsson, Håkan; Olswold, Curtis; Orr, Nick; Pankratz, V. Shane; Park, Sue K.; Park-Simon, Tjoung-Won; Lloyd, Rachel; Perez, Jose I.A.; Peterlongo, Paolo; Peto, Julian; Phillips, Kelly-Anne; Pinchev, Mila; Plaseska-Karanfilska, Dijana; Prentice, Ross; Presneau, Nadege; Prokofieva, Darya; Pugh, Elizabeth; Pylkäs, Katri; Rack, Brigitte; Radice, Paolo; Rahman, Nazneen; Rennert, Gadi; Rennert, Hedy S.; Rhenius, Valerie; Romero, Atocha; Romm, Jane; Ruddy, Kathryn J; Rüdiger, Thomas; Rudolph, Anja; Ruebner, Matthias; Rutgers, Emiel J. Th.; Saloustros, Emmanouil; Sandler, Dale P.; Sangrajrang, Suleeporn; Sawyer, Elinor J.; Schmidt, Daniel F.; Schmutzler, Rita K.; Schneeweiss, Andreas; Schoemaker, Minouk J.; Schumacher, Fredrick; Schürmann, Peter; Scott, Rodney J.; Scott, Christopher; Seal, Sheila; Seynaeve, Caroline; Shah, Mitul; Sharma, Priyanka; Shen, Chen-Yang; Sheng, Grace; Sherman, Mark E.; Shrubsole, Martha J.; Shu, Xiao-Ou; Smeets, Ann; Sohn, Christof; Southey, Melissa C.; Spinelli, John J.; Stegmaier, Christa; Stewart-Brown, Sarah; Stone, Jennifer; Stram, Daniel O.; Surowy, Harald; Swerdlow, Anthony; Tamimi, Rulla; Taylor, Jack A.; Tengström, Maria; Teo, Soo H.; Terry, Mary Beth; Tessier, Daniel C.; Thanasitthichai, Somchai; Thöne, Kathrin; Tollenaar, Rob A.E.M.; Tomlinson, Ian; Tong, Ling; Torres, Diana; Truong, Thérèse; Tseng, Chiu-chen; Tsugane, Shoichiro; Ulmer, Hans-Ulrich; Ursin, Giske; Untch, Michael; Vachon, Celine; van Asperen, Christi J.; Van Den Berg, David; van den Ouweland, Ans M.W.; van der Kolk, Lizet; van der Luijt, Rob B.; Vincent, Daniel; Vollenweider, Jason; Waisfisz, Quinten; Wang-Gohrke, Shan; Weinberg, Clarice R.; Wendt, Camilla; Whittemore, Alice S.; Wildiers, Hans; Willett, Walter; Winqvist, Robert; Wolk, Alicja; Wu, Anna H.; Xia, Lucy; Yamaji, Taiki; Yang, Xiaohong R.; Yip, Cheng Har; Yoo, Keun-Young; Yu, Jyh-Cherng; Zheng, Wei; Zheng, Ying; Zhu, Bin; Ziogas, Argyrios; Ziv, Elad; Lakhani, Sunil R.; Antoniou, Antonis C.; Droit, Arnaud; Andrulis, Irene L.; Amos, Christopher I.; Couch, Fergus J.; Pharoah, Paul D.P.; Chang-Claude, Jenny; Hall, Per; Hunter, David J.; Milne, Roger L.; García-Closas, Montserrat; Schmidt, Marjanka K.; Chanock, Stephen J.; Dunning, Alison M.; Edwards, Stacey L.; Bader, Gary D.; Chenevix-Trench, Georgia; Simard, Jacques; Kraft, Peter; Easton, Douglas F.

    2017-01-01

    Breast cancer risk is influenced by rare coding variants in susceptibility genes such as BRCA1 and many common, mainly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. We report results from a genome-wide association study (GWAS) of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry1. We identified 65 new loci associated with overall breast cancer at pcancer due to all SNPs in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the utility of genetic risk scores for individualized screening and prevention. PMID:29059683

  2. Genetic Variation in NFKBIE Is Associated With Increased Risk of Pneumococcal Meningitis in Children

    DEFF Research Database (Denmark)

    Lundbo, Lene F; Harboe, Zitta Barrella; Clausen, Louise N

    2016-01-01

    NFKBIA, NFKBIE and NFKBIZ. We aimed to replicate previous findings of genetic variation associated with invasive pneumococcal disease (IPD), and to assess whether similar associations could be found in invasive meningococcal disease (IMD). METHODS: Cases with IPD and IMD and controls were identified......BACKGROUND: Streptococcus pneumoniae and Neisseria meningitidis are frequent pathogens in life-threatening infections. Genetic variation in the immune system may predispose to these infections. Nuclear factor-κB is a key component of the TLR-pathway, controlled by inhibitors, encoded by the genes.......86-1.35). The remaining SNPs were not associated with susceptibility to invasive disease. None of the SNPs were associated with risk of IMD or mortality. CONCLUSIONS: A NFKBIE polymorphism was associated with increased risk of pneumococcal meningitis....

  3. COMPARATIVE EVALUATION OF RISK FACTORS FOR CARDIOVASCULAR DISEASE (CVD) IN GENETICALLY PREDISPOSED RATS

    Science.gov (United States)

    Rodent CVD models are increasingly used for understanding individual differences in susceptibility to environmental stressors such as air pollution. We characterized pathologies and a number of known human risk factors of CVD in genetically predisposed, male young adult Spontaneo...

  4. Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent.

    Directory of Open Access Journals (Sweden)

    Yan Guo

    2016-08-01

    Full Text Available Observational epidemiological studies have shown that high body mass index (BMI is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors.We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC (cases  =  46,325, controls  =  42,482. We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively.In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR]  =  0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56-0.75, p = 3.32 × 10-10. The associations were similar for both premenopausal (OR   =   0.44, 95% CI:0.31-0.62, p  =  9.91 × 10-8 and postmenopausal breast cancer (OR  =  0.57, 95% CI: 0.46-0.71, p  =  1.88 × 10-8. This association was replicated in the data from the DRIVE consortium (OR  =  0.72, 95% CI: 0.60-0.84, p   =   1.64 × 10-7. Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs in association with breast cancer risk at p < 0.05; for 16 of them, the

  5. Ischemic stroke risk, smoking, and the genetics of inflammation in a biracial population: the stroke prevention in young women study

    OpenAIRE

    Cole, John W; Brown, David W; Giles, Wayne H; Stine, Oscar C; O'Connell, Jeffrey R; Mitchell, Braxton D; Sorkin, John D; Wozniak, Marcella A; Stern, Barney J; Sparks, Mary J; Dobbins, Mark T; Shoffner, Latasha T; Zappala, Nancy K; Reinhart, Laurie J; Kittner, Steven J

    2008-01-01

    Abstract Background Although cigarette smoking is a well-established risk factor for vascular disease, the genetic mechanisms that link cigarette smoking to an increased incidence of stroke are not well understood. Genetic variations within the genes of the inflammatory pathways are thought to partially mediate this risk. Here we evaluate the association of several inflammatory gene single nucleotide polymorphisms (SNPs) with ischemic stroke risk among young women, further stratified by curre...

  6. Genetic effects of ionising radiation in man

    International Nuclear Information System (INIS)

    Sankaranarayanan, K.

    1991-01-01

    A review is given of genetic risk estimation in man. Topics covered include the methods used, the germ cell stages and radiation conditions relevant for genetic risk estimation, doubling dose estimates, the classification and prevalence of naturally-occurring genetic disorders, the source of data used in the direct method of risk estimation, the genetic risk estimates from the mid-1970s to the present, the estimates of genetic risk used in ICRP 26 in 1977 and ICRP's current assessment of genetic risks. (UK)

  7. Occupational genetic risks for nurses at radiotherapy oncology wards

    Energy Technology Data Exchange (ETDEWEB)

    Srb, V; Kubzova, E

    1985-05-31

    A lymphocyte chromosome analysis of short-term cultured whole peripheral blood of 14 nurses in the radiotherapy/oncology ward of the radiological clinic (working in health risk conditions for an average of 14 years) classified them into a high risk genetic group. They were found to have 4.7% cells with chromosomal aberrations as compared with 1.5% such cells in the control group. The said difference had a high statistical significance (p<0.001). Only aberrations of the structural type were evaluated.The mitotic activity of peripheral blood lymphocytes in the study group was also adversely affected (MI=1.8) compared with the control group (MI=2.9). Cytogenetic peripheral lymphocyte analysis used as a collective biological exposure test is being considered for incorporation in the system of preventive medical chec-kups of nurses working in radiotherapy/oncology wards.

  8. Occupational genetic risks for nurses at radiotherapy oncology wards

    International Nuclear Information System (INIS)

    Srb, V.; Kubzova, E.

    1985-01-01

    A lymphocyte chromosome analysis of short-term cultured whole peripheral blood of 14 nurses in the radiotherapy/oncology ward of the radiological clinic (working in health risk conditions for an average of 14 years) classified them into a high risk genetic group. They were found to have 4.7% cells with chromosomal aberrations as compared with 1.5% such cells in the control group. The said difference had a high statistical significance (p<0.001). Only aberrations of the structural type were evaluated.The mitotic activity of peripheral blood lymphocytes in the study group was also adversely affected (MI=1.8) compared with the control group (MI=2.9). Cytogenetic peripheral lymphocyte analysis used as a collective biological exposure test is being considered for incorporation in the system of preventive medical chec-kups of nurses working in radiotherapy/oncology wards. (author)

  9. Skin barrier and contact allergy: Genetic risk factor analyses

    DEFF Research Database (Denmark)

    Ross-Hansen, Katrine

    2013-01-01

    allergy. Objectives To evaluate the effect of specific gene polymorphisms on the risk of developing contact allergy by a candidate gene approach. These included polymorphisms in the glutathione S-transferase genes (GSTM1, -T1 and -P1 variants), the claudin-1 gene (CLDN1), and the filaggrin gene (FLG......) in particular. Methods Epidemiological genetic association studies were performed on a general Danish population. Participants were patch tested, answered a questionnaire on general health and were genotyped for GST, CLDN1 and FLG polymorphisms. Filaggrin’s nickel binding potential was evaluated biochemically...

  10. Genetic consequences of forest fragmentation for a highly specialized arboreal mammal--the edible dormouse.

    Directory of Open Access Journals (Sweden)

    Joanna Fietz

    Full Text Available Habitat loss and fragmentation represent the most serious extinction threats for many species and have been demonstrated to be especially detrimental for mammals. Particularly, highly specialized species with low dispersal abilities will encounter a high risk of extinction in fragmented landscapes. Here we studied the edible dormouse (Glis glis, a small arboreal mammal that is distributed throughout Central Europe, where forests are mostly fragmented at different spatial scales. The aim of this study was to investigate the effect of habitat fragmentation on genetic population structures using the example of edible dormouse populations inhabiting forest fragments in south western Germany. We genotyped 380 adult individuals captured between 2001 and 2009 in four different forest fragments and one large continuous forest using 14 species-specific microsatellites. We hypothesised, that populations in small forest patches have a lower genetic diversity and are more isolated compared to populations living in continuous forests. In accordance with our expectations we found that dormice inhabiting forest fragments were isolated from each other. Furthermore, their genetic population structure was more unstable over the study period than in the large continuous forest. Even though we could not detect lower genetic variability within individuals inhabiting forest fragments, strong genetic isolation and an overall high risk to mate with close relatives might be precursors to a reduced genetic variability and the onset of inbreeding depression. Results of this study highlight that connectivity among habitat fragments can already be strongly hampered before genetic erosion within small and isolated populations becomes evident.

  11. Human genetics as a tool to identify progranulin regulators.

    Science.gov (United States)

    Nicholson, Alexandra M; Finch, NiCole A; Rademakers, Rosa

    2011-11-01

    Frontotemporal lobar degeneration (FTLD) is a common neurodegenerative disorder that predominantly affects individuals under the age of 65. It is known that the most common pathological subtype is FTLD with TAR DNA-binding protein 43 inclusions (FTLD-TDP). FTLD has a strong genetic component with about 50% of cases having a positive family history. Mutations identified in the progranulin gene (GRN) have been shown to cause FTLD-TDP as a result of progranulin haploinsufficiency. These findings suggest a progranulin-dependent mechanism in this pathological FTLD subtype. Thus, identifying regulators of progranulin levels is essential for new therapies and treatments for FTLD and related disorders. In this review, we discuss the role of genetic studies in identifying progranulin regulators, beginning with the discovery of pathogenic GRN mutations and additional GRN risk variants. We also cover more recent genetic advances, including the detection of variants in the transmembrane protein 106 B gene that increase FTLD-TDP risk presumably by modulating progranulin levels and the identification of a potential progranulin receptor, sortilin. This review highlights the importance of genetic studies in the context of FTLD and further emphasizes the need for future genetic and cell biology research to continue the effort in finding a cure for progranulin-related diseases.

  12. Diet Quality and Change in Blood Lipids during 16 Years of Follow-up and Their Interaction with Genetic Risk for Dyslipidemia.

    Science.gov (United States)

    Sonestedt, Emily; Hellstrand, Sophie; Drake, Isabel; Schulz, Christina-Alexandra; Ericson, Ulrika; Hlebowicz, Joanna; Persson, Margaretha M; Gullberg, Bo; Hedblad, Bo; Engström, Gunnar; Orho-Melander, Marju

    2016-05-09

    A high diet quality according to the Swedish nutrition recommendations is associated with a reduced risk of cardiovascular disease in the population-based Malmö Diet and Cancer cohort. To further clarify this protective association, we examined the association between high diet quality and change in triglycerides, high density lipoprotein-cholesterol (HDL-C), and low density lipoprotein-cholesterol (LDL-C) after 16 years of follow-up in 3152 individuals (61% women; 46-68 years at baseline). In addition, we examined if genetic risk scores composed of 80 lipid-associated genetic variants modify these associations. A diet quality index based on intakes of saturated fat, polyunsaturated fat, sucrose, fiber, fruit and vegetables, and fish was constructed. A high diet quality was associated with lower risk of developing high triglycerides (p = 0.02) and high LDL-C (p = 0.03) during follow-up compared with a low diet quality. We found an association between diet quality and long-term change in HDL-C only among those with lower genetic risk for low HDL-C as opposed to those with higher genetic risk (p-interaction = 0.04). Among those with lower genetic risk for low HDL-C, low diet quality was associated with decreased HDL-C during follow-up (p = 0.05). In conclusion, individuals with high adherence to the Swedish nutrition recommendation had lower risk of developing high triglycerides and LDL-C during 16 years of follow-up.

  13. Melanoma genetics

    DEFF Research Database (Denmark)

    Read, Jazlyn; Wadt, Karin A W; Hayward, Nicholas K

    2015-01-01

    Approximately 10% of melanoma cases report a relative affected with melanoma, and a positive family history is associated with an increased risk of developing melanoma. Although the majority of genetic alterations associated with melanoma development are somatic, the underlying presence of herita......Approximately 10% of melanoma cases report a relative affected with melanoma, and a positive family history is associated with an increased risk of developing melanoma. Although the majority of genetic alterations associated with melanoma development are somatic, the underlying presence...... in a combined total of approximately 50% of familial melanoma cases, the underlying genetic basis is unexplained for the remainder of high-density melanoma families. Aside from the possibility of extremely rare mutations in a few additional high penetrance genes yet to be discovered, this suggests a likely...... polygenic component to susceptibility, and a unique level of personal melanoma risk influenced by multiple low-risk alleles and genetic modifiers. In addition to conferring a risk of cutaneous melanoma, some 'melanoma' predisposition genes have been linked to other cancers, with cancer clustering observed...

  14. Importance of genetic factors in the occurrence of epilepsy syndrome type: a twin study

    DEFF Research Database (Denmark)

    Corey, Linda A; Pellock, John M; Kjeldsen, Marianne J

    2011-01-01

    not appear to play an important role in determining risk for frontal, occipital or temporal lobe epilepsy. These results suggest that, while genetic factors contribute to risk for major syndrome types, determined when possible, their contribution to risk for localization-related syndrome sub......Although there is strong evidence that genetic factors contribute to risk for epilepsy, their role in the determination of syndrome type is less clear. This study was undertaken to address this question. Information related to epilepsy was obtained from twins included in 455 monozygotic and 868...... dizygotic pairs ascertained from population-based twin registries in Denmark, Norway and the United States. Syndrome type was determined based on medical record information and detailed clinical interviews and classified using the International Classification Systems for the Epilepsies and Epileptic...

  15. Host genetic risk factors for West Nile virus infection and disease progression.

    Directory of Open Access Journals (Sweden)

    Abigail W Bigham

    Full Text Available West Nile virus (WNV, a category B pathogen endemic in parts of Africa, Asia and Europe, emerged in North America in 1999, and spread rapidly across the continental U.S. Outcomes of infection with WNV range from asymptomatic to severe neuroinvasive disease manifested as encephalitis, paralysis, and/or death. Neuroinvasive WNV disease occurs in less than one percent of cases, and although host genetic factors are thought to influence risk for symptomatic disease, the identity of these factors remains largely unknown. We tested 360 common haplotype tagging and/or functional SNPs in 86 genes that encode key regulators of immune function in 753 individuals infected with WNV including: 422 symptomatic WNV cases and 331 cases with asymptomatic infections. After applying a Bonferroni correction for multiple tests and controlling for population stratification, SNPs in IRF3 (OR 0.54, p = 0.035 and MX1, (OR 0.19, p = 0.014 were associated with symptomatic WNV infection and a single SNP in OAS1 (OR 9.79, p = 0.003 was associated with increased risk for West Nile encephalitis and paralysis (WNE/P. Together, these results suggest that genetic variation in the interferon response pathway is associated with both risk for symptomatic WNV infection and WNV disease progression.

  16. Genetics in endocrinology: genetic variation in deiodinases: a systematic review of potential clinical effects in humans.

    Science.gov (United States)

    Verloop, Herman; Dekkers, Olaf M; Peeters, Robin P; Schoones, Jan W; Smit, Johannes W A

    2014-09-01

    Iodothyronine deiodinases represent a family of selenoproteins involved in peripheral and local homeostasis of thyroid hormone action. Deiodinases are expressed in multiple organs and thyroid hormone affects numerous biological systems, thus genetic variation in deiodinases may affect multiple clinical endpoints. Interest in clinical effects of genetic variation in deiodinases has clearly increased. We aimed to provide an overview for the role of deiodinase polymorphisms in human physiology and morbidity. In this systematic review, studies evaluating the relationship between deiodinase polymorphisms and clinical parameters in humans were eligible. No restrictions on publication date were imposed. The following databases were searched up to August 2013: Pubmed, EMBASE (OVID-version), Web of Science, COCHRANE Library, CINAHL (EbscoHOST-version), Academic Search Premier (EbscoHOST-version), and ScienceDirect. Deiodinase physiology at molecular and tissue level is described, and finally the role of these polymorphisms in pathophysiological conditions is reviewed. Deiodinase type 1 (D1) polymorphisms particularly show moderate-to-strong relationships with thyroid hormone parameters, IGF1 production, and risk for depression. D2 variants correlate with thyroid hormone levels, insulin resistance, bipolar mood disorder, psychological well-being, mental retardation, hypertension, and risk for osteoarthritis. D3 polymorphisms showed no relationship with inter-individual variation in serum thyroid hormone parameters. One D3 polymorphism was associated with risk for osteoarthritis. Genetic deiodinase profiles only explain a small proportion of inter-individual variations in serum thyroid hormone levels. Evidence suggests a role of genetic deiodinase variants in certain pathophysiological conditions. The value for determination of deiodinase polymorphism in clinical practice needs further investigation. © 2014 European Society of Endocrinology.

  17. Genetic risk factors for the posterior cortical atrophy variant of Alzheimer's disease.

    Science.gov (United States)

    Schott, Jonathan M; Crutch, Sebastian J; Carrasquillo, Minerva M; Uphill, James; Shakespeare, Tim J; Ryan, Natalie S; Yong, Keir X; Lehmann, Manja; Ertekin-Taner, Nilufer; Graff-Radford, Neill R; Boeve, Bradley F; Murray, Melissa E; Khan, Qurat Ul Ain; Petersen, Ronald C; Dickson, Dennis W; Knopman, David S; Rabinovici, Gil D; Miller, Bruce L; González, Aida Suárez; Gil-Néciga, Eulogio; Snowden, Julie S; Harris, Jenny; Pickering-Brown, Stuart M; Louwersheimer, Eva; van der Flier, Wiesje M; Scheltens, Philip; Pijnenburg, Yolande A; Galasko, Douglas; Sarazin, Marie; Dubois, Bruno; Magnin, Eloi; Galimberti, Daniela; Scarpini, Elio; Cappa, Stefano F; Hodges, John R; Halliday, Glenda M; Bartley, Lauren; Carrillo, Maria C; Bras, Jose T; Hardy, John; Rossor, Martin N; Collinge, John; Fox, Nick C; Mead, Simon

    2016-08-01

    The genetics underlying posterior cortical atrophy (PCA), typically a rare variant of Alzheimer's disease (AD), remain uncertain. We genotyped 302 PCA patients from 11 centers, calculated risk at 24 loci for AD/DLB and performed an exploratory genome-wide association study. We confirm that variation in/near APOE/TOMM40 (P = 6 × 10(-14)) alters PCA risk, but with smaller effect than for typical AD (PCA: odds ratio [OR] = 2.03, typical AD: OR = 2.83, P = .0007). We found evidence for risk in/near CR1 (P = 7 × 10(-4)), ABCA7 (P = .02) and BIN1 (P = .04). ORs at variants near INPP5D and NME8 did not overlap between PCA and typical AD. Exploratory genome-wide association studies confirmed APOE and identified three novel loci: rs76854344 near CNTNAP5 (P = 8 × 10(-10) OR = 1.9 [1.5-2.3]); rs72907046 near FAM46A (P = 1 × 10(-9) OR = 3.2 [2.1-4.9]); and rs2525776 near SEMA3C (P = 1 × 10(-8), OR = 3.3 [2.1-5.1]). We provide evidence for genetic risk factors specifically related to PCA. We identify three candidate loci that, if replicated, may provide insights into selective vulnerability and phenotypic diversity in AD. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  18. Genetic and environmental influences on cardiovascular risk factors and cognitive function

    DEFF Research Database (Denmark)

    Xu, Chunsheng; Tian, Xiaocao; Sun, Jianping

    2018-01-01

    AIM: To explore the genetic and environmental influences on cardiovascular risk factors (CVRF) and cognitive function in the world's largest and rapidly aging Chinese population. METHODS: Cognitive function and CVRF, including body mass index, systolic blood pressure, diastolic blood pressure......, pulse pressure, glucose, total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDLC) and low-density lipoprotein cholesterol were measured in 379 complete twin pairs. Univariate and bivariate twin models were fitted to estimate the genetic and environmental components in the variance...... and covariance of CVRF and cognition. RESULTS: Mild-to-high heritability was estimated for CVRF and cognition (0.27-0.74). Unique environmental factors showed low-to-moderate contributions (0.23-0.56). Only HDLC presented significant common environmental contribution (0.50). Bivariate analysis showed...

  19. Genetic risk for attention-deficit/hyperactivity disorder contributes to neurodevelopmental traits in the general population.

    Science.gov (United States)

    Martin, Joanna; Hamshere, Marian L; Stergiakouli, Evangelia; O'Donovan, Michael C; Thapar, Anita

    2014-10-15

    Attention-deficit/hyperactivity disorder (ADHD) can be viewed as the extreme end of traits in the general population. Epidemiological and twin studies suggest that ADHD frequently co-occurs with and shares genetic susceptibility with autism spectrum disorder (ASD) and ASD-related traits. The aims of this study were to determine whether a composite of common molecular genetic variants, previously found to be associated with clinically diagnosed ADHD, predicts ADHD and ASD-related traits in the general population. Polygenic risk scores were calculated in the Avon Longitudinal Study of Parents and Children (ALSPAC) population sample (N = 8229) based on a discovery case-control genome-wide association study of childhood ADHD. Regression analyses were used to assess whether polygenic scores predicted ADHD traits and ASD-related measures (pragmatic language abilities and social cognition) in the ALSPAC sample. Polygenic scores were also compared in boys and girls endorsing any (rating ≥ 1) ADHD item (n = 3623). Polygenic risk for ADHD showed a positive association with ADHD traits (hyperactive-impulsive, p = .0039; inattentive, p = .037). Polygenic risk for ADHD was also negatively associated with pragmatic language abilities (p = .037) but not with social cognition (p = .43). In children with a rating ≥ 1 for ADHD traits, girls had a higher polygenic score than boys (p = .003). These findings provide molecular genetic evidence that risk alleles for the categorical disorder of ADHD influence hyperactive-impulsive and attentional traits in the general population. The results further suggest that common genetic variation that contributes to ADHD diagnosis may also influence ASD-related traits, which at their extreme are a characteristic feature of ASD. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  20. Contribution of Genetic Background, Traditional Risk Factors, and HIV-Related Factors to Coronary Artery Disease Events in HIV-Positive Persons

    Science.gov (United States)

    Rotger, Margalida; Glass, Tracy R.; Junier, Thomas; Lundgren, Jens; Neaton, James D.; Poloni, Estella S.; van 't Wout, Angélique B.; Lubomirov, Rubin; Colombo, Sara; Martinez, Raquel; Rauch, Andri; Günthard, Huldrych F.; Neuhaus, Jacqueline; Wentworth, Deborah; van Manen, Danielle; Gras, Luuk A.; Schuitemaker, Hanneke; Albini, Laura; Torti, Carlo; Jacobson, Lisa P.; Li, Xiuhong; Kingsley, Lawrence A.; Carli, Federica; Guaraldi, Giovanni; Ford, Emily S.; Sereti, Irini; Hadigan, Colleen; Martinez, Esteban; Arnedo, Mireia; Egaña-Gorroño, Lander; Gatell, Jose M.; Law, Matthew; Bendall, Courtney; Petoumenos, Kathy; Rockstroh, Jürgen; Wasmuth, Jan-Christian; Kabamba, Kabeya; Delforge, Marc; De Wit, Stephane; Berger, Florian; Mauss, Stefan; de Paz Sierra, Mariana; Losso, Marcelo; Belloso, Waldo H.; Leyes, Maria; Campins, Antoni; Mondi, Annalisa; De Luca, Andrea; Bernardino, Ignacio; Barriuso-Iglesias, Mónica; Torrecilla-Rodriguez, Ana; Gonzalez-Garcia, Juan; Arribas, José R.; Fanti, Iuri; Gel, Silvia; Puig, Jordi; Negredo, Eugenia; Gutierrez, Mar; Domingo, Pere; Fischer, Julia; Fätkenheuer, Gerd; Alonso-Villaverde, Carlos; Macken, Alan; Woo, James; McGinty, Tara; Mallon, Patrick; Mangili, Alexandra; Skinner, Sally; Wanke, Christine A.; Reiss, Peter; Weber, Rainer; Bucher, Heiner C.; Fellay, Jacques; Telenti, Amalio; Tarr, Philip E.

    2013-01-01

    Background Persons infected with human immunodeficiency virus (HIV) have increased rates of coronary artery disease (CAD). The relative contribution of genetic background, HIV-related factors, antiretroviral medications, and traditional risk factors to CAD has not been fully evaluated in the setting of HIV infection. Methods In the general population, 23 common single-nucleotide polymorphisms (SNPs) were shown to be associated with CAD through genome-wide association analysis. Using the Metabochip, we genotyped 1875 HIV-positive, white individuals enrolled in 24 HIV observational studies, including 571 participants with a first CAD event during the 9-year study period and 1304 controls matched on sex and cohort. Results A genetic risk score built from 23 CAD-associated SNPs contributed significantly to CAD (P = 2.9×10−4). In the final multivariable model, participants with an unfavorable genetic background (top genetic score quartile) had a CAD odds ratio (OR) of 1.47 (95% confidence interval [CI], 1.05–2.04). This effect was similar to hypertension (OR = 1.36; 95% CI, 1.06–1.73), hypercholesterolemia (OR = 1.51; 95% CI, 1.16–1.96), diabetes (OR = 1.66; 95% CI, 1.10–2.49), ≥1 year lopinavir exposure (OR = 1.36; 95% CI, 1.06–1.73), and current abacavir treatment (OR = 1.56; 95% CI, 1.17–2.07). The effect of the genetic risk score was additive to the effect of nongenetic CAD risk factors, and did not change after adjustment for family history of CAD. Conclusions In the setting of HIV infection, the effect of an unfavorable genetic background was similar to traditional CAD risk factors and certain adverse antiretroviral exposures. Genetic testing may provide prognostic information complementary to family history of CAD. PMID:23532479

  1. Pathways to childhood depressive symptoms: the role of social, cognitive, and genetic risk factors.

    Science.gov (United States)

    Lau, Jennifer Y F; Rijsdijk, Frühling; Gregory, Alice M; McGuffin, Peter; Eley, Thalia C

    2007-11-01

    Childhood depressive conditions have been explored from multiple theoretical approaches but with few empirical attempts to address the interrelationships among these different domains and their combined effects. In the present study, the authors examined different pathways through which social, cognitive, and genetic risk factors may be expressed to influence depressive symptoms in 300 pairs of child twins from a longitudinal study. Path analysis supported several indirect routes. First, risks associated with living in a step- or single-parent family and punitive parenting did not directly influence depressive outcome but were instead mediated through maternal depressive symptoms and child negative attributional style. Second, the effects of negative attributional style on depressive outcome were greatly exacerbated in the presence of precipitating negative life events. Third, independent of these social and cognitive risk mechanisms, modest genetic effects were also implicated in symptoms, with some indication that these risks are expressed through exposure to negative stressors. Together, these routes accounted for approximately 13% of total phenotypic variance in depressive symptoms. Theoretical and analytical implications of these results are discussed in the context of several design-related caveats. (c) 2007 APA.

  2. Parent of origin, mosaicism, and recurrence risk: probabilistic modeling explains the broken symmetry of transmission genetics.

    Science.gov (United States)

    Campbell, Ian M; Stewart, Jonathan R; James, Regis A; Lupski, James R; Stankiewicz, Paweł; Olofsson, Peter; Shaw, Chad A

    2014-10-02

    Most new mutations are observed to arise in fathers, and increasing paternal age positively correlates with the risk of new variants. Interestingly, new mutations in X-linked recessive disease show elevated familial recurrence rates. In male offspring, these mutations must be inherited from mothers. We previously developed a simulation model to consider parental mosaicism as a source of transmitted mutations. In this paper, we extend and formalize the model to provide analytical results and flexible formulas. The results implicate parent of origin and parental mosaicism as central variables in recurrence risk. Consistent with empirical data, our model predicts that more transmitted mutations arise in fathers and that this tendency increases as fathers age. Notably, the lack of expansion later in the male germline determines relatively lower variance in the proportion of mutants, which decreases with paternal age. Subsequently, observation of a transmitted mutation has less impact on the expected risk for future offspring. Conversely, for the female germline, which arrests after clonal expansion in early development, variance in the mutant proportion is higher, and observation of a transmitted mutation dramatically increases the expected risk of recurrence in another pregnancy. Parental somatic mosaicism considerably elevates risk for both parents. These findings have important implications for genetic counseling and for understanding patterns of recurrence in transmission genetics. We provide a convenient online tool and source code implementing our analytical results. These tools permit varying the underlying parameters that influence recurrence risk and could be useful for analyzing risk in diverse family structures. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  3. On the genetic risk after high dose radioiodine therapy with regard to the gonadal dose

    International Nuclear Information System (INIS)

    Ehrenheim, C.; Hauswirth, C.; Fitschen, J.; Martin, E.; Oetting, G.; Hundeshagen, H.

    1997-01-01

    Aim: The genetic risk for the offspring of patients treated with high doses of radioiodine was to be assessed with special regard to the gonadal dose caused by diagnostic and therapeutic procedures. Methods: 41 young females (aged between 19 and 39 years) and four young males (aged 26 to 36 years) treated with radioiodine because of a thyroid carcinoma were interviewed by use of a questionnaire. The course of pregnancy and birth history could be documented as well as the congenital and developmental conditions of 56 children. Results: The amount of radioactivity applied for therapy and whole body scans ranged over 4,144 and 35,15 GBq I-131; the individual gonadal dose was calculated based on the MIRD model and ranged over 0,2 and 2,2 Sv (0,51 Sv at a mean). The period of time between the last radioiodine application and confinement was at least 9 months, not exceeding 14 years. As to the course of pregnancy and birth two early abortions, one extrauterine gravidity and one premature birth due to an insufficiency of the placenta were stated. In one case a chromosomal translocation 7/14 occured as a genetic defect which lead to an interruption. The children's development was unconspicuous except of two cases of neurodermatitis as well as multiple allergies and an early closure of the anterior fontanelle in one child each. Conclusion: Although the genetic risk is supposed to increase with the gonadal dose achieved (doubling dose 1 Sv) and the increased risk of any congenital anomaly was calculated as about 13% at a mean in our patients, the rate of genetic determined diseases was not elevated (1,8% or 1/57). Thus, no increase of genetic defects or congenital malformations was reported in a total of 408 children described in the literature and in our group. (orig.) [de

  4. Genetic Risk for Alcoholic Chronic Pancreatitis

    Directory of Open Access Journals (Sweden)

    Flair José Carrilho

    2011-06-01

    Full Text Available In recent years many studies have examined the genetic predisposition to pancreatic diseases. Pancreatic disease of an alcoholic etiology was determined to be a multi-factorial disease, where environmental factors interact with the genetic profile of the individual. In this review we discuss the main results from studies examining the frequency of genetic mutations in alcoholic chronic pancreatitis.

  5. Impact of strong selection for the PrP major gene on genetic variability of four French sheep breeds (Open Access publication

    Directory of Open Access Journals (Sweden)

    Pantano Thais

    2008-11-01

    Full Text Available Abstract Effective selection on the PrP gene has been implemented since October 2001 in all French sheep breeds. After four years, the ARR "resistant" allele frequency increased by about 35% in young males. The aim of this study was to evaluate the impact of this strong selection on genetic variability. It is focussed on four French sheep breeds and based on the comparison of two groups of 94 animals within each breed: the first group of animals was born before the selection began, and the second, 3–4 years later. Genetic variability was assessed using genealogical and molecular data (29 microsatellite markers. The expected loss of genetic variability on the PrP gene was confirmed. Moreover, among the five markers located in the PrP region, only the three closest ones were affected. The evolution of the number of alleles, heterozygote deficiency within population, expected heterozygosity and the Reynolds distances agreed with the criteria from pedigree and pointed out that neutral genetic variability was not much affected. This trend depended on breed, i.e. on their initial states (population size, PrP frequencies and on the selection strategies for improving scrapie resistance while carrying out selection for production traits.

  6. Do natural methods for fertility regulation increase the risks of genetic errors?

    Science.gov (United States)

    Serra, A

    1981-09-01

    Genetic errors of many kinds are connected with the reproductive processes and are favored by a nunber of largely uncontrollable, endogenous, and/or exogenous factors. For a long time human beings have taken into their own hands the control of this process. The regulation of fertility is clearly a forceful request to any family, to any community, were it only to lower the level of the consequences of genetic errors. In connection with this request, and in the context of the Congress for the Family of Africa and Europe (Catholic University, January 1981), 1 question must still be raised and possibly answered. The question is: do or can the so called "natural methods" for the regulation of fertility increase the risks of genetic errors with their generally dramatic effects on families and on communities. It is important to try to give as far as possible a scientifically based answer to this question. Fr. Haring, a moral theologian, citing scientific evidence finds it shocking that the rhythm method, so strongly and recently endorsed again by Church authorities, should be classified among the means of "birth control" by way of spontaneous abortion or at least by spontaneous loss of a large number of zygotes which, due to the concrete application of the rhythm method, lack of necessary vitality for survival. He goes on to state that the scientific research provides overwhelming evidence that the rhythm method in its traditional form is responsible for a disproportionate waste of zygotes and a disproportionate frequency of spontaneous abortions and a defective childern. Professor Hilgers, a reproductive physiologist, takes on opposite view, maintaining that the hypotheses are arbitrary and the alarm false. The strongest evidence upon which Fr. Haring bases his moral principles about the use of the natural methods of fertility regulation is a paper by Guerrero and Rojos (1975). These authors examined, retrospectively, the success of 965 pregnancies which occurred in

  7. Genetic variations in a PTEN/AKT/mTOR axis and prostate cancer risk in a Chinese population.

    Directory of Open Access Journals (Sweden)

    Jiawei Chen

    Full Text Available Genetic variations in a PTEN/AKT/mTOR signaling axis may influence cellular functions including cell growth, proliferation and apoptosis, and then increase the individual's risk of cancer. Accordingly, we explore the association between single nucleotide polymorphisms (SNPs of these genes and prostate cancer (PCa in our Chinese population.Subjects were recruited from 666 PCa patients and 708 cancer-free controls, and eight SNPs in the PTEN/AKT/mTOR axis were determined by the TaqMan assay. Odds ratios (OR and 95% confidence intervals (95% CI were evaluated by logistic regression.We observed significant associations between PCa risk and mTOR rs2295080 [P = 0.027, OR = 0.85, 95%CI = 0.74-0.98], and AKT2 rs7254617 (P = 0.003, OR = 1.35, 95%CI = 1.11-1.64. When estimated these two SNPs together, the combined genotypes with 2-4 risk alleles (rs2295080 T and rs7254617 A alleles were associated with an increased risk of PCa compared with 0-1 risk alleles, which was more pronounced among subgroups of age >71 years, smokers, drinkers and no family history of cancer. Results of stratified analyses by cliniopathological parameters revealed that the frequencies of the combined genotypes with 2-4 risk alleles in advanced stage were significantly higher than in localized stage (P = 0.022, but there was no significant association in Gleason score and PSA level.Our results indicate, for the first time that the two variants in AKT2 and mTOR, particularly the joint genotypes with 2-4 risk alleles may influence PCa susceptibility and progression in Chinese, and the association appeared to be more strong in the subgroup of smokers and drinkers.

  8. A genome-wide association study identifies rs2000999 as a strong genetic determinant of circulating haptoglobin levels.

    Directory of Open Access Journals (Sweden)

    Philippe Froguel

    Full Text Available Haptoglobin is an acute phase inflammatory marker. Its main function is to bind hemoglobin released from erythrocytes to aid its elimination, and thereby haptoglobin prevents the generation of reactive oxygen species in the blood. Haptoglobin levels have been repeatedly associated with a variety of inflammation-linked infectious and non-infectious diseases, including malaria, tuberculosis, human immunodeficiency virus, hepatitis C, diabetes, carotid atherosclerosis, and acute myocardial infarction. However, a comprehensive genetic assessment of the inter-individual variability of circulating haptoglobin levels has not been conducted so far.We used a genome-wide association study initially conducted in 631 French children followed by a replication in three additional European sample sets and we identified a common single nucleotide polymorphism (SNP, rs2000999 located in the Haptoglobin gene (HP as a strong genetic predictor of circulating Haptoglobin levels (P(overall = 8.1 × 10(-59, explaining 45.4% of its genetic variability (11.8% of Hp global variance. The functional relevance of rs2000999 was further demonstrated by its specific association with HP mRNA levels (β = 0.23 ± 0.08, P = 0.007. Finally, SNP rs2000999 was associated with decreased total and low-density lipoprotein cholesterol in 8,789 European children (P(total cholesterol = 0.002 and P(LDL = 0.0008.Given the central position of haptoglobin in many inflammation-related metabolic pathways, the relevance of rs2000999 genotyping when evaluating haptoglobin concentration should be further investigated in order to improve its diagnostic/therapeutic and/or prevention impact.

  9. The rearing environment and risk for drug abuse: a Swedish national high-risk adopted and not adopted co-sibling control study.

    Science.gov (United States)

    Kendler, K S; Ohlsson, H; Sundquist, K; Sundquist, J

    2016-05-01

    Although drug abuse (DA) is strongly familial, with important genetic influences, we need to know more about the role of rearing environment in the risk for DA. To address this question, we utilized a high-risk adopted and non-adopted co-sibling control design. High-risk offspring had one or more biological parents registered for DA, alcohol use disorders or criminal behavior. Using Swedish registries, we identified 1161 high-risk full-sibships and 3085 high-risk half-sibships containing at least one member who was adopted-away and one member who was not. Registration for DA was via national criminal, medical and pharmacy registers. In Sweden, adoptive families are screened to provide high-quality rearing environment for adoptees. Controlling for parental age at birth and gender (and, in half-siblings, high-risk status of the other parent), risk for DA was substantially lower in the full- and half-siblings who were adopted v. not adopted [hazard ratios and 95% confidence intervals: 0.55 (0.45-0·69) and 0.55 (95% CI 0.48-0.63), respectively]. The protective effect of adoption on risk for DA was significantly stronger in the full- and half-sibling pairs with very high familial liability (two high-risk parents) and significantly weaker when the adoptive family was broken by death or divorce, or contained a high-risk parent. In both full- and half-sibling pairs, we found replicated evidence that rearing environment strongly impacts on risk for DA. High-quality rearing environments can substantively reduce risk for DA in those at high genetic risk.

  10. Genetics of variation in HOMA-IR and cardiovascular risk factors in Mexican-Americans.

    Science.gov (United States)

    Voruganti, V Saroja; Lopez-Alvarenga, Juan C; Nath, Subrata D; Rainwater, David L; Bauer, Richard; Cole, Shelley A; Maccluer, Jean W; Blangero, John; Comuzzie, Anthony G

    2008-03-01

    Insulin resistance is a major biochemical defect underlying the pathogenesis of cardiovascular disease (CVD). Mexican-Americans are known to have an unfavorable cardiovascular profile. Thus, the aim of this study was to investigate the genetic effect on variation in HOMA-IR and to evaluate its genetic correlations with other phenotypes related to risk of CVD in Mexican-Americans. The homeostatic model assessment method (HOMA-IR) is one of several approaches that are used to measure insulin resistance and was used here to generate a quantitative phenotype for genetic analysis. For 644 adults who had participated in the San Antonio Family Heart Study (SAFHS), estimates of genetic contribution were computed using a variance components method implemented in SOLAR. Traits that exhibited significant heritabilities were body mass index (BMI) (h (2) = 0.43), waist circumference (h (2) = 0.48), systolic blood pressure (h (2) = 0.30), diastolic blood pressure (h (2) = 0.21), pulse pressure (h (2) = 0.32), triglycerides (h (2) = 0.51), LDL cholesterol (h (2) = 0.31), HDL cholesterol (h (2) = 0.24), C-reactive protein (h (2) = 0.17), and HOMA-IR (h (2) = 0.33). A genome-wide scan for HOMA-IR revealed significant evidence of linkage on chromosome 12q24 (close to PAH (phenylalanine hydroxylase), LOD = 3.01, p HOMA-IR with BMI (rho (G) = 0.36), waist circumference (rho (G) = 0.47), pulse pressure (rho (G) = 0.39), and HDL cholesterol (rho (G) = -0.18). Identification of significant linkage for HOMA-IR on chromosome 12q replicates previous family-based studies reporting linkage of phenotypes associated with type 2 diabetes in the same chromosomal region. Significant genetic correlations between HOMA-IR and phenotypes related to CVD risk factors suggest that a common set of gene(s) influence the regulation of these phenotypes.

  11. Population genomic analysis suggests strong influence of river network on spatial distribution of genetic variation in invasive saltcedar across the southwestern United States

    Science.gov (United States)

    Lee, Soo-Rang; Jo, Yeong-Seok; Park, Chan-Ho; Friedman, Jonathan M.; Olson, Matthew S.

    2018-01-01

    Understanding the complex influences of landscape and anthropogenic elements that shape the population genetic structure of invasive species provides insight into patterns of colonization and spread. The application of landscape genomics techniques to these questions may offer detailed, previously undocumented insights into factors influencing species invasions. We investigated the spatial pattern of genetic variation and the influences of landscape factors on population similarity in an invasive riparian shrub, saltcedar (Tamarix L.) by analysing 1,997 genomewide SNP markers for 259 individuals from 25 populations collected throughout the southwestern United States. Our results revealed a broad-scale spatial genetic differentiation of saltcedar populations between the Colorado and Rio Grande river basins and identified potential barriers to population similarity along both river systems. River pathways most strongly contributed to population similarity. In contrast, low temperature and dams likely served as barriers to population similarity. We hypothesize that large-scale geographic patterns in genetic diversity resulted from a combination of early introductions from distinct populations, the subsequent influence of natural selection, dispersal barriers and founder effects during range expansion.

  12. Genetic Test Reporting and Counseling for Melanoma Risk in Minors May Improve Sun Protection Without Inducing Distress.

    Science.gov (United States)

    Stump, Tammy K; Aspinwall, Lisa G; Kohlmann, Wendy; Champine, Marjan; Hauglid, Jamie; Wu, Yelena P; Scott, Emily; Cassidy, Pamela; Leachman, Sancy A

    2018-01-19

    Genetic testing of minors is advised only for conditions in which benefits of early intervention outweigh potential psychological harms. This study investigated whether genetic counseling and test reporting for the CDKN2A/p16 mutation, which confers highly elevated melanoma risk, improved sun protection without inducing distress. Eighteen minors (M age  = 12.4, SD = 1.9) from melanoma-prone families completed measures of protective behavior and distress at baseline, 1 week (distress only), 1 month, and 1 year following test disclosure. Participants and their mothers were individually interviewed on the psychological and behavioral impact of genetic testing 1 month and 1 year post-disclosure. Carriers (n = 9) and noncarriers (n = 9) reported significantly fewer sunburns and a greater proportion reported sun protection adherence between baseline and 1 year post-disclosure; results did not vary by mutation status. Anxiety symptoms remained low post-disclosure, while depressive symptoms and cancer worry decreased. Child and parent interviews corroborated these findings. Mothers indicated that genetic testing was beneficial (100%) because it promoted risk awareness (90.9%) and sun protection (81.8%) without making their children scared (89.9%); several noted their child's greater independent practice of sun protection (45.4%). In this small initial study, minors undergoing CDKN2A/p16 genetic testing reported behavioral improvements and consistently low distress, suggesting such testing may be safely implemented early in life, allowing greater opportunity for risk-reducing lifestyle changes.

  13. Perception of risks and benefits of in vitro fertilization, genetic engineering and biotechnology.

    Science.gov (United States)

    Macer, D R

    1994-01-01

    The use of new biotechnology in medicine has become an everyday experience, but many people still express concern about biotechnology. Concerns are evoked particularly by the phrases genetic engineering and in vitro fertilization (IVF), and these concerns persist despite more than a decade of their use in medicine. Mailed nationwide opinion surveys on attitudes to biotechnology were conducted in Japan, among samples of the public (N = 551), high school biology teachers (N = 228), scientists (N = 555) and nurses (N = 301). People do see more benefits coming from science than harm when balanced against the risks. There were especially mixed perceptions of benefit and risk about IVF and genetic engineering, and a relatively high degree of worry compared to other developments of science and technology. A discussion of assisted reproductive technologies and surrogacy in Japan is also made. The opinions of people in Japan were compared to the results of previous surveys conducted in Japan, and international surveys conducted in Australia, China, Europe, New Zealand, U.K. and U.S.A. Japanese have a very high awareness of biotechnology, 97% saying that they had heard of the word. They also have a high level of awareness of IVF and genetic engineering. Genetic engineering was said to be a worthwhile research area for Japan by 76%, while 58% perceived research on IVF as being worthwhile, however 61% were worried about research on IVF or genetic engineering. Japanese expressed more concern about IVF and genetic engineering than New Zealanders. The major reason cited for rejection of genetic manipulation research in Japan and New Zealand was that it was seen as interfering with nature, playing God or as unethical. The emotions concerning these technologies are complex, and we should avoid using simplistic public opinion data as measures of public perceptions. The level of concern expressed by scientists and teachers in Japan suggest that public education "technology promotion

  14. Resignifying the sickle cell gene: Narratives of genetic risk, impairment and repair.

    Science.gov (United States)

    Berghs, Maria; Dyson, Simon M; Atkin, Karl

    2017-03-01

    Connecting theoretical discussion with empirical qualitative work, this article examines how sickle cell became a site of public health intervention in terms of 'racialised' risks. Historically, sickle cell became socio-politically allied to ideas of repair, in terms of the state improving the health of a neglected ethnic minority population. Yet, we elucidate how partial improvements in care and education arose alongside preventative public health screening efforts. Using qualitative research based in the United Kingdom, we show how a focus on collective efforts of repair can lie in tension with how services and individuals understand and negotiate antenatal screening. We illustrate how screening for sickle cell disorder calls into question narrative identity, undoing paradigms in which ethnicity, disablement and genetic impairment become framed. Research participants noted that rather than 'choices', it is 'risks' and their negotiation that are a part of discourses of modernity and the new genetics. Furthermore, while biomedical paradigms are rationally and ethically (de)constructed by participants, this was never fully engaged with by professionals, contributing to overall perception of antenatal screening as disempowering and leading to disengagement.

  15. Genetically Modified Foods: A Brief Overview of the Risk Assessment Process.

    Science.gov (United States)

    Finkelstein, Paige E

    2016-02-18

    Billions of people worldwide are unable to meet their daily micro nutritional needs. Genetically modified (GM) foods, while initially developed to tolerate herbicides and resist disease and insects, have the potential to help alleviate this issue that is currently posing a serious public health concern. However, there is a negative public perception surrounding GM foods, calling for more research regarding the risks that GM foods could pose to the public, specifically on the topics of allergenicity and gene transfer. The risk assessments of GM foods should be performed on a case-by-case basis, by a process outlined by the WHO. The goal of determining food safety is to obtain reasonable certainty that under normal levels of consumption, there will be no harm to people. Current research has shown that GM foods do not cause increased allergenicity or have a meaningful risk of gene transfer to people. GM foods should become publicly accepted products that can bring significant benefit to people at risk of under nutrition.

  16. Genetic and environmental determinants of violence risk in psychotic disorders: a multivariate quantitative genetic study of 1.8 million Swedish twins and siblings.

    Science.gov (United States)

    Sariaslan, A; Larsson, H; Fazel, S

    2016-09-01

    Patients diagnosed with psychotic disorders (for example, schizophrenia and bipolar disorder) have elevated risks of committing violent acts, particularly if they are comorbid with substance misuse. Despite recent insights from quantitative and molecular genetic studies demonstrating considerable pleiotropy in the genetic architecture of these phenotypes, there is currently a lack of large-scale studies that have specifically examined the aetiological links between psychotic disorders and violence. Using a sample of all Swedish individuals born between 1958 and 1989 (n=3 332 101), we identified a total of 923 259 twin-sibling pairs. Patients were identified using the National Patient Register using validated algorithms based on International Classification of Diseases (ICD) 8-10. Univariate quantitative genetic models revealed that all phenotypes (schizophrenia, bipolar disorder, substance misuse, and violent crime) were highly heritable (h(2)=53-71%). Multivariate models further revealed that schizophrenia was a stronger predictor of violence (r=0.32; 95% confidence interval: 0.30-0.33) than bipolar disorder (r=0.23; 0.21-0.25), and large proportions (51-67%) of these phenotypic correlations were explained by genetic factors shared between each disorder, substance misuse, and violence. Importantly, we found that genetic influences that were unrelated to substance misuse explained approximately a fifth (21%; 20-22%) of the correlation with violent criminality in bipolar disorder but none of the same correlation in schizophrenia (Pbipolar disordergenetically similar phenotypes as the latter sources may include aetiologically important clues. Clinically, these findings underline the importance of assessing risk of different phenotypes together and integrating interventions for psychiatric disorders, substance misuse, and violence.

  17. GRECOS Project (Genotyping Recurrence Risk of Stroke): The Use of Genetics to Predict the Vascular Recurrence After Stroke.

    Science.gov (United States)

    Fernández-Cadenas, Israel; Mendióroz, Maite; Giralt, Dolors; Nafria, Cristina; Garcia, Elena; Carrera, Caty; Gallego-Fabrega, Cristina; Domingues-Montanari, Sophie; Delgado, Pilar; Ribó, Marc; Castellanos, Mar; Martínez, Sergi; Freijo, Marimar; Jiménez-Conde, Jordi; Rubiera, Marta; Alvarez-Sabín, José; Molina, Carlos A; Font, Maria Angels; Grau Olivares, Marta; Palomeras, Ernest; Perez de la Ossa, Natalia; Martinez-Zabaleta, Maite; Masjuan, Jaime; Moniche, Francisco; Canovas, David; Piñana, Carlos; Purroy, Francisco; Cocho, Dolores; Navas, Inma; Tejero, Carlos; Aymerich, Nuria; Cullell, Natalia; Muiño, Elena; Serena, Joaquín; Rubio, Francisco; Davalos, Antoni; Roquer, Jaume; Arenillas, Juan Francisco; Martí-Fábregas, Joan; Keene, Keith; Chen, Wei-Min; Worrall, Bradford; Sale, Michele; Arboix, Adrià; Krupinski, Jerzy; Montaner, Joan

    2017-05-01

    Vascular recurrence occurs in 11% of patients during the first year after ischemic stroke (IS) or transient ischemic attack. Clinical scores do not predict the whole vascular recurrence risk; therefore, we aimed to find genetic variants associated with recurrence that might improve the clinical predictive models in IS. We analyzed 256 polymorphisms from 115 candidate genes in 3 patient cohorts comprising 4482 IS or transient ischemic attack patients. The discovery cohort was prospectively recruited and included 1494 patients, 6.2% of them developed a new IS during the first year of follow-up. Replication analysis was performed in 2988 patients using SNPlex or HumanOmni1-Quad technology. We generated a predictive model using Cox regression (GRECOS score [Genotyping Reurrence Risk of Stroke]) and generated risk groups using a classification tree method. The analyses revealed that rs1800801 in the MGP gene (hazard ratio, 1.33; P =9×10 - 03 ), a gene related to artery calcification, was associated with new IS during the first year of follow-up. This polymorphism was replicated in a Spanish cohort (n=1.305); however, it was not significantly associated in a North American cohort (n=1.683). The GRECOS score predicted new IS ( P =3.2×10 - 09 ) and could classify patients, from low risk of stroke recurrence (1.9%) to high risk (12.6%). Moreover, the addition of genetic risk factors to the GRECOS score improves the prediction compared with previous Stroke Prognosis Instrument-II score ( P =0.03). The use of genetics could be useful to estimate vascular recurrence risk after IS. Genetic variability in the MGP gene was associated with vascular recurrence in the Spanish population. © 2017 American Heart Association, Inc.

  18. What can be offered to couples at (possibly) increased genetic risk?

    Science.gov (United States)

    Read, Andrew P; Donnai, Dian

    2012-07-01

    We review the reasons why a couple might seek specialist genetic counselling about a possible reproductive risk and the options available to them. Most commonly, the couple will be concerned about the risk of recurrence of a medical condition that has already occurred in the family. Sometimes, the increased risk may come from their ethnicity or because of a consanguineous marriage, rather than because any problem has occurred previously. The geneticist must identify the exact nature of any problem and determine the risks in the light of the mode of inheritance, any investigations undertaken and any other relevant information. The geneticist will then review the options open to the couple, and help them arrive at their own decision in a non-directive way. Some couples may opt to do nothing and let nature take its course but others may request prenatal or pre-implantation diagnosis, or they may avoid the conception of an at-risk child by using donor gametes, adoption or even decide not to have children.

  19. Evidence for shared genetic risk between ADHD symptoms and reduced mathematics ability: a twin study.

    Science.gov (United States)

    Greven, Corina U; Kovas, Yulia; Willcutt, Erik G; Petrill, Stephen A; Plomin, Robert

    2014-01-01

    Attention-deficit/hyperactivity disorder (ADHD) symptoms and mathematics ability are associated, but little is known about the genetic and environmental influences underlying this association. Data came from more than 6,000 twelve-year-old twin pairs from the UK population-representative Twins Early Development Study. Parents rated each twin's behaviour using a DSM-IV-based 18-item questionnaire of inattentive and hyperactive-impulsive ADHD symptoms. Mathematics tests based on the UK National Curriculum were completed by each twin. The twins also completed standardised tests of reading and general cognitive ability. Multivariate twin model fitting was applied. Inattentive and hyperactive-impulsive ADHD symptoms were highly heritable (67% and 73% respectively). Mathematics ability was moderately heritable (46%). Mathematics ability and inattentiveness showed a significantly greater phenotypic correlation (r(p) = -.26) and genetic correlation (r(A) = -.41) than mathematics ability and hyperactivity-impulsivity (r(p) = -.18; r(A) = -.22). The genetic correlation between inattentiveness and mathematics ability was largely independent from hyperactivity-impulsivity, and was only partially accounted for by genetic influences related to reading and general cognitive ability. Results revealed the novel finding that mathematics ability shows significantly stronger phenotypic and genetic associations with inattentiveness than with hyperactivity-impulsivity. Genetic associations between inattentiveness and mathematics ability could only partially be accounted for by hyperactivity-impulsivity, reading and general cognitive ability. Results suggest that mathematics ability is associated with ADHD symptoms largely because it shares genetic risk factors with inattentiveness, and provide further evidence for considering inattentiveness and hyperactivity-impulsivity separately. DNA markers for ADHD symptoms (especially inattentiveness) may also be candidate risk factors for

  20. Genetic and environmental risk factors in adolescent substance use.

    Science.gov (United States)

    Silberg, Judy; Rutter, Michael; D'Onofrio, Brian; Eaves, Lindon

    2003-07-01

    The present study was undertaken with the goal of understanding the causes of association between substance use and both conduct disturbance (CD) and depression in adolescent boys and girls. Multivariate genetic structural equation models were fitted to multi-informant, multi-wave, longitudinal data collected in extensive home interviews with parents and children with respect to 307 MZ male, 392 MZ female, 185 DZ male, and 187 DZ female, same-sex twin pairs aged 12-17 years from the Virginia Twin Study of Adolescent Behavioral Development (VTSABD). Although conduct disturbance and depression were moderately associated with substance use, the pattern of genetic and environmental risk differed for males and females and across the two disorders. Genetic factors were predominant in girls' substance use whereas boys' use was mediated primarily by shared environmental factors reflecting family dysfunction and deviant peers. The patterns of correlations across the two waves of the study were consistent with conduct disturbance leading to substance use in both males and females, but depression leading to smoking, drug use and, to a lesser extent, alcohol use in girls. The comorbidity between substance use and depression, and between substance use and conduct disturbance in childhood/adolescence, probably reflects rather different mediating mechanisms--as well as a different time frame, with conduct disturbance preceding substance use but depression following it. In both, the co-occurrence partially reflected a shared liability but, in girls, genetic influences played an important role in the comorbidity involving depression, whereas in both sexes (but especially in boys) environmental factors played a substantial role. The extent to which these differences reflect genuine differences in the causal mechanisms underlying substance use and CD/depression in boys and girls revealed in the present analysis awaits replication from studies of other general population samples.

  1. Genetic determinants of LDL, lipoprotein(a), triglyceride-rich lipoproteins and HDL: concordance and discordance with cardiovascular disease risk

    DEFF Research Database (Denmark)

    Nordestgaard, Børge G; Tybjærg-Hansen, Anne

    2011-01-01

    To evaluate whether new and known genetic determinants of plasma levels of LDL cholesterol, lipoprotein(a), triglyceride-rich lipoproteins, and HDL cholesterol associate with the risk of cardiovascular disease expected from the effect on lipoprotein levels. Concordance or discordance of such gene......To evaluate whether new and known genetic determinants of plasma levels of LDL cholesterol, lipoprotein(a), triglyceride-rich lipoproteins, and HDL cholesterol associate with the risk of cardiovascular disease expected from the effect on lipoprotein levels. Concordance or discordance...

  2. Association of genetic markers in the BCL-2 family of apoptosis-related genes with endometrial cancer risk in a Chinese population.

    Directory of Open Access Journals (Sweden)

    Tsogzolmaa Dorjgochoo

    Full Text Available In vitro studies have demonstrated the role of the BCL-2 family of genes in endometrial carcinogenesis. The role of genetic variants in BCL-2 genes and their interactions with non-genetic factors in the development of endometrial cancer has not been investigated in epidemiological studies.We examined the relationship between BCL-2 gene family variants and endometrial cancer risk among 1,028 patients and 1,922 age-matched community controls from Shanghai, China. We also investigated possible interactions between genetic variants and established risk factors (demographic, lifestyle and clinical. Individuals were genotyped for 86 tagging single nucleotide polymorphisms (SNPs in the BCL2, BAX, BAD and BAK1 genes.Significant associations with endometrial cancer risk were found for 9 SNPs in the BCL2 gene (P trend<0.05 for all. For SNPs rs17759659 and rs7243091 (minor allele for both: G, the associations were independent. The odds ratio was 1.27 (95% CI: 1.04-1.53 for women with AG genotype for the SNP rs17759659 and 1.82 (95% CI: 1.21-2.73 for women with the GG genotype for the SNP rs7243091. No interaction between these two SNPs and established non-genetic risk factors of endometrial cancer was noticed.Genetic polymorphisms in the BCL2 gene may be associated with the risk of endometrial cancer in Chinese women.

  3. Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population

    DEFF Research Database (Denmark)

    Robinson, Elise B; St Pourcain, Beate; Anttila, Verneri

    2016-01-01

    Almost all genetic risk factors for autism spectrum disorders (ASDs) can be found in the general population, but the effects of this risk are unclear in people not ascertained for neuropsychiatric symptoms. Using several large ASD consortium and population-based resources (total n > 38,000), we...... and developmental traits, the severe tail of which can result in diagnosis with an ASD or other neuropsychiatric disorder. A continuum model should inform the design and interpretation of studies of neuropsychiatric disease biology....

  4. Class II HLA interactions modulate genetic risk for multiple sclerosis

    Science.gov (United States)

    Dilthey, Alexander T; Xifara, Dionysia K; Ban, Maria; Shah, Tejas S; Patsopoulos, Nikolaos A; Alfredsson, Lars; Anderson, Carl A; Attfield, Katherine E; Baranzini, Sergio E; Barrett, Jeffrey; Binder, Thomas M C; Booth, David; Buck, Dorothea; Celius, Elisabeth G; Cotsapas, Chris; D’Alfonso, Sandra; Dendrou, Calliope A; Donnelly, Peter; Dubois, Bénédicte; Fontaine, Bertrand; Fugger, Lars; Goris, An; Gourraud, Pierre-Antoine; Graetz, Christiane; Hemmer, Bernhard; Hillert, Jan; Kockum, Ingrid; Leslie, Stephen; Lill, Christina M; Martinelli-Boneschi, Filippo; Oksenberg, Jorge R; Olsson, Tomas; Oturai, Annette; Saarela, Janna; Søndergaard, Helle Bach; Spurkland, Anne; Taylor, Bruce; Winkelmann, Juliane; Zipp, Frauke; Haines, Jonathan L; Pericak-Vance, Margaret A; Spencer, Chris C A; Stewart, Graeme; Hafler, David A; Ivinson, Adrian J; Harbo, Hanne F; Hauser, Stephen L; De Jager, Philip L; Compston, Alastair; McCauley, Jacob L; Sawcer, Stephen; McVean, Gil

    2016-01-01

    Association studies have greatly refined the understanding of how variation within the human leukocyte antigen (HLA) genes influences risk of multiple sclerosis. However, the extent to which major effects are modulated by interactions is poorly characterized. We analyzed high-density SNP data on 17,465 cases and 30,385 controls from 11 cohorts of European ancestry, in combination with imputation of classical HLA alleles, to build a high-resolution map of HLA genetic risk and assess the evidence for interactions involving classical HLA alleles. Among new and previously identified class II risk alleles (HLA-DRB1*15:01, HLA-DRB1*13:03, HLA-DRB1*03:01, HLA-DRB1*08:01 and HLA-DQB1*03:02) and class I protective alleles (HLA-A*02:01, HLA-B*44:02, HLA-B*38:01 and HLA-B*55:01), we find evidence for two interactions involving pairs of class II alleles: HLA-DQA1*01:01–HLA-DRB1*15:01 and HLA-DQB1*03:01–HLA-DQB1*03:02. We find no evidence for interactions between classical HLA alleles and non-HLA risk-associated variants and estimate a minimal effect of polygenic epistasis in modulating major risk alleles. PMID:26343388

  5. Inflammatory Dietary Pattern, IL-17F Genetic Variant, and the Risk of Colorectal Cancer.

    Science.gov (United States)

    Cho, Young Ae; Lee, Jeonghee; Oh, Jae Hwan; Chang, Hee Jin; Sohn, Dae Kyung; Shin, Aesun; Kim, Jeongseon

    2018-06-05

    A proinflammatory diet may increase the risk of colorectal cancer, but its role may differ according to individuals' genetic variants. We aimed to examine whether a specific dietary pattern reflecting inflammation was associated with a risk of colorectal cancer and whether IL-17F genetic variant altered this association. In a study of 695 colorectal cancer cases and 1846 controls, we derived a reduced rank regression dietary pattern using 32 food groups as predictors and the plasma C-reactive protein (CRP) concentration as the response. High CRP levels were associated with a high risk of colorectal cancer (OR (95% CI) = 3.58 (2.65⁻4.82) for the highest quartile vs. lowest quartile). After adjusting for potential confounding factors, high pattern scores were associated with a high risk of colorectal cancer (OR (95% CI) = 9.98 (6.81⁻14.62) for the highest quartile vs. lowest quartile). When stratified by the IL-17F rs763780 genotype, this association was stronger for individuals carrying the C allele ( p for interaction = 0.034), particularly for individuals with rectal cancer ( p for interaction = 0.011). In conclusion, a dietary pattern reflecting inflammation was significantly associated with colorectal cancer risk. Moreover, this association could be modified according to the IL-17F rs763780 genotype and anatomic site.

  6. Demographic, psychosocial, and genetic risk associated with smokeless tobacco use among Mexican heritage youth.

    Science.gov (United States)

    Wilkinson, Anna V; Koehly, Laura M; Vandewater, Elizabeth A; Yu, Robert K; Fisher-Hoch, Susan P; Prokhorov, Alexander V; Kohl, Harold W; Spitz, Margaret R; Shete, Sanjay

    2015-06-26

    Despite well-established negative health consequences of smokeless tobacco use (STU), the number and variety of alternative non-combustible tobacco products on the market have increased tremendously over the last 10 years, as has the market share of these products relative to cigarettes. While STU among non-Hispanic white youth has decreased over the last 10 years, the prevalence has remained constant among Hispanic youth. Here we examine demographic, psychosocial, and genetic risk associated with STU among Mexican heritage youth. Participants (50.5 % girls) reported on psychosocial risk factors in 2008-09 (n = 1,087, mean age = 14.3 years), and smokeless tobacco use in 2010-11 (mean age = 16.7 years). Participants provided a saliva sample that was genotyped for genes in the dopamine, serotonin and opioid pathways. Overall 62 (5.7 %) participants reported lifetime STU. We identified five single nucleotide polymorphisms that increased the risk for lifetime use. Specifically, rs2023902 on SERGEF (OR = 1.93; 95 % CI: 1.05-3.53), rs16941667 on ALDH2 (OR = 3.14; 95 % CI: 1.65-5.94), and rs17721739 on TPH1 (OR = 1.71; 95 % CI: 1.00-2.91) in the dopamine pathway, rs514912 on TRH-DE (OR = 1.84; 95 % CI: 1.25-2.71) in the serotonin pathway, and rs42451417 on the serotonin transporter gene, SLC6A4 (OR = 3.53; 95 % CI: 1.56-7.97). After controlling for genetic risk, being male (OR = 1.86; 95 % CI: 1.02-3.41), obesity status (OR = 2.22; 95 % CI: 1.21-4.09), and both higher levels of anxiety (OR = 1.04; 95 % CI: 1.01-1.08) and social disinhibition (OR = 1.26; 95 % CI: 1.07-1.48) were associated with increased use. High subjective social status (OR = 0.78; 95 % CI: 0.64-0.93) was protective against use, while higher parental education (OR = 2.01; 95 % CI: 1.03-3.93) was associated with increased use. These data suggest that use of genetic risk, along with psychosocial, demographic, and behavioral risk factors may increase our ability to identify youth at increased risk for STU

  7. Regulating genetically modified food. Policy trajectories, political culture, and risk perceptions in the U.S., Canada, and EU.

    Science.gov (United States)

    Wohlers, Anton E

    2010-09-01

    This paper examines whether national differences in political culture add an explanatory dimension to the formulation of policy in the area of biotechnology, especially with respect to genetically modified food. The analysis links the formulation of protective regulatory policies governing genetically modified food to both country and region-specific differences in uncertainty tolerance levels and risk perceptions in the United States, Canada, and European Union. Based on polling data and document analysis, the findings illustrate that these differences matter. Following a mostly opportunistic risk perception within an environment of high tolerance for uncertainty, policymakers in the United States and Canada modified existing regulatory frameworks that govern genetically modified food in their respective countries. In contrast, the mostly cautious perception of new food technologies and low tolerance for uncertainty among European Union member states has contributed to the creation of elaborate and stringent regulatory policies governing genetically modified food.

  8. Roles of Vascular and Metabolic Components in Cognitive Dysfunction of Alzheimer disease: Short- and Long-term Modification by Non-genetic Risk Factors

    Directory of Open Access Journals (Sweden)

    Naoyuki eSato

    2013-11-01

    Full Text Available It is well known that a specific set of genetic and non-genetic risk factors contributes to the onset of Alzheimer disease (AD. Non-genetic risk factors include diabetes, hypertension in mid-life, and probably dyslipidemia in mid-life. This review focuses on the vascular and metabolic components of non-genetic risk factors. The mechanisms whereby non-genetic risk factors modify cognitive dysfunction are divided into four components, short- and long-term effects of vascular and metabolic factors. These consist of 1 compromised vascular reactivity, 2 vascular lesions, 3 hypo/hyperglycemia, and 4 exacerbated AD histopathological features, respectively. Vascular factors compromise cerebrovascular reactivity in response to neuronal activity and also cause irreversible vascular lesions. On the other hand, representative short-term effects of metabolic factors on cognitive dysfunction occur due to hypoglycemia or hyperglycemia. Non-genetic risk factors also modify the pathological manifestations of AD in the long-term. Therefore, vascular and metabolic factors contribute to aggravation of cognitive dysfunction in AD through short-term and long-term effects. Beta-amyloid could be involved in both vascular and metabolic components. It might be beneficial to support treatment in AD patients by appropriate therapeutic management of non-genetic risk factors, considering the contributions of these four elements to the manifestation of cognitive dysfunction in individual patients, though all components are not always present. It should be clarified how these four components interact with each other. To answer this question, a clinical prospective study that follows up clinical features with respect to these four components: 1 functional MRI or SPECT for cerebrovascular reactivity, 2 MRI for ischemic lesions and atrophy, 3 clinical episodes of hypoglycemia and hyperglycemia, 4 amyloid-PET and tau-PET for pathological features of AD, would be required.

  9. Roles of vascular and metabolic components in cognitive dysfunction of Alzheimer disease: short- and long-term modification by non-genetic risk factors.

    Science.gov (United States)

    Sato, Naoyuki; Morishita, Ryuichi

    2013-11-05

    It is well known that a specific set of genetic and non-genetic risk factors contributes to the onset of Alzheimer disease (AD). Non-genetic risk factors include diabetes, hypertension in mid-life, and probably dyslipidemia in mid-life. This review focuses on the vascular and metabolic components of non-genetic risk factors. The mechanisms whereby non-genetic risk factors modify cognitive dysfunction are divided into four components, short- and long-term effects of vascular and metabolic factors. These consist of (1) compromised vascular reactivity, (2) vascular lesions, (3) hypo/hyperglycemia, and (4) exacerbated AD histopathological features, respectively. Vascular factors compromise cerebrovascular reactivity in response to neuronal activity and also cause irreversible vascular lesions. On the other hand, representative short-term effects of metabolic factors on cognitive dysfunction occur due to hypoglycemia or hyperglycemia. Non-genetic risk factors also modify the pathological manifestations of AD in the long-term. Therefore, vascular and metabolic factors contribute to aggravation of cognitive dysfunction in AD through short-term and long-term effects. β-amyloid could be involved in both vascular and metabolic components. It might be beneficial to support treatment in AD patients by appropriate therapeutic management of non-genetic risk factors, considering the contributions of these four elements to the manifestation of cognitive dysfunction in individual patients, though all components are not always present. It should be clarified how these four components interact with each other. To answer this question, a clinical prospective study that follows up clinical features with respect to these four components: (1) functional MRI or SPECT for cerebrovascular reactivity, (2) MRI for ischemic lesions and atrophy, (3) clinical episodes of hypoglycemia and hyperglycemia, (4) amyloid-PET and tau-PET for pathological features of AD, would be required.

  10. Genetics of Triglycerides and the Risk of Atherosclerosis.

    Science.gov (United States)

    Dron, Jacqueline S; Hegele, Robert A

    2017-07-01

    Plasma triglycerides are routinely measured with a lipid profile, and elevated plasma triglycerides are commonly encountered in the clinic. The confounded nature of this trait, which is correlated with numerous other metabolic perturbations, including depressed high-density lipoprotein cholesterol (HDL-C), has thwarted efforts to directly implicate triglycerides as causal in atherogenesis. Human genetic approaches involving large-scale populations and high-throughput genomic assessment under a Mendelian randomization framework have undertaken to sort out questions of causality. We review recent large-scale meta-analyses of cohorts and population-based sequencing studies designed to address whether common and rare variants in genes whose products are determinants of plasma triglycerides are also associated with clinical cardiovascular endpoints. The studied loci include genes encoding lipoprotein lipase and proteins that interact with it, such as apolipoprotein (apo) A-V, apo C-III and angiopoietin-like proteins 3 and 4, and common polymorphisms identified in genome-wide association studies. Triglyceride-raising variant alleles of these genes showed generally strong associations with clinical cardiovascular endpoints. However, in most cases, a second lipid disturbance-usually depressed HDL-C-was concurrently associated. While the findings collectively shift our understanding towards a potential causal role for triglycerides, we still cannot rule out the possibilities that triglycerides are a component of a joint phenotype with low HDL-C or that they are but markers of deeper causal metabolic disturbances that are not routinely measured in epidemiological-scale genetic studies.

  11. The association of XRCC3 Thr241Met genetic variant with risk of ...

    African Journals Online (AJOL)

    Background: Previous studies suggest that the X-ray repair cross-complementing group 3 gene (XRCC3) Thr241Met genetic variant could be potentially associated with the risk of prostate cancer. However, results from these published studies were conflicting rather than conclusive. Objectives:This meta-analysis aimed to ...

  12. The assessment of genetic risk of breast cancer : a set of GP guidelines

    NARCIS (Netherlands)

    de Bock, GH; Vlieland, TPMV; Hageman, GCHA; Oosterwijk, JC; Springer, MP; Kievit, J

    Background. Assessing a genetic risk for developing breast cancer is not an easy task for a GP. Current expert guidelines for referring and counselling women with a family history positive for breast cancer are complex and difficult to apply in general practice, and have only two strategies (to

  13. Prediction of breast cancer risk based on common genetic variants in women of East Asian ancestry.

    Science.gov (United States)

    Wen, Wanqing; Shu, Xiao-Ou; Guo, Xingyi; Cai, Qiuyin; Long, Jirong; Bolla, Manjeet K; Michailidou, Kyriaki; Dennis, Joe; Wang, Qin; Gao, Yu-Tang; Zheng, Ying; Dunning, Alison M; García-Closas, Montserrat; Brennan, Paul; Chen, Shou-Tung; Choi, Ji-Yeob; Hartman, Mikael; Ito, Hidemi; Lophatananon, Artitaya; Matsuo, Keitaro; Miao, Hui; Muir, Kenneth; Sangrajrang, Suleeporn; Shen, Chen-Yang; Teo, Soo H; Tseng, Chiu-Chen; Wu, Anna H; Yip, Cheng Har; Simard, Jacques; Pharoah, Paul D P; Hall, Per; Kang, Daehee; Xiang, Yongbing; Easton, Douglas F; Zheng, Wei

    2016-12-08

    Approximately 100 common breast cancer susceptibility alleles have been identified in genome-wide association studies (GWAS). The utility of these variants in breast cancer risk prediction models has not been evaluated adequately in women of Asian ancestry. We evaluated 88 breast cancer risk variants that were identified previously by GWAS in 11,760 cases and 11,612 controls of Asian ancestry. SNPs confirmed to be associated with breast cancer risk in Asian women were used to construct a polygenic risk score (PRS). The relative and absolute risks of breast cancer by the PRS percentiles were estimated based on the PRS distribution, and were used to stratify women into different levels of breast cancer risk. We confirmed significant associations with breast cancer risk for SNPs in 44 of the 78 previously reported loci at P women in the middle quintile of the PRS, women in the top 1% group had a 2.70-fold elevated risk of breast cancer (95% CI: 2.15-3.40). The risk prediction model with the PRS had an area under the receiver operating characteristic curve of 0.606. The lifetime risk of breast cancer for Shanghai Chinese women in the lowest and highest 1% of the PRS was 1.35% and 10.06%, respectively. Approximately one-half of GWAS-identified breast cancer risk variants can be directly replicated in East Asian women. Collectively, common genetic variants are important predictors for breast cancer risk. Using common genetic variants for breast cancer could help identify women at high risk of breast cancer.

  14. [The forecast of illicit drug use in adolescents with addictive behavior: personality traits and the level of genetic risk of substance dependence.

    Science.gov (United States)

    Yakovlev, A N; Brodyansky, V M; Schurina, A V; Romashkin, R A; Kibitov, A O

    2016-01-01

    To clarify the psychological mechanism underlying the genetic risk of substance addiction at the first stage of drug use by adolescents. Genetic risk was evaluated by genotyping of 5 polymorphisms of the dopaminergic system genes (dopamine receptor D2 and D4 genes and tyrosine hydroxylase gene). Psychological testing was performed using the Russian version of Temperament and Character Inventory (TCI-125). Seventy-five adolescents, aged 14-17 years, (girls 32%), who misused alcohol, including 22 adolescents using drugs, were examined. The level of genetic risk was directly correlated with the probability of drug use by boys, for girls the correlation was not confirmed. The increase of the level of genetic risk for boys was correlated with the increase on the scale «Self-directedness» of TCI-125 that may reflect a probable tendency to replacement of negative information, feeling of illusory wellbeing. The findings clarify the direction of measures for the prevention of drug use.

  15. Different psychological effects of cannabis use in adolescents at genetic high risk for schizophrenia and with attention deficit/hyperactivity disorder (ADHD).

    Science.gov (United States)

    Hollis, Chris; Groom, Madeleine J; Das, Debasis; Calton, Tim; Bates, Alan T; Andrews, Hayley K; Jackson, Georgina M; Liddle, Peter F

    2008-10-01

    Controversy exists regarding whether young people at risk for schizophrenia are at increased risk of adverse mental effects of cannabis use. We examined cannabis use and mental health functioning in three groups of young people aged 14-21; 36 non-psychotic siblings of adolescents with schizophrenia (genetic high risk group), 25 adolescents with attention deficit hyperactivity disorder (ADHD) and 72 healthy controls. The groups were sub-divided into 'users' and 'non-users' of cannabis based on how often they had used cannabis previously. Mental health functioning was quantified by creating a composite index derived from scores on the Schizotypal Personality Questionnaire (SPQ), Strengths and Difficulties Questionnaire (SDQ) and Global Assessment of Function (GAF). A significant positive association between cannabis use and mental health disturbance was confined to young people at genetic high risk for schizophrenia. To determine whether the relationship was specific to particular dimensions of mental health function, a second composite index was created based on scores from the SPQ Disorganisation and SDQ hyperactivity-inattention sub-scales. Again, there was a significant positive association between cannabis use and factor scores which was specific to the genetic high risk group. There was a trend for this association to be negative in the ADHD group (p=0.07). The findings support the view that young people at genetic high risk for schizophrenia are particularly vulnerable to mental health problems associated with cannabis use. Further research is needed to investigate the basis of relationships between cannabis and mental health in genetically vulnerable individuals.

  16. Genetic Stratification in Myeloid Diseases: From Risk Assessment to Clinical Decision Support Tool

    Directory of Open Access Journals (Sweden)

    Yishai Ofran

    2014-10-01

    Full Text Available Genetic aberrations have become a dominant factor in the stratification of myeloid malignancies. Cytogenetic and a few mutation studies are the backbone of risk assessment models of myeloid malignancies which are a major consideration in clinical decisions, especially patient assignment for allogeneic stem cell transplantation. Progress in our understanding of the genetic basis of the pathogenesis of myeloid malignancies and the growing capabilities of mass sequencing may add new roles for the clinical usage of genetic data. A few recently identified mutations recognized to be associated with specific diseases or clinical scenarios may soon become part of the diagnostic criteria of such conditions. Mutational studies may also advance our capabilities for a more efficient patient selection process, assigning the most effective therapy at the best timing for each patient. The clinical utility of genetic data is anticipated to advance further with the adoption of deep sequencing and next-generation sequencing techniques. We herein suggest some future potential applications of sequential genetic data to identify pending deteriorations at time points which are the best for aggressive interventions such as allogeneic stem cell transplantation. Genetics is moving from being mostly a prognostic factor to becoming a multitasking decision support tool for hematologists. Physicians must pay attention to advances in molecular hematology as it will soon be accessible and influential for most of our patients.

  17. Genetic influences on alcohol use behaviors have diverging developmental trajectories: a prospective study among male and female twins.

    Science.gov (United States)

    Meyers, Jacquelyn L; Salvatore, Jessica E; Vuoksimaa, Eero; Korhonen, Tellervo; Pulkkinen, Lea; Rose, Richard J; Kaprio, Jaakko; Dick, Danielle M

    2014-11-01

    Both alcohol-specific genetic factors and genetic factors related to externalizing behavior influence problematic alcohol use. Little is known, however, about the etiologic role of these 2 components of genetic risk on alcohol-related behaviors across development. Prior studies conducted in a male cohort of twins suggest that externalizing genetic factors are important for predicting heavy alcohol use in adolescence, whereas alcohol-specific genetic factors increase in importance during the transition to adulthood. In this report, we studied twin brothers and sisters and brother-sister twin pairs to examine such developmental trajectories and investigate whether sex and cotwin sex effects modify these genetic influences. We used prospective, longitudinal twin data collected between ages 12 and 22 within the population-based FinnTwin12 cohort study (analytic n = 1,864). Our dependent measures of alcohol use behaviors included alcohol initiation (age 12), intoxication frequency (ages 14 and 17), and alcohol dependence criteria (age 22). Each individual's genetic risk of alcohol use disorders (AUD-GR) was indexed by his/her parents' and cotwin's DSM-IV Alcohol Dependence (AD) criterion counts. Likewise, each individual's genetic risk of externalizing disorders (EXT-GR) was indexed with a composite measure of parents' and cotwin's DSM-IV Conduct Disorder and Antisocial Personality Disorder criterion counts. EXT-GR was most strongly related to alcohol use behaviors during adolescence, while AUD-GR was most strongly related to alcohol problems in young adulthood. Further, sex of the twin and sex of the cotwin significantly moderated the associations between genetic risk and alcohol use behaviors across development: AUD-GR influenced early adolescent alcohol use behaviors in females more than in males, and EXT-GR influenced age 22 AD more in males than in females. In addition, the associations of AUD-GR and EXT-GR with intoxication frequency were greater among 14- and

  18. Genetic risk profiles for a childhood with severe overweight.

    Science.gov (United States)

    González, J R; Estévez, M N; Giralt, P S; Cáceres, A; Pérez, L M L; González-Carpio, M; Ballester, F; Sunyer, J; Rodríguez-López, R

    2014-08-01

    The objective of this study was the description of a valid genetic risk score (GRS) to predict individuals with high susceptibility to childhood overweight by their genetic profiles. Case-control study including a group of children with high-risk familial predisposition to morbid obesity. Birth cohort from general population constituted the validation sample. For the discovery sample, 218 children with non-syndromic obesity and 190 control individuals were included. The validation sample was 653 children from two birth cohorts belonging to the INMA (Infancia y Medio Ambiente [Environment and Childhood] )project. 109 SNPs located in the genes FTO, SEC16B, BDNF, ETV5, SH2B1, GNPDA2, LYPLAL1, MSRA, TFAP2, KCTD15, MTCH2 and NEGR1, previously reported in association to body mass index (BMI) were analysed. For the validation sample, association between genome-wide data and BMI measurements between 3.5 and 5 years of age, were evaluated. The GRS includes six SNPs in the genes FTO, TFAP2B, SEC16B, ETV5 and SH2B1. The score distribution differs among cases and controls (P = 9.2 × 10(-14) ) showing a significant linear association with obesity (odds ratio [OR] per allele = 1.69; confidence interval [CI] 95% = 1.46-1.97; P = 4.3 × 10(-1) and area under the receiver operating characteristic curve [AUC] = 0.727; CI 95% = 0.676-0.778). The results were validated by the INMA cohort (OR per allele = 1.23 CI 95% = 1.03-1.48 and AUC = 0.601 CI 95% = 0.522-0.680). The use of our proposed genetic score provides useful information to determine those children who are susceptible to obesity. To improve the efficiency of clinical prevention and treatment of obesity, it is essential to design individualized based protocols in advance knowledge of the molecular basis of inherited susceptibility. © 2013 The Authors. Pediatric Obesity © 2013 International Association for the Study of Obesity.

  19. Methylation diet and methyl group genetics in risk for adenomatous polyp occurrence

    Directory of Open Access Journals (Sweden)

    Mark Lucock

    2015-06-01

    Conclusion: A methylation diet influences methyl group synthesis in the regulation of blood homocysteine level, and is modulated by genetic interactions. Methylation-related nutrients also interact with key genes to modify risk of AP, a precursor of colorectal cancer. Independent of diet, two methylation-related genes (A2756G-MS and A66G-MSR were directly associated with AP occurrence.

  20. A large-scale genetic analysis reveals a strong contribution of the HLA class II region to giant cell arteritis susceptibility.

    Science.gov (United States)

    Carmona, F David; Mackie, Sarah L; Martín, Jose-Ezequiel; Taylor, John C; Vaglio, Augusto; Eyre, Stephen; Bossini-Castillo, Lara; Castañeda, Santos; Cid, Maria C; Hernández-Rodríguez, José; Prieto-González, Sergio; Solans, Roser; Ramentol-Sintas, Marc; González-Escribano, M Francisca; Ortiz-Fernández, Lourdes; Morado, Inmaculada C; Narváez, Javier; Miranda-Filloy, José A; Beretta, Lorenzo; Lunardi, Claudio; Cimmino, Marco A; Gianfreda, Davide; Santilli, Daniele; Ramirez, Giuseppe A; Soriano, Alessandra; Muratore, Francesco; Pazzola, Giulia; Addimanda, Olga; Wijmenga, Cisca; Witte, Torsten; Schirmer, Jan H; Moosig, Frank; Schönau, Verena; Franke, Andre; Palm, Øyvind; Molberg, Øyvind; Diamantopoulos, Andreas P; Carette, Simon; Cuthbertson, David; Forbess, Lindsy J; Hoffman, Gary S; Khalidi, Nader A; Koening, Curry L; Langford, Carol A; McAlear, Carol A; Moreland, Larry; Monach, Paul A; Pagnoux, Christian; Seo, Philip; Spiera, Robert; Sreih, Antoine G; Warrington, Kenneth J; Ytterberg, Steven R; Gregersen, Peter K; Pease, Colin T; Gough, Andrew; Green, Michael; Hordon, Lesley; Jarrett, Stephen; Watts, Richard; Levy, Sarah; Patel, Yusuf; Kamath, Sanjeet; Dasgupta, Bhaskar; Worthington, Jane; Koeleman, Bobby P C; de Bakker, Paul I W; Barrett, Jennifer H; Salvarani, Carlo; Merkel, Peter A; González-Gay, Miguel A; Morgan, Ann W; Martín, Javier

    2015-04-02

    We conducted a large-scale genetic analysis on giant cell arteritis (GCA), a polygenic immune-mediated vasculitis. A case-control cohort, comprising 1,651 case subjects with GCA and 15,306 unrelated control subjects from six different countries of European ancestry, was genotyped by the Immunochip array. We also imputed HLA data with a previously validated imputation method to perform a more comprehensive analysis of this genomic region. The strongest association signals were observed in the HLA region, with rs477515 representing the highest peak (p = 4.05 × 10(-40), OR = 1.73). A multivariate model including class II amino acids of HLA-DRβ1 and HLA-DQα1 and one class I amino acid of HLA-B explained most of the HLA association with GCA, consistent with previously reported associations of classical HLA alleles like HLA-DRB1(∗)04. An omnibus test on polymorphic amino acid positions highlighted DRβ1 13 (p = 4.08 × 10(-43)) and HLA-DQα1 47 (p = 4.02 × 10(-46)), 56, and 76 (both p = 1.84 × 10(-45)) as relevant positions for disease susceptibility. Outside the HLA region, the most significant loci included PTPN22 (rs2476601, p = 1.73 × 10(-6), OR = 1.38), LRRC32 (rs10160518, p = 4.39 × 10(-6), OR = 1.20), and REL (rs115674477, p = 1.10 × 10(-5), OR = 1.63). Our study provides evidence of a strong contribution of HLA class I and II molecules to susceptibility to GCA. In the non-HLA region, we confirmed a key role for the functional PTPN22 rs2476601 variant and proposed other putative risk loci for GCA involved in Th1, Th17, and Treg cell function. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  1. Traumatic Stress Interacts With Bipolar Disorder Genetic Risk to Increase Risk for Suicide Attempts.

    Science.gov (United States)

    Wilcox, Holly C; Fullerton, Janice M; Glowinski, Anne L; Benke, Kelly; Kamali, Masoud; Hulvershorn, Leslie A; Stapp, Emma K; Edenberg, Howard J; Roberts, Gloria M P; Ghaziuddin, Neera; Fisher, Carrie; Brucksch, Christine; Frankland, Andrew; Toma, Claudio; Shaw, Alex D; Kastelic, Elizabeth; Miller, Leslie; McInnis, Melvin G; Mitchell, Philip B; Nurnberger, John I

    2017-12-01

    Bipolar disorder (BD) is one of the most heritable psychiatric conditions and is associated with high suicide risk. To explore the reasons for this link, this study examined the interaction between traumatic stress and BD polygenic risk score in relation to suicidal ideation, suicide attempt, and nonsuicidal self-injury (NSSI) in adolescent and young adult offspring and relatives of persons with BD (BD-relatives) compared with adolescent and young adult offspring of individuals without psychiatric disorders (controls). Data were collected from 4 sites in the United States and 1 site in Australia from 2006 through 2012. Generalized estimating equation models were used to compare rates of ideation, attempts, and NSSI between BD-relatives (n = 307) and controls (n = 166) and to determine the contribution of demographic factors, traumatic stress exposure, lifetime mood or substance (alcohol/drug) use disorders, and BD polygenic risk score. After adjusting for demographic characteristics and mood and substance use disorders, BD-relatives were at increased risk for suicidal ideation and attempts but not for NSSI. Independent of BD-relative versus control status, demographic factors, or mood and substance use disorders, exposure to trauma within the past year (including bullying, sexual abuse, and domestic violence) was associated with suicide attempts (p = .014), and BD polygenic risk score was marginally associated with attempts (p = .061). Importantly, the interaction between BD polygenic risk score and traumatic event exposures was significantly associated with attempts, independent of demographics, relative versus control status, and mood and substance use disorders (p = .041). BD-relatives are at increased risk for suicide attempts and ideation, especially if they are exposed to trauma and have evidence of increased genetic vulnerability. Copyright © 2017 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

  2. Sudden infant death syndrome, childhood thrombosis, and presence of genetic risk factors for thrombosis

    DEFF Research Database (Denmark)

    Larsen, TB; Nørgaard-Pedersen, B; Lundemose, JB

    2000-01-01

    in the child. This prompted us to investigate these genetic markers of thromboembolic disease in 121 cases of sudden infant death syndrome and in relevant controls, in the expectation of a more frequent occurrence of these markers if thrombosis is an etiological factor in sudden infant death syndrome...... or unknown risk factors for thrombosis as possible etiological factors for sudden infant death syndrome. It is likely that we must continuously employ the exclusion principle on possible etiological causes in genetic material from a large group of victims of sudden infant death syndrome if the phenomenon...

  3. Physical distance, genetic relationship, age, and leprosy classification are independent risk factors for leprosy in contacts of patients with leprosy.

    Science.gov (United States)

    Moet, F Johannes; Pahan, David; Schuring, Ron P; Oskam, Linda; Richardus, Jan H

    2006-02-01

    Close contacts of patients with leprosy have a higher risk of developing leprosy. Several risk factors have been identified, including genetic relationship and physical distance. Their independent contributions to the risk of developing leprosy, however, have never been sufficiently quantified. Logistic-regression analysis was performed on intake data from a prospective cohort study of 1037 patients newly diagnosed as having leprosy and their 21,870 contacts. Higher age showed an increased risk, with a bimodal distribution. Contacts of patients with paucibacillary (PB) leprosy with 2-5 lesions (PB2-5) and those with multibacillary (MB) leprosy had a higher risk than did contacts of patients with single-lesion PB leprosy. The core household group had a higher risk than other contacts living under the same roof and next-door neighbors, who again had a higher risk than neighbors of neighbors. A close genetic relationship indicated an increased risk when blood-related children, parents, and siblings were pooled together. Age of the contact, the disease classification of the index patient, and physical and genetic distance were independently associated with the risk of a contact acquiring leprosy. Contact surveys in leprosy should be not only focused on household contacts but also extended to neighbors and consanguineous relatives, especially when the patient has PB2-5 or MB leprosy.

  4. Genetic counselors’ implicit racial attitudes and their relationship to communication

    Science.gov (United States)

    Schaa, Kendra L; Roter, Debra L; Biesecker, Barbara B; Cooper, Lisa A; Erby, Lori H

    2015-01-01

    Objective Implicit racial attitudes are thought to shape interpersonal interactions and may contribute to health care disparities. This study explored the relationship between genetic counselors’ implicit racial attitudes and their communication during simulated genetic counseling sessions. Methods A nationally representative sample of genetic counselors completed a web-based survey that included the Race Implicit Association Test (IAT). A subset of these counselors (n=67) had participated in an earlier study in which they were video recorded counseling Black, Hispanic and non-Hispanic White simulated clients (SC) about their prenatal or cancer risks. The counselors’ IAT scores were related to their session communication through robust regression modeling. Results Genetic counselors showed a moderate to strong pro-White bias on the Race IAT (M=0.41, SD=0.35). Counselors with stronger pro-White bias were rated as displaying lower levels of positive affect (pcommunication (pcommunication in minority client sessions and may contribute to racial disparities in processes of care related to genetic services. PMID:25622081

  5. [About twins: Epidemiological, genetic, and obstetrical aspects, specific risks, and outcome].

    Science.gov (United States)

    Tauzin, M; Felix, A; Michot, C; Dedieu, C; Aoust, L; Fortas, F; Guillier, C; Ngo, J; Wachter, P-Y; Petermann, L; Kermorvant-Duchemin, E

    2017-12-01

    The incidence of twin pregnancies has increased steadily for the last 40 years due to assisted reproductive technology and increased maternal childbearing age. Multiple pregnancies, especially monochorionic twin pregnancies, carry a high risk for the mother and the fetuses and require close follow-up. Twins are exposed to a higher risk of perinatal anoxia, in utero fetal demise, preterm birth, congenital malformations, fetal growth restriction, and vascular complications. Compared to singletons, twins are at higher risk of perinatal mortality and impaired neurodevelopmental outcome, justifying a thorough follow-up by pediatricians, including assessment and management of familial and psychosocial impact. This paper discusses the epidemiological, obstetrical, and genetic issues raised by twin pregnancies and reviews the data on the perinatal and neurological long-term outcomes of twins, as well as the psychosocial impact of multiple births on twins and their families. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  6. Interactions of Lipid Genetic Risk Scores with Estimates of Metabolic Health in a Danish Population

    DEFF Research Database (Denmark)

    Justesen, Johanne M; Allin, Kristine H; Sandholt, Camilla H

    2015-01-01

    Background—There are several well-established lifestyle factors influencing dyslipidemia and currently; 157 genetic susceptibility loci have been reported to be associated with serum lipid levels at genome-wide statistical significance. However, the interplay between lifestyle risk factors...... and these susceptibility loci has not been fully elucidated. We tested whether genetic risk scores (GRS) of lipid-associated single nucleotide polymorphisms associate with fasting serum lipid traits and whether the effects are modulated by lifestyle factors or estimates of metabolic health. Methods and Results—The single......-cholesterol, high-density lipoprotein-cholesterol, or triglyceride, 4 weighted GRS were constructed. In a cross-sectional design, we investigated whether the effect of these weighted GRSs on lipid levels were modulated by diet, alcohol consumption, physical activity, and smoking or the individual metabolic health...

  7. Whole-genome sequencing of monozygotic twins discordant for schizophrenia indicates multiple genetic risk factors for schizophrenia

    Institute of Scientific and Technical Information of China (English)

    Jinsong Tang; Fan He; Fengyu Zhang; Yin Yao Shugart; Chunyu Liu; Yanqing Tang; Raymond C.K.Chan; Chuan-Yue Wang; Yong-Gang Yao; Xiaogang Chen; Yu Fan; Hong Li; Qun Xiang; Deng-Feng Zhang; Zongchang Li; Ying He; Yanhui Liao; Ya Wang

    2017-01-01

    Schizophrenia is a common disorder with a high heritability,but its genetic architecture is still elusive.We implemented whole-genome sequencing (WGS) analysis of 8 families with monozygotic (MZ) twin pairs discordant for schizophrenia to assess potential association of de novo mutations (DNMs) or inherited variants with susceptibility to schizophrenia.Eight non-synonymous DNMs (including one splicing site) were identified and shared by twins,which were either located in previously reported schizophrenia risk genes (p.V24689I mutation in TTN,p.S2506T mutation in GCN1L1,IVS3+1G > T in DOCK1) or had a benign to damaging effect according to in silico prediction analysis.By searching the inherited rare damaging or loss-of-function (LOF) variants and common susceptible alleles from three classes of schizophrenia candidate genes,we were able to distill genetic alterations in several schizophrenia risk genes,including GAD1,PLXNA2,RELN and FEZ1.Four inherited copy number variations (CNVs;including a large deletion at 16p13.11) implicated for schizophrenia were identified in four families,respectively.Most of families carried both missense DNMs and inherited risk variants,which might suggest that DNMs,inherited rare damaging variants and common risk alleles together conferred to schizophrenia susceptibility.Our results support that schizophrenia is caused by a combination of multiple genetic factors,with each DNM/variant showing a relatively small effect size.

  8. Genetic insights into age-related macular degeneration: Controversies addressing Risk, Causality, and Therapeutics

    Science.gov (United States)

    Gorin, Michael B.

    2012-01-01

    Age-related macular degeneration (AMD) is a common condition among the elderly population that leads to the progressive central vision loss and serious compromise of quality of life for its sufferers. It is also one of the few disorders for whom the investigation of its genetics has yielded rich insights into its diversity and causality and holds the promise of enabling clinicians to provide better risk assessments for individuals as well as to develop and selectively deploy new therapeutics to either prevent or slow the development of disease and lessen the threat of vision loss. The genetics of AMD began initially with the appreciation of familial aggregation and increase risk and expanded with the initial association of APOE variants with the disease. The first major breakthroughs came with family-based linkage studies of affected (and discordant) sibs, which identified a number of genetic loci and led to the targeted search of the 1q31 and 10q26 loci for associated variants. Three of the initial four reports for the CFH variant, Y402H, were based on regional candidate searches, as were the two initial reports of the ARMS2/HTRA1 locus variants. Case-control association studies initially also played a role in discovering the major genetic variants for AMD, and the success of those early studies have been used to fuel enthusiasm for the methodology for a number of diseases. Until 2010, all of the subsequent genetic variants associated with AMD came from candidate gene testing based on the complement factor pathway. In 2010, several large-scale genome-wide association studies (GWAS) identified genes that had not been previously identified. Much of this historical information is available in a number of recent reviews.(Chen et al., 2010b; Deangelis et al., 2011; Fafowora and Gorin, 2012b; Francis and Klein, 2011; Kokotas et al., 2011) Large meta analysis of AMD GWAS has added new loci and variants to this collection.(Chen et al., 2010a; Kopplin et al., 2010; Yu et

  9. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

    Science.gov (United States)

    Ehret, Georg B; Munroe, Patricia B; Rice, Kenneth M; Bochud, Murielle; Johnson, Andrew D; Chasman, Daniel I; Smith, Albert V; Tobin, Martin D; Verwoert, Germaine C; Hwang, Shih-Jen; Pihur, Vasyl; Vollenweider, Peter; O'Reilly, Paul F; Amin, Najaf; Bragg-Gresham, Jennifer L; Teumer, Alexander; Glazer, Nicole L; Launer, Lenore; Zhao, Jing Hua; Aulchenko, Yurii; Heath, Simon; Sõber, Siim; Parsa, Afshin; Luan, Jian'an; Arora, Pankaj; Dehghan, Abbas; Zhang, Feng; Lucas, Gavin; Hicks, Andrew A; Jackson, Anne U; Peden, John F; Tanaka, Toshiko; Wild, Sarah H; Rudan, Igor; Igl, Wilmar; Milaneschi, Yuri; Parker, Alex N; Fava, Cristiano; Chambers, John C; Fox, Ervin R; Kumari, Meena; Go, Min Jin; van der Harst, Pim; Kao, Wen Hong Linda; Sjögren, Marketa; Vinay, D G; Alexander, Myriam; Tabara, Yasuharu; Shaw-Hawkins, Sue; Whincup, Peter H; Liu, Yongmei; Shi, Gang; Kuusisto, Johanna; Tayo, Bamidele; Seielstad, Mark; Sim, Xueling; Nguyen, Khanh-Dung Hoang; Lehtimäki, Terho; Matullo, Giuseppe; Wu, Ying; Gaunt, Tom R; Onland-Moret, N Charlotte; Cooper, Matthew N; Platou, Carl G P; Org, Elin; Hardy, Rebecca; Dahgam, Santosh; Palmen, Jutta; Vitart, Veronique; Braund, Peter S; Kuznetsova, Tatiana; Uiterwaal, Cuno S P M; Adeyemo, Adebowale; Palmas, Walter; Campbell, Harry; Ludwig, Barbara; Tomaszewski, Maciej; Tzoulaki, Ioanna; Palmer, Nicholette D; Aspelund, Thor; Garcia, Melissa; Chang, Yen-Pei C; O'Connell, Jeffrey R; Steinle, Nanette I; Grobbee, Diederick E; Arking, Dan E; Kardia, Sharon L; Morrison, Alanna C; Hernandez, Dena; Najjar, Samer; McArdle, Wendy L; Hadley, David; Brown, Morris J; Connell, John M; Hingorani, Aroon D; Day, Ian N M; Lawlor, Debbie A; Beilby, John P; Lawrence, Robert W; Clarke, Robert; Hopewell, Jemma C; Ongen, Halit; Dreisbach, Albert W; Li, Yali; Young, J Hunter; Bis, Joshua C; Kähönen, Mika; Viikari, Jorma; Adair, Linda S; Lee, Nanette R; Chen, Ming-Huei; Olden, Matthias; Pattaro, Cristian; Bolton, Judith A Hoffman; Köttgen, Anna; Bergmann, Sven; Mooser, Vincent; Chaturvedi, Nish; Frayling, Timothy M; Islam, Muhammad; Jafar, Tazeen H; Erdmann, Jeanette; Kulkarni, Smita R; Bornstein, Stefan R; Grässler, Jürgen; Groop, Leif; Voight, Benjamin F; Kettunen, Johannes; Howard, Philip; Taylor, Andrew; Guarrera, Simonetta; Ricceri, Fulvio; Emilsson, Valur; Plump, Andrew; Barroso, Inês; Khaw, Kay-Tee; Weder, Alan B; Hunt, Steven C; Sun, Yan V; Bergman, Richard N; Collins, Francis S; Bonnycastle, Lori L; Scott, Laura J; Stringham, Heather M; Peltonen, Leena; Perola, Markus; Vartiainen, Erkki; Brand, Stefan-Martin; Staessen, Jan A; Wang, Thomas J; Burton, Paul R; Soler Artigas, Maria; Dong, Yanbin; Snieder, Harold; Wang, Xiaoling; Zhu, Haidong; Lohman, Kurt K; Rudock, Megan E; Heckbert, Susan R; Smith, Nicholas L; Wiggins, Kerri L; Doumatey, Ayo; Shriner, Daniel; Veldre, Gudrun; Viigimaa, Margus; Kinra, Sanjay; Prabhakaran, Dorairaj; Tripathy, Vikal; Langefeld, Carl D; Rosengren, Annika; Thelle, Dag S; Corsi, Anna Maria; Singleton, Andrew; Forrester, Terrence; Hilton, Gina; McKenzie, Colin A; Salako, Tunde; Iwai, Naoharu; Kita, Yoshikuni; Ogihara, Toshio; Ohkubo, Takayoshi; Okamura, Tomonori; Ueshima, Hirotsugu; Umemura, Satoshi; Eyheramendy, Susana; Meitinger, Thomas; Wichmann, H-Erich; Cho, Yoon Shin; Kim, Hyung-Lae; Lee, Jong-Young; Scott, James; Sehmi, Joban S; Zhang, Weihua; Hedblad, Bo; Nilsson, Peter; Smith, George Davey; Wong, Andrew; Narisu, Narisu; Stančáková, Alena; Raffel, Leslie J; Yao, Jie; Kathiresan, Sekar; O'Donnell, Christopher J; Schwartz, Stephen M; Ikram, M Arfan; Longstreth, W T; Mosley, Thomas H; Seshadri, Sudha; Shrine, Nick R G; Wain, Louise V; Morken, Mario A; Swift, Amy J; Laitinen, Jaana; Prokopenko, Inga; Zitting, Paavo; Cooper, Jackie A; Humphries, Steve E; Danesh, John; Rasheed, Asif; Goel, Anuj; Hamsten, Anders; Watkins, Hugh; Bakker, Stephan J L; van Gilst, Wiek H; Janipalli, Charles S; Mani, K Radha; Yajnik, Chittaranjan S; Hofman, Albert; Mattace-Raso, Francesco U S; Oostra, Ben A; Demirkan, Ayse; Isaacs, Aaron; Rivadeneira, Fernando; Lakatta, Edward G; Orru, Marco; Scuteri, Angelo; Ala-Korpela, Mika; Kangas, Antti J; Lyytikäinen, Leo-Pekka; Soininen, Pasi; Tukiainen, Taru; Würtz, Peter; Ong, Rick Twee-Hee; Dörr, Marcus; Kroemer, Heyo K; Völker, Uwe; Völzke, Henry; Galan, Pilar; Hercberg, Serge; Lathrop, Mark; Zelenika, Diana; Deloukas, Panos; Mangino, Massimo; Spector, Tim D; Zhai, Guangju; Meschia, James F; Nalls, Michael A; Sharma, Pankaj; Terzic, Janos; Kumar, M V Kranthi; Denniff, Matthew; Zukowska-Szczechowska, Ewa; Wagenknecht, Lynne E; Fowkes, F Gerald R; Charchar, Fadi J; Schwarz, Peter E H; Hayward, Caroline; Guo, Xiuqing; Rotimi, Charles; Bots, Michiel L; Brand, Eva; Samani, Nilesh J; Polasek, Ozren; Talmud, Philippa J; Nyberg, Fredrik; Kuh, Diana; Laan, Maris; Hveem, Kristian; Palmer, Lyle J; van der Schouw, Yvonne T; Casas, Juan P; Mohlke, Karen L; Vineis, Paolo; Raitakari, Olli; Ganesh, Santhi K; Wong, Tien Y; Tai, E Shyong; Cooper, Richard S; Laakso, Markku; Rao, Dabeeru C; Harris, Tamara B; Morris, Richard W; Dominiczak, Anna F; Kivimaki, Mika; Marmot, Michael G; Miki, Tetsuro; Saleheen, Danish; Chandak, Giriraj R; Coresh, Josef; Navis, Gerjan; Salomaa, Veikko; Han, Bok-Ghee; Zhu, Xiaofeng; Kooner, Jaspal S; Melander, Olle; Ridker, Paul M; Bandinelli, Stefania; Gyllensten, Ulf B; Wright, Alan F; Wilson, James F; Ferrucci, Luigi; Farrall, Martin; Tuomilehto, Jaakko; Pramstaller, Peter P; Elosua, Roberto; Soranzo, Nicole; Sijbrands, Eric J G; Altshuler, David; Loos, Ruth J F; Shuldiner, Alan R; Gieger, Christian; Meneton, Pierre; Uitterlinden, Andre G; Wareham, Nicholas J; Gudnason, Vilmundur; Rotter, Jerome I; Rettig, Rainer; Uda, Manuela; Strachan, David P; Witteman, Jacqueline C M; Hartikainen, Anna-Liisa; Beckmann, Jacques S; Boerwinkle, Eric; Vasan, Ramachandran S; Boehnke, Michael; Larson, Martin G; Järvelin, Marjo-Riitta; Psaty, Bruce M; Abecasis, Gonçalo R; Chakravarti, Aravinda; Elliott, Paul; van Duijn, Cornelia M; Newton-Cheh, Christopher; Levy, Daniel; Caulfield, Mark J; Johnson, Toby

    2011-09-11

    Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

  10. Genetics and Other Risk Factors for Past Concussions in Active-Duty Soldiers.

    Science.gov (United States)

    Dretsch, Michael N; Silverberg, Noah; Gardner, Andrew J; Panenka, William J; Emmerich, Tanja; Crynen, Gogce; Ait-Ghezala, Ghania; Chaytow, Helena; Mathura, Venkat; Crawford, Fiona C; Iverson, Grant L

    2017-02-15

    Risk factors for concussion in active-duty military service members are poorly understood. The present study examined the association between self-reported concussion history and genetics (apolipoprotein E [APOE], brain-derived neurotrophic factor [BDNF], and D2 dopamine receptor genes [DRD2]), trait personality measures (impulsive-sensation seeking and trait aggression-hostility), and current alcohol use. The sample included 458 soldiers who were preparing to deploy for Operation Iraqi Freedom/Operation Enduring Freedom. For those with the BDNF Met/Met genotype, 57.9% (11/19) had a history of one or more prior concussions, compared with 35.6% (154/432) of those with other BDNF genotypes (p = 0.049, odds ratio [OR] = 2.48). APOE and DRD2 genotypes were not associated with risk for past concussions. Those with the BDNF Met/Met genotype also reported greater aggression and hostility personality characteristics. When combined in a predictive model, prior military deployments, being male, and having the BDNF Met/Met genotype were independently associated with increased lifetime history of concussions in active-duty soldiers. Replication in larger independent samples is necessary to have more confidence in both the positive and negative genetic associations reported in this study.

  11. Stroke genetics: prospects for personalized medicine

    Directory of Open Access Journals (Sweden)

    Markus Hugh S

    2012-09-01

    Full Text Available Abstract Epidemiologic evidence supports a genetic predisposition to stroke. Recent advances, primarily using the genome-wide association study approach, are transforming what we know about the genetics of multifactorial stroke, and are identifying novel stroke genes. The current findings are consistent with different stroke subtypes having different genetic architecture. These discoveries may identify novel pathways involved in stroke pathogenesis, and suggest new treatment approaches. However, the already identified genetic variants explain only a small proportion of overall stroke risk, and therefore are not currently useful in predicting risk for the individual patient. Such risk prediction may become a reality as identification of a greater number of stroke risk variants that explain the majority of genetic risk proceeds, and perhaps when information on rare variants, identified by whole-genome sequencing, is also incorporated into risk algorithms. Pharmacogenomics may offer the potential for earlier implementation of 'personalized genetic' medicine. Genetic variants affecting clopidogrel and warfarin metabolism may identify non-responders and reduce side-effects, but these approaches have not yet been widely adopted in clinical practice.

  12. A study on genetic variants of Fibroblast growth factor receptor 2 (FGFR2 and the risk of breast cancer from North India.

    Directory of Open Access Journals (Sweden)

    Sarah Siddiqui

    Full Text Available Genome-Wide Association Studies (GWAS have identified Fibroblast growth factor receptor 2 (FGFR2 as a candidate gene for breast cancer with single nucleotide polymorphisms (SNPs located in intron 2 region as the susceptibility loci strongly associated with the risk. However, replicate studies have often failed to extrapolate the association to diverse ethnic regions. This hints towards the existing heterogeneity among different populations, arising due to differential linkage disequilibrium (LD structures and frequencies of SNPs within the associated regions of the genome. It is therefore important to revisit the previously linked candidates in varied population groups to unravel the extent of heterogeneity. In an attempt to investigate the role of FGFR2 polymorphisms in susceptibility to the risk of breast cancer among North Indian women, we genotyped rs2981582, rs1219648, rs2981578 and rs7895676 polymorphisms in 368 breast cancer patients and 484 healthy controls by Polymerase chain reaction-Restriction fragment length polymorphism (PCR-RFLP assay. We observed a statistically significant association with breast cancer risk for all the four genetic variants (P<0.05. In per-allele model for rs2981582, rs1219648, rs7895676 and in dominant model for rs2981578, association remained significant after bonferroni correction (P<0.0125. On performing stratified analysis, significant correlations with various clinicopathological as well as environmental and lifestyle characteristics were observed. It was evident that rs1219648 and rs2981578 interacted with exogenous hormone use and advanced clinical stage III (after Bonferroni correction, P<0.000694, respectively. Furthermore, combined analysis on these four loci revealed that compared to women with 0-1 risk loci, those with 2-4 risk loci had increased risk (OR = 1.645, 95%CI = 1.152-2.347, P = 0.006. In haplotype analysis, for rs2981578, rs2981582 and rs1219648, risk haplotype (GTG was

  13. MMP9 polymorphisms and breast cancer risk: a report from the Shanghai Breast Cancer Genetics Study.

    Science.gov (United States)

    Beeghly-Fadiel, Alicia; Lu, Wei; Shu, Xiao-Ou; Long, Jirong; Cai, Qiuyin; Xiang, Yongbin; Gao, Yu-Tang; Zheng, Wei

    2011-04-01

    In addition to tumor invasion and angiogenesis, matrix metalloproteinase (MMP)9 also contributes to carcinogenesis and tumor growth. Genetic variation that may influence MMP9 expression was evaluated among participants of the Shanghai Breast Cancer Genetics Study (SBCGS) for associations with breast cancer susceptibility. In stage 1, 11 MMP9 single nucleotide polymorphisms (SNPs) were genotyped by the Affymetrix Targeted Genotyping System and/or the Affymetrix Genome-Wide Human SNP Array 6.0 among 4,227 SBCGS participants. One SNP was further genotyped using the Sequenom iPLEX MassARRAY platform among an additional 6,270 SBCGS participants. Associations with breast cancer risk were evaluated by odds ratios (OR) and 95% confidence intervals (CI) from logistic regression models that included adjustment for age, education, and genotyping stage when appropriate. In Stage 1, rare allele homozygotes for a promoter SNP (rs3918241) or a non-synonymous SNP (rs2274756, R668Q) tended to occur more frequently among breast cancer cases (P value = 0.116 and 0.056, respectively). Given their high linkage disequilibrium (D' = 1.0, r (2) = 0.97), one (rs3918241) was selected for additional analysis. An association with breast cancer risk was not supported by additional Stage 2 genotyping. In combined analysis, no elevated risk of breast cancer among homozygotes was found (OR: 1.2, 95% CI: 0.8-1.8). Common genetic variation in MMP9 was not found to be significantly associated with breast cancer susceptibility among participants of the Shanghai Breast Cancer Genetics Study.

  14. Genetic variants in FGFR2 and FGFR4 genes and skin cancer risk in the Nurses' Health Study

    International Nuclear Information System (INIS)

    Nan, Hongmei; Qureshi, Abrar A; Hunter, David J; Han, Jiali

    2009-01-01

    The human fibroblast growth factor (FGF) and its receptor (FGFR) play an important role in tumorigenesis. Deregulation of the FGFR2 gene has been identified in a number of cancer sites. Overexpression of the FGFR4 protein has been linked to cutaneous melanoma progression. Previous studies reported associations between genetic variants in the FGFR2 and FGFR4 genes and development of various cancers. We evaluated the associations of four genetic variants in the FGFR2 gene highly related to breast cancer risk and the three common tag-SNPs in the FGFR4 gene with skin cancer risk in a nested case-control study of Caucasians within the Nurses' Health Study (NHS) among 218 melanoma cases, 285 squamous cell carcinoma (SCC) cases, 300 basal cell carcinoma (BCC) cases, and 870 controls. We found no evidence for associations between these seven genetic variants and the risks of melanoma and nonmelanocytic skin cancer. Given the power of this study, we did not detect any contribution of genetic variants in the FGFR2 or FGFR4 genes to inherited predisposition to skin cancer among Caucasian women

  15. Enrichment of minor allele of SNPs and genetic prediction of type 2 diabetes risk in British population.

    Directory of Open Access Journals (Sweden)

    Xiaoyun Lei

    Full Text Available Type 2 diabetes (T2D is a complex disorder characterized by high blood sugar, insulin resistance, and relative lack of insulin. The collective effects of genome wide minor alleles of common SNPs, or the minor allele content (MAC in an individual, have been linked with quantitative variations of complex traits and diseases. Here we studied MAC in T2D using previously published SNP datasets and found higher MAC in cases relative to matched controls. A set of 357 SNPs was found to have the best predictive accuracy in a British population. A weighted risk score calculated by using this set produced an area under the curve (AUC score of 0.86, which is comparable to risk models built by phenotypic markers. These results identify a novel genetic risk element in T2D susceptibility and provide a potentially useful genetic method to identify individuals with high risk of T2D.

  16. Polygenic risk score and heritability estimates reveals a genetic relationship between ASD and OCD.

    Science.gov (United States)

    Guo, W; Samuels, J F; Wang, Y; Cao, H; Ritter, M; Nestadt, P S; Krasnow, J; Greenberg, B D; Fyer, A J; McCracken, J T; Geller, D A; Murphy, D L; Knowles, J A; Grados, M A; Riddle, M A; Rasmussen, S A; McLaughlin, N C; Nurmi, E L; Askland, K D; Cullen, B A; Piacentini, J; Pauls, D L; Bienvenu, O J; Stewart, S E; Goes, F S; Maher, B; Pulver, A E; Valle, D; Mattheisen, M; Qian, J; Nestadt, G; Shugart, Y Y

    2017-07-01

    Obsessive-compulsive disorder (OCD) and Autism spectrum disorder (ASD) are both highly heritable neurodevelopmental disorders that conceivably share genetic risk factors. However, the underlying genetic determinants remain largely unknown. In this work, the authors describe a combined genome-wide association study (GWAS) of ASD and OCD. The OCD dataset includes 2998 individuals in nuclear families. The ASD dataset includes 6898 individuals in case-parents trios. GWAS summary statistics were examined for potential enrichment of functional variants associated with gene expression levels in brain regions. The top ranked SNP is rs4785741 (chromosome 16) with P value=6.9×10 -7 in our re-analysis. Polygenic risk score analyses were conducted to investigate the genetic relationship within and across the two disorders. These analyses identified a significant polygenic component of ASD, predicting 0.11% of the phenotypic variance in an independent OCD data set. In addition, we examined the genomic architecture of ASD and OCD by estimating heritability on different chromosomes and different allele frequencies, analyzing genome-wide common variant data by using the Genome-wide Complex Trait Analysis (GCTA) program. The estimated global heritability of OCD is 0.427 (se=0.093) and 0.174 (se=0.053) for ASD in these imputed data. Published by Elsevier B.V.

  17. Cancer Genetics Services Directory

    Science.gov (United States)

    ... Services Directory Cancer Prevention Overview Research NCI Cancer Genetics Services Directory This directory lists professionals who provide services related to cancer genetics (cancer risk assessment, genetic counseling, genetic susceptibility testing, ...

  18. The Role of Environment and Lifestyle in Determining the Risk of Multiple Sclerosis.

    Science.gov (United States)

    Hedström, Anna Karin; Olsson, Tomas; Alfredsson, Lars

    2015-01-01

    MS is a complex disease where both genetic and environmental factors contribute to disease susceptibility. The substantially increased risk of developing MS in relatives of affected individuals gives solid evidence for a genetic base for susceptibility, whereas the modest familial risk, most strikingly demonstrated in the twin studies, is a very strong argument for an important role of lifestyle/environmental factors in determining the risk of MS, sometimes interacting with MS risk genes. Lifestyle factors and environmental exposures are harder to accurately study and quantify than genetic factors. However, it is important to identify these factors since they, as opposed to risk genes, are potentially preventable. We have reviewed the evidence for environmental factors that have been repeatedly shown to influence the risk of MS: Epstein-Barr virus (EBV) infection, ultraviolet radiation (UVR) exposure habits /vitamin D status, and smoking. We have also reviewed a number of additional environmental factors, published in the past 5 years, that have been described to influence MS risk. Independent replication, preferably by a variety of methods, may give still more firm evidence for their involvement.

  19. Genetic risks from radiation: recent assessments by the BEIR and UNSCEAR Committees and suggestions as to how future research can improve such estimates

    International Nuclear Information System (INIS)

    Selby, P.B.

    1979-01-01

    Recently two widely-recognized committees, namely the UNSCEAR and BEIR Committees, have reevaluated their estimates of genetic risks from radiation. Their estimates for gene mutations are based on two different approaches, one being the doubling-dose approach and the other being a new direct approach based on an empirical determination of the amount of dominant induced damage in the skeletons of mice in the first generation following irradiation. The estimates made by these committees are in reasonably good agreement and suggest that the genetic risks from present exposures resulting from nuclear power production are small. There is room for much improvement in the reliability of the risk estimates. The relatively new approach of measuring the amount of induced damage to the mouse skeleton shows great promise of improving knowledge about how changes in the mutation frequency affect the incidence of genetic disorders. Such findings may have considerable influence on genetic risk estimates for radiation and on the development of risk estimates for other less-well-understood environmental mutagens

  20. Dietary Magnesium and Genetic Interactions in Diabetes and Related Risk Factors: A Brief Overview of Current Knowledge

    Science.gov (United States)

    Hruby, Adela; McKeown, Nicola M.; Song, Yiqing; Djoussé, Luc

    2013-01-01

    Nutritional genomics has exploded in the last decade, yielding insights—both nutrigenomic and nutrigenetic—into the physiology of dietary interactions and our genes. Among these are insights into the regulation of magnesium transport and homeostasis and mechanisms underlying magnesium’s role in insulin and glucose handling. Recent observational evidence has attempted to examine some promising research avenues on interaction between genetics and dietary magnesium in relation to diabetes and diabetes risk factors. This brief review summarizes the recent evidence on dietary magnesium’s role in diabetes and related traits in the presence of underlying genetic risk, and discusses future potential research directions. PMID:24322525

  1. Efficacy of a web-based intelligent tutoring system for communicating genetic risk of breast cancer: a fuzzy-trace theory approach.

    Science.gov (United States)

    Wolfe, Christopher R; Reyna, Valerie F; Widmer, Colin L; Cedillos, Elizabeth M; Fisher, Christopher R; Brust-Renck, Priscila G; Weil, Audrey M

    2015-01-01

    . Many healthy women consider genetic testing for breast cancer risk, yet BRCA testing issues are complex. . To determine whether an intelligent tutor, BRCA Gist, grounded in fuzzy-trace theory (FTT), increases gist comprehension and knowledge about genetic testing for breast cancer risk, improving decision making. . In 2 experiments, 410 healthy undergraduate women were randomly assigned to 1 of 3 groups: an online module using a Web-based tutoring system (BRCA Gist) that uses artificial intelligence technology, a second group read highly similar content from the National Cancer Institute (NCI) Web site, and a third that completed an unrelated tutorial. . BRCA Gist applied FTT and was designed to help participants develop gist comprehension of topics relevant to decisions about BRCA genetic testing, including how breast cancer spreads, inherited genetic mutations, and base rates. . We measured content knowledge, gist comprehension of decision-relevant information, interest in testing, and genetic risk and testing judgments. . Control knowledge scores ranged from 54% to 56%, NCI improved significantly to 65% and 70%, and BRCA Gist improved significantly more to 75% and 77%, P tutors, such as BRCA Gist, are scalable, cost-effective ways of helping people understand complex issues, improving decision making. © The Author(s) 2014.

  2. Bilirubin and Stroke Risk Using a Mendelian Randomization Design.

    Science.gov (United States)

    Lee, Sun Ju; Jee, Yon Ho; Jung, Keum Ji; Hong, Seri; Shin, Eun Soon; Jee, Sun Ha

    2017-05-01

    Circulating bilirubin, a natural antioxidant, is associated with decreased risk of stroke. However, the nature of the relationship between the two remains unknown. We used a Mendelian randomization analysis to assess the causal effect of serum bilirubin on stroke risk in Koreans. The 14 single-nucleotide polymorphisms (SNPs) (bilirubin level in the KCPS-II (Korean Cancer Prevention Study-II) Biobank subcohort consisting of 4793 healthy Korean and 806 stroke cases. Weighted genetic risk score was calculated using 14 SNPs selected from the top SNPs. Both rs6742078 (F statistics=138) and weighted genetic risk score with 14 SNPs (F statistics=187) were strongly associated with bilirubin levels. Simultaneously, serum bilirubin level was associated with decreased risk of stroke in an ordinary least-squares analysis. However, in 2-stage least-squares Mendelian randomization analysis, no causal relationship between serum bilirubin and stroke risk was found. There is no evidence that bilirubin level is causally associated with risk of stroke in Koreans. Therefore, bilirubin level is not a risk determinant of stroke. © 2017 American Heart Association, Inc.

  3. Genetic risk scores link body fat distribution with specific cardiometabolic profiles

    DEFF Research Database (Denmark)

    Svendstrup, Mathilde; Sandholt, Camilla H; Andersson Galijatovic, Ehm Astrid

    2016-01-01

    , including fasting serum triglyceride (β = 0.98% mmol/L, P = 3.33 × 10(-) (8) ) and Matsuda index (β = -0.74%, P = 1.29 × 10(-) (4) ). No similar associations for Clusters 2 and 3 were found. The three clusters showed different patterns of association with waist circumference, hip circumference, and height......OBJECTIVE: Forty-nine known single nucleotide polymorphisms (SNPs) associating with body mass index (BMI)-adjusted waist-hip-ratio (WHR) (WHRadjBMI) were recently suggested to cluster into three groups with different associations to cardiometabolic traits. Genetic risk scores of the clusters...... risk scores and anthropometry and blood samples at fasting and during an oral glucose tolerance test were tested. Analyses were adjusted for age, sex, and BMI. RESULTS: Cluster 1 associated with an increased risk of diabetes (HR = 1.05, P = 2.74 × 10(-) (4) ) and with a poor metabolic profile...

  4. Neurocognitive functioning in parents of schizophrenia patients: Attentional and executive performance vary with genetic loading.

    Science.gov (United States)

    Schulze-Rauschenbach, Svenja; Lennertz, Leonhard; Ruhrmann, Stephan; Petrovsky, Nadine; Ettinger, Ulrich; Pukrop, Ralf; Dreher, Jan; Klosterkötter, Joachim; Maier, Wolfgang; Wagner, Michael

    2015-12-30

    Neuropsychological deficits are candidate endophenotypes of schizophrenia which can assist to explain the neurocognitive impact of genetic risk variants. The identification of endophenotypes is often based on the familiality of these phenotypes. Several studies demonstrate neuropsychological deficits in unaffected biological relatives of schizophrenia patients without differentiating between genetic and non-genetic factors underlying these deficits. We assessed N=129 unaffected biological parents of schizophrenia patients, N=28 schizophrenia patients (paranoid subtype), and N=143 controls without a family history of schizophrenia with an extensive neuropsychological test battery. Direct comparison of N=22 parents with an ancestral history of schizophrenia (more likely carriers, MLC) and N=17 of their spouses without such a history (less likely carriers, LLC) allowed the separation of genetic and non-genetic aspects in cognition. Overall, parents showed significant deficits in neuropsychological tasks from all cognitive domains with medium effect sizes. Direct comparisons of MLC- and LLC-parents showed that attentional and executive tasks were most strongly affected by genetic loading. To conclude, unaffected parents of schizophrenia patients showed modest yet significant impairments in attention, memory, and executive functioning. In particular, attentional and executive impairments varied most strongly with genetic loading for schizophrenia, prioritising these dysfunctions for genotype-endophenotype analyses. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  5. Associated genetic syndromes and extracardiac malformations strongly influence outcomes of fetuses with congenital heart diseases.

    Science.gov (United States)

    Bensemlali, Myriam; Bajolle, Fanny; Ladouceur, Magalie; Fermont, Laurent; Lévy, Marilyne; Le Bidois, Jérôme; Salomon, Laurent J; Bonnet, Damien

    2016-05-01

    Congenital heart disease (CHD) is often associated with extracardiac malformations (ECMs) and genetic syndromes. To determine the effect of cytogenetic anomalies and/or ECMs associated with CHD on parental decision to choose termination of pregnancy (TOP) or compassionate care (CC), as well as on the outcome of children born alive. This 10-year retrospective study included all prenatally diagnosed cases of CHD in a single tertiary referral centre. From January 2002 to December 2011, 2036 consecutive cases of fetal CHD (798 TOPs and 1238 live births, including 59 with postnatal CC) were included. CHD was associated with a known cytogenetic anomaly in 9.8% of cases and a major ECM in 11.7% of cases. The proportion of prenatally identified associated cytogenetic anomalies was significantly lower in the live-birth group than in the TOP plus CC group (4.2% vs 17.5%; P<0.001); this was also true for ECMs (8.1% vs 16.7%; P<0.001). The mortality rate was higher in the group with an associated cytogenetic anomaly or ECM (29.1%) than in cases with isolated CHD; a 2.4-fold increase in the death rate was observed (95% confidence interval 1.34-4.38; P=0.003). These associations remained significant after multivariable analysis, including the severity of the CHD (uni- or biventricular physiology). Prenatal diagnosis of a known cytogenetic anomaly or major ECM strongly influences parental decision to choose TOP or postnatal CC. Genetic syndromes and ECMs are associated with a higher mortality rate, independent of the complexity of the CHD. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  6. Age at natural menopause genetic risk score in relation to age at natural menopause and primary open-angle glaucoma in a US-based sample.

    Science.gov (United States)

    Pasquale, Louis R; Aschard, Hugues; Kang, Jae H; Bailey, Jessica N Cooke; Lindström, Sara; Chasman, Daniel I; Christen, William G; Allingham, R Rand; Ashley-Koch, Allison; Lee, Richard K; Moroi, Sayoko E; Brilliant, Murray H; Wollstein, Gadi; Schuman, Joel S; Fingert, John; Budenz, Donald L; Realini, Tony; Gaasterland, Terry; Gaasterland, Douglas; Scott, William K; Singh, Kuldev; Sit, Arthur J; Igo, Robert P; Song, Yeunjoo E; Hark, Lisa; Ritch, Robert; Rhee, Douglas J; Gulati, Vikas; Havens, Shane; Vollrath, Douglas; Zack, Donald J; Medeiros, Felipe; Weinreb, Robert N; Pericak-Vance, Margaret A; Liu, Yutao; Kraft, Peter; Richards, Julia E; Rosner, Bernard A; Hauser, Michael A; Haines, Jonathan L; Wiggs, Janey L

    2017-02-01

    Several attributes of female reproductive history, including age at natural menopause (ANM), have been related to primary open-angle glaucoma (POAG). We assembled 18 previously reported common genetic variants that predict ANM to determine their association with ANM or POAG. Using data from the Nurses' Health Study (7,143 women), we validated the ANM weighted genetic risk score in relation to self-reported ANM. Subsequently, to assess the relation with POAG, we used data from 2,160 female POAG cases and 29,110 controls in the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (NEIGHBORHOOD), which consists of 8 datasets with imputed genotypes to 5.6+ million markers. Associations with POAG were assessed in each dataset, and site-specific results were meta-analyzed using the inverse weighted variance method. The genetic risk score was associated with self-reported ANM (P = 2.2 × 10) and predicted 4.8% of the variance in ANM. The ANM genetic risk score was not associated with POAG (Odds Ratio (OR) = 1.002; 95% Confidence Interval (CI): 0.998, 1.007; P = 0.28). No single genetic variant in the panel achieved nominal association with POAG (P ≥0.20). Compared to the middle 80 percent, there was also no association with the lowest 10 percentile or highest 90 percentile of genetic risk score with POAG (OR = 0.75; 95% CI: 0.47, 1.21; P = 0.23 and OR = 1.10; 95% CI: 0.72, 1.69; P = 0.65, respectively). A genetic risk score predicting 4.8% of ANM variation was not related to POAG; thus, genetic determinants of ANM are unlikely to explain the previously reported association between the two phenotypes.

  7. Friendship Experiences and Anxiety Among Children: A Genetically Informed Study.

    Science.gov (United States)

    Poirier, Catherine Serra; Brendgen, Mara; Girard, Alain; Vitaro, Frank; Dionne, Ginette; Boivin, Michel

    2016-01-01

    This study examined (a) whether, in line with a gene-environment correlation (rGE), a genetic disposition for anxiety puts children at risk of having anxious friends or having no reciprocal friends; (b) to what extent these friendship experiences are related to anxiety symptoms, when controlling for sex and genetic disposition for this trait; and (c) the additive and interactive predictive links of the reciprocal best friend's anxiety symptoms and of friendship quality with children's anxiety symptoms. Using a genetically informed design based on 521 monozygotic and ic twins (264 girls; 87% of European descent) assessed in Grade 4 (M age = 10.04 years, SD = .26), anxiety symptoms and perceived friendship quality were measured with self-report questionnaires. Results indicated that, in line with rGE, children with a strong genetic disposition for anxiety were more likely to have anxious friends than nonanxious friends. Moreover, controlling for their genetic risk for anxiety, children with anxious friends showed higher levels of anxiety symptoms than children with nonanxious friends but did not differ from those without reciprocal friends. Additional analyses suggested a possible contagion of anxiety symptoms between reciprocal best friends when perceived negative features of friendship were high. These results underline the importance of teaching strategies such as problem solving that enhance friendship quality to limit the potential social contagion of anxiety symptoms.

  8. "What is this genetics, anyway?" Understandings of genetics, illness causality and inheritance among British Pakistani users of genetic services.

    Science.gov (United States)

    Shaw, Alison; Hurst, Jane A

    2008-08-01

    Misconceptions about basic genetic concepts and inheritance patterns may be widespread in the general population. This paper investigates understandings of genetics, illness causality and inheritance among British Pakistanis referred to a UK genetics clinic. During participant observation of genetics clinic consultations and semi-structured interviews in Urdu or English in respondents' homes, we identified an array of environmental, behavioral and spiritual understandings of the causes of medical and intellectual problems. Misconceptions about the location of genetic information in the body and of genetic mechanisms of inheritance were common, reflected the range of everyday theories observed for White British patients and included the belief that a child receives more genetic material from the father than the mother. Despite some participants' conversational use of genetic terminology, some patients had assimilated genetic information in ways that conflict with genetic theory with potentially serious clinical consequences. Additionally, skepticism of genetic theories of illness reflected a rejection of a dominant discourse of genetic risk that stigmatizes cousin marriages. Patients referred to genetics clinics may not easily surrender their lay or personal theories about the causes of their own or their child's condition and their understandings of genetic risk. Genetic counselors may need to identify, work with and at times challenge patients' understandings of illness causality and inheritance.

  9. Genetic Susceptibility to Vitiligo: GWAS Approaches for Identifying Vitiligo Susceptibility Genes and Loci

    Science.gov (United States)

    Shen, Changbing; Gao, Jing; Sheng, Yujun; Dou, Jinfa; Zhou, Fusheng; Zheng, Xiaodong; Ko, Randy; Tang, Xianfa; Zhu, Caihong; Yin, Xianyong; Sun, Liangdan; Cui, Yong; Zhang, Xuejun

    2016-01-01

    Vitiligo is an autoimmune disease with a strong genetic component, characterized by areas of depigmented skin resulting from loss of epidermal melanocytes. Genetic factors are known to play key roles in vitiligo through discoveries in association studies and family studies. Previously, vitiligo susceptibility genes were mainly revealed through linkage analysis and candidate gene studies. Recently, our understanding of the genetic basis of vitiligo has been rapidly advancing through genome-wide association study (GWAS). More than 40 robust susceptible loci have been identified and confirmed to be associated with vitiligo by using GWAS. Most of these associated genes participate in important pathways involved in the pathogenesis of vitiligo. Many susceptible loci with unknown functions in the pathogenesis of vitiligo have also been identified, indicating that additional molecular mechanisms may contribute to the risk of developing vitiligo. In this review, we summarize the key loci that are of genome-wide significance, which have been shown to influence vitiligo risk. These genetic loci may help build the foundation for genetic diagnosis and personalize treatment for patients with vitiligo in the future. However, substantial additional studies, including gene-targeted and functional studies, are required to confirm the causality of the genetic variants and their biological relevance in the development of vitiligo. PMID:26870082

  10. Rhinovirus Wheezing Illness and Genetic Risk of Childhood-Onset Asthma

    DEFF Research Database (Denmark)

    Calışkan, Minal; Bochkov, Yury A; Kreiner-Møller, Eskil

    2013-01-01

    Background Both genetic variation at the 17q21 locus and virus-induced respiratory wheezing illnesses are associated with the development of asthma. Our aim was to determine the effects of these two factors on the risk of asthma in the Childhood Origins of Asthma (COAST) and the Copenhagen...... Prospective Study on Asthma in Childhood (COPSAC) birth cohorts. Methods We tested genotypes at the 17q21 locus for associations with asthma and with human rhinovirus (HRV) and respiratory syncytial virus (RSV) wheezing illnesses and tested for interactions between 17q21 genotypes and HRV and RSV wheezing...... illnesses with respect to the risk of asthma. Finally, we examined genotype-specific expression of 17q21 genes in unstimulated and HRV-stimulated peripheral-blood mononuclear cells (PBMCs). Results The 17q21 variants were associated with HRV wheezing illnesses in early life, but not with RSV wheezing...

  11. Genetic risk prediction and neurobiological understanding of alcoholism

    Science.gov (United States)

    Levey, D F; Le-Niculescu, H; Frank, J; Ayalew, M; Jain, N; Kirlin, B; Learman, R; Winiger, E; Rodd, Z; Shekhar, A; Schork, N; Kiefe, F; Wodarz, N; Müller-Myhsok, B; Dahmen, N; Nöthen, M; Sherva, R; Farrer, L; Smith, A H; Kranzler, H R; Rietschel, M; Gelernter, J; Niculescu, A B

    2014-01-01

    We have used a translational Convergent Functional Genomics (CFG) approach to discover genes involved in alcoholism, by gene-level integration of genome-wide association study (GWAS) data from a German alcohol dependence cohort with other genetic and gene expression data, from human and animal model studies, similar to our previous work in bipolar disorder and schizophrenia. A panel of all the nominally significant P-value SNPs in the top candidate genes discovered by CFG  (n=135 genes, 713 SNPs) was used to generate a genetic  risk prediction score (GRPS), which showed a trend towards significance (P=0.053) in separating  alcohol dependent individuals from controls in an independent German test cohort. We then validated and prioritized our top findings from this discovery work, and subsequently tested them in three independent cohorts, from two continents. In order to validate and prioritize the key genes that drive behavior without some of the pleiotropic environmental confounds present in humans, we used a stress-reactive animal model of alcoholism developed by our group, the D-box binding protein (DBP) knockout mouse, consistent with the surfeit of stress theory of addiction proposed by Koob and colleagues. A much smaller panel (n=11 genes, 66 SNPs) of the top CFG-discovered genes for alcoholism, cross-validated and prioritized by this stress-reactive animal model showed better predictive ability in the independent German test cohort (P=0.041). The top CFG scoring gene for alcoholism from the initial discovery step, synuclein alpha (SNCA) remained the top gene after the stress-reactive animal model cross-validation. We also tested this small panel of genes in two other independent test cohorts from the United States, one with alcohol dependence (P=0.00012) and one with alcohol abuse (a less severe form of alcoholism; P=0.0094). SNCA by itself was able to separate alcoholics from controls in the alcohol-dependent cohort (P=0.000013) and the alcohol abuse

  12. Experience of parental cancer in childhood is a risk factor for psychological distress during genetic cancer susceptibility testing

    NARCIS (Netherlands)

    van Oostrom, I.; Meijers-Heijboer, H.; Duivenvoorden, H. J.; Brocker-Vriends, A. H. J. T.; van Asperen, C. J.; Sijmons, R. H.; Seynaeve, C.; Van Gool, A. R.; Klijn, J. G. M.; Tibben, A.

    Background: This study explores the effect of age at the time of parental cancer diagnosis or death on psychological distress and cancer risk perception in individuals undergoing genetic testing for a specific cancer susceptibility. Patients and methods: Cancer-related distress, worry and risk

  13. The effect of genetic test-based risk information on behavioral outcomes: A critical examination of failed trials and a call to action.

    Science.gov (United States)

    Austin, Jehannine

    2015-12-01

    Encouraging individuals at risk for common complex disease like heart disease, cancer, and diabetes to adopt lifestyle changes (e.g., smoking cessation, exercise, proper nutrition, increased screening) could be powerful public health tools to decrease the enormous personal and economic burden of these conditions. Theoretically, genetic risk information appears to be a compelling tool that could be used to provoke at-risk individuals to adopt these lifestyle changes. Unfortunately, however, numerous studies now have shown that providing individuals with genetic test-based risk information has little to no impact on their behavior. In this article (a commentary not a systematic review), the failed trials in which genetic information has been used as a tool to induce behavior change will be critically examined in order to identify new and potentially more effective ways forward. © 2015 Wiley Periodicals, Inc.

  14. F8 haplotype and inhibitor risk: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort

    Science.gov (United States)

    Schwarz, John; Astermark, Jan; Menius, Erika D.; Carrington, Mary; Donfield, Sharyne M.; Gomperts, Edward D.; Nelson, George W.; Oldenburg, Johannes; Pavlova, Anna; Shapiro, Amy D.; Winkler, Cheryl A.; Berntorp, Erik

    2012-01-01

    Background Ancestral background, specifically African descent, confers higher risk for development of inhibitory antibodies to factor VIII (FVIII) in hemophilia A. It has been suggested that differences in the distribution of factor VIII gene (F8) haplotypes, and mismatch between endogenous F8 haplotypes and those comprising products used for treatment could contribute to risk. Design and Methods Data from the HIGS Combined Cohort were used to determine the association between F8 haplotype 3 (H3) vs. haplotypes 1 and 2 (H1+H2) and inhibitor risk among individuals of genetically-determined African descent. Other variables known to affect inhibitor risk including type of F8 mutation and HLA were included in the analysis. A second research question regarding risk related to mismatch in endogenous F8 haplotype and recombinant FVIII products used for treatment was addressed. Results H3 was associated with higher inhibitor risk among those genetically-identified (N=49) as of African ancestry, but the association did not remain significant after adjustment for F8 mutation type and the HLA variables. Among subjects of all racial ancestries enrolled in HIGS who reported early use of recombinant products (N=223), mismatch in endogenous haplotype and the FVIII proteins constituting the products used did not confer greater risk for inhibitor development. Conclusion H3 was not an independent predictor of inhibitor risk. Further, our findings did not support a higher risk of inhibitors in the presence of a haplotype mismatch between the FVIII molecule infused and that of the individual. PMID:22958194

  15. Filaggrin loss-of-function mutations, atopic dermatitis and risk of actinic keratosis

    DEFF Research Database (Denmark)

    Andersen, Y M F; Egeberg, A; Balslev, E

    2017-01-01

    BACKGROUND: Common loss-of-function mutations in filaggrin gene (FLG) represent a strong genetic risk factor for atopic dermatitis (AD). Homozygous mutation carriers typically display ichthyosis vulgaris (IV) and many have concomitant AD. Previously, homozygous, but not heterozygous, filaggrin ge...

  16. Familial clustering and genetic risk for dementia in a genetically isolated Dutch population.

    NARCIS (Netherlands)

    K. Sleegers (Kristel); F. Forey; J. Theuns (Jessie); Y.S. Aulchenko (Yurii); S. Rademakers (Suzanne); M. Cruts (Marc); W.A. van Gool (Willem); P. Heutink (Peter); B.A. Oostra (Ben); J.C. van Swieten (John); C.M. van Duijn (Cornelia); C. van Broeckhoven (Christine)

    2004-01-01

    textabstractDespite advances in elucidating the genetic epidemiology of Alzheimer's disease and frontotemporal dementia, the aetiology for most patients with dementia remains unclear. We examined the genetic epidemiology of dementia in a recent genetically isolated Dutch population founded around

  17. Validation of reported genetic risk factors for periodontitis in a large-scale replication study

    NARCIS (Netherlands)

    Schaefer, A.S.; Bochenek, G.; Manke, T.; Nothnagel, M.; Graetz, C.; Thien, A.; Jockel-Schneider, Y.; Harks, I.; Staufenbiel, I.; Wijmenga, C.; Eberhard, J.; Guzeldemir-Akcakanat, E.; Cine, N.; Folwaczny, M.; Noack, B.; Meyle, J.; Eickholz, P.; Trombelli, L.; Scapoli, C.; Nohutcu, R.; Bruckmann, C.; Doerfer, C.; Jepsen, S.; Loos, B.G.; Schreiber, S.

    2013-01-01

    Aim Many studies investigated the role of genetic variants in periodontitis, but few were established as risk factors. We aimed to validate the associations of recent candidate genes in aggressive periodontitis (AgP). Material and Methods We analysed 23 genes in 600 German AgP patients and 1441

  18. Validation of reported genetic risk factors for periodontitis in a large-scale replication study

    NARCIS (Netherlands)

    Schaefer, Arne S.; Bochenek, Gregor; Manke, Thomas; Nothnagel, Michael; Graetz, Christian; Thien, Anneke; Jockel-Schneider, Yvonne; Harks, Inga; Staufenbiel, Ingmar; Wijmenga, Cisca; Eberhard, Joerg; Guzeldemir-Akcakanat, Esra; Cine, Naci; Folwaczny, Mathias; Noack, Barbara; Meyle, Joerg; Eickholz, Peter; Trombelli, Leonardo; Scapoli, Chiara; Nohutcu, Rahime; Bruckmann, Corinna; Doerfer, Christof; Jepsen, Soren; Loos, Bruno G.; Schreiber, Stefan

    Aim Many studies investigated the role of genetic variants in periodontitis, but few were established as risk factors. We aimed to validate the associations of recent candidate genes in aggressive periodontitis (AgP). Material and Methods We analysed 23 genes in 600 German AgP patients and 1441

  19. Genetics of breast cancer: Applications to the Mexican population

    Directory of Open Access Journals (Sweden)

    Elad Ziv

    2011-10-01

    Full Text Available Breast cancer research has yielded several important results including the strong susceptibility genes,BRCA1 and BRCA2 and more recently 19 genes and genetic loci that confer a more moderate risk.The pace of discovery is accelerating as genetic technology and computational methods improve. These discoveries will change the way that breast cancer risk is understood in Mexico over the next few decades.La investigación en cáncer de mama ha dado varios resultados importantes incluyendo los genes fuertemente susceptibles, BRCA1 y BRCA2, y más recientemente 19 genes y loci genéticos que confieren un riesgo moderado. El ritmo de los descubrimientos se acelera conforme mejora la tecnología y métodos computacionales.Estosdescubrimientoscambiarán la forma en que la investigación del cáncer es comprendida en México en las próximas décadas.

  20. Familial clustering and genetic risk for dementia in a genetically isolated Dutch population

    NARCIS (Netherlands)

    Sleegers, K.; Roks, G.; Theuns, J.; Aulchenko, Y. S.; Rademakers, R.; Cruts, M.; van Gool, W. A.; van Broeckhoven, C.; Heutink, P.; Oostra, B. A.; van Swieten, J. C.; van Duijn, C. M.

    2004-01-01

    Despite advances in elucidating the genetic epidemiology of Alzheimer's disease and frontotemporal dementia, the aetiology for most patients with dementia remains unclear. We examined the genetic epidemiology of dementia in a recent genetically isolated Dutch population founded around 1750. The

  1. "Soldier's Heart": A Genetic Basis for Elevated Cardiovascular Disease Risk Associated with Post-traumatic Stress Disorder.

    Science.gov (United States)

    Pollard, Harvey B; Shivakumar, Chittari; Starr, Joshua; Eidelman, Ofer; Jacobowitz, David M; Dalgard, Clifton L; Srivastava, Meera; Wilkerson, Matthew D; Stein, Murray B; Ursano, Robert J

    2016-01-01

    "Soldier's Heart," is an American Civil War term linking post-traumatic stress disorder (PTSD) with increased propensity for cardiovascular disease (CVD). We have hypothesized that there might be a quantifiable genetic basis for this linkage. To test this hypothesis we identified a comprehensive set of candidate risk genes for PTSD, and tested whether any were also independent risk genes for CVD. A functional analysis algorithm was used to identify associated signaling networks. We identified 106 PTSD studies that report one or more polymorphic variants in 87 candidate genes in 83,463 subjects and controls. The top upstream drivers for these PTSD risk genes are predicted to be the glucocorticoid receptor (NR3C1) and Tumor Necrosis Factor alpha (TNFA). We find that 37 of the PTSD candidate risk genes are also candidate independent risk genes for CVD. The association between PTSD and CVD is significant by Fisher's Exact Test ( P = 3 × 10 -54 ). We also find 15 PTSD risk genes that are independently associated with Type 2 Diabetes Mellitus (T2DM; also significant by Fisher's Exact Test ( P = 1.8 × 10 -16 ). Our findings offer quantitative evidence for a genetic link between post-traumatic stress and cardiovascular disease, Computationally, the common mechanism for this linkage between PTSD and CVD is innate immunity and NFκB-mediated inflammation.

  2. Polycystic ovary syndrome is not associated with genetic variants that mark risk of type 2 diabetes.

    Science.gov (United States)

    Saxena, R; Welt, C K

    2013-06-01

    Polycystic ovary syndrome (PCOS) is a disorder of irregular menses, hyperandrogenism and/or polycystic ovary morphology. A large proportion of women with PCOS also exhibit insulin resistance, β-cell dysfunction, impaired glucose tolerance and/or type 2 diabetes (T2D). We therefore hypothesized that genetic variants that predispose to risk of T2D also result in risk of PCOS. Variants robustly associated with T2D in candidate gene or genome-wide association studies (GWAS; n = 56 SNPs from 33 loci) were genotyped in women of European ancestry with PCOS (n = 525) and controls (n = 472), aged 18-45 years. Metabolic, reproductive and anthropomorphic data were examined as a function of the T2D variants. All genetic association analyses were adjusted for age, BMI and ancestry and were reported after correction for multiple testing. There was a nominal association between variants in KCNJ11 and risk of PCOS. However, a risk score of 33 independent T2D-associated variants from GWAS was not significantly associated with PCOS. T2D variants were associated with PCOS phenotype parameters including those in THADA and WFS1 with testosterone levels, ENPP/PC1 with triglyceride levels, FTO with glucose levels and KCNJ11 with FSH levels. Diabetes risk variants are not important risk variants for PCOS.

  3. DEVELOPMENT OF AQUATIC MODELS FOR TESTING THE RELATIONSHIP BETWEEN GENETIC DIVERSITY AND POPULATION EXTINCTION RISK

    Science.gov (United States)

    The relationship between population adaptive potential and extinction risk in a changing environment is not well understood. Although the expectation is that genetic diversity is directly related to the capacity of populations to adapt, the statistical and predictive aspects of ...

  4. Genetic risk variants in the CDKN2A/B, RTEL1 and EGFR genes are associated with somatic biomarkers in glioma.

    Science.gov (United States)

    Ghasimi, Soma; Wibom, Carl; Dahlin, Anna M; Brännström, Thomas; Golovleva, Irina; Andersson, Ulrika; Melin, Beatrice

    2016-05-01

    During the last years, genome wide association studies have discovered common germline genetic variants associated with specific glioma subtypes. We aimed to study the association between these germline risk variants and tumor phenotypes, including copy number aberrations and protein expression. A total of 91 glioma patients were included. Thirteen well known genetic risk variants in TERT, EGFR, CCDC26, CDKN2A, CDKN2B, PHLDB1, TP53, and RTEL1 were selected for investigation of possible correlations with the glioma somatic markers: EGFR amplification, 1p/19q codeletion and protein expression of p53, Ki-67, and mutated IDH1. The CDKN2A/B risk variant, rs4977756, and the CDKN2B risk variant, rs1412829 were inversely associated (p = 0.049 and p = 0.002, respectively) with absence of a mutated IDH1, i.e., the majority of patients homozygous for the risk allele showed no or low expression of mutated IDH1. The RTEL1 risk variant, rs6010620 was associated (p = 0.013) with not having 1p/19q codeletion, i.e., the majority of patients homozygous for the risk allele did not show 1p/19q codeletion. In addition, the EGFR risk variant rs17172430 and the CDKN2B risk variant rs1412829, both showed a trend for association (p = 0.055 and p = 0.051, respectively) with increased EGFR copy number, i.e., the majority of patients homozygote for the risk alleles showed chromosomal gain or amplification of EGFR. Our findings indicate that CDKN2A/B risk genotypes are associated with primary glioblastoma without IDH mutation, and that there is an inverse association between RTEL1 risk genotypes and 1p/19q codeletion, suggesting that these genetic variants have a molecular impact on the genesis of high graded brain tumors. Further experimental studies are needed to delineate the functional mechanism of the association between genotype and somatic genetic aberrations.

  5. The structure of genetic and environmental risk factors for phobias in women.

    Science.gov (United States)

    Czajkowski, N; Kendler, K S; Tambs, K; Røysamb, E; Reichborn-Kjennerud, T

    2011-09-01

    To explore the genetic and environmental factors underlying the co-occurrence of lifetime diagnoses of DSM-IV phobia. Female twins (n=1430) from the population-based Norwegian Institute of Public Health Twin Panel were assessed at personal interview for DSM-IV lifetime specific phobia, social phobia and agoraphobia. Comorbidity between the phobias were assessed by odds ratios (ORs) and polychoric correlations and multivariate twin models were fitted in Mx. Phenotypic correlations of lifetime phobia diagnoses ranged from 0.55 (agoraphobia and social phobia, OR 10.95) to 0.06 (animal phobia and social phobia, OR 1.21). In the best fitting twin model, which did not include shared environmental factors, heritability estimates for the phobias ranged from 0.43 to 0.63. Comorbidity between the phobias was accounted for by two common liability factors. The first loaded principally on animal phobia and did not influence the complex phobias (agoraphobia and social phobia). The second liability factor strongly influenced the complex phobias, but also loaded weak to moderate on all the other phobias. Blood phobia was mainly influenced by a specific genetic factor, which accounted for 51% of the total and 81% of the genetic variance. Phobias are highly co-morbid and heritable. Our results suggest that the co-morbidity between phobias is best explained by two distinct liability factors rather than a single factor, as has been assumed in most previous multivariate twin analyses. One of these factors was specific to the simple phobias, while the other was more general. Blood phobia was mainly influenced by disorder specific genetic factors.

  6. A genetic risk score is associated with polycystic ovary syndrome-related traits.

    Science.gov (United States)

    Lee, Hyejin; Oh, Jee-Young; Sung, Yeon-Ah; Chung, Hye Won

    2016-01-01

    Is a genetic risk score (GRS) associated with polycystic ovary syndrome (PCOS) and its related clinical features? The GRS calculated by genome-wide association studies (GWASs) was significantly associated with PCOS status and its related clinical features. PCOS is a heterogeneous disorder and is characterized by oligomenorrhea, hyperandrogenism and polycystic ovary morphology. Although recent GWASs have identified multiple genes associated with PCOS, a comprehensive genetic risk study of these loci with PCOS and related traits (e.g. free testosterone, menstruation number/year and ovarian morphology) has not been performed. This study was designed as a cross-sectional case-control study. We recruited 862 women with PCOS and 860 controls. Women with PCOS were divided into four subgroups: (1) oligomenorrhea + hyperandrogenism + polycystic ovary, (2) oligomenorrhea + hyperandrogenism, (3) oligomenorrhea + polycystic ovary and (4) hyperandrogenism + polycystic ovary. Genomic DNA was genotyped for the PCOS susceptibility loci using the HumanOmni1-Quad v1 array. Venous blood was drawn in the early follicular phase to measure baseline metabolic and hormonal parameters. A GRS was calculated by summing the number of risk alleles from 11 single-nucleotide polymorphisms (SNPs) that were identified in previous GWASs on PCOS. A weighted GRS (wGRS) was calculated by multiplying the number of risk alleles for each SNP by its estimated effect (beta) obtained from the association analysis. The GRS was higher in women with PCOS than in controls (8.8 versus 8.2, P treatment approaches, which could potentially improve health outcomes. None of the authors have any conflicts of interest to declare. No funding was obtained for the study. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  7. Shared Genetic Aetiology between Cognitive Ability and Cardiovascular Disease Risk Factors: Generation Scotland's Scottish Family Health Study

    Science.gov (United States)

    Luciano, Michelle; Batty, G. David; McGilchrist, Mark; Linksted, Pamela; Fitzpatrick, Bridie; Jackson, Cathy; Pattie, Alison; Dominiczak, Anna F.; Morris, Andrew D.; Smith, Blair H.; Porteous, David; Deary, Ian J.

    2010-01-01

    People with higher general cognitive ability in early life have more favourable levels of cardiovascular disease (CVD) risk factors in adulthood and CVD itself. The mechanism of these associations is not known. Here we examine whether general cognitive ability and CVD risk factors share genetic and/or environmental aetiology. In this large,…

  8. Genetics 'risk carriers' and life style 'risk-takers' : which risks deserve our legal protection in insurance?

    NARCIS (Netherlands)

    Hoyweghen, van I.; Horstman, K.; Schepers, R.

    2007-01-01

    Over the past years, one of the most contentious topics in policy debates on genetics has been the use of genetic testing in insurance. In the rush to confront concerns about potential abuses of genetic information, most countries throughout Europe and the US have enacted genetics-specific

  9. Experience of parental cancer in childhood is a risk factor for psychological distress during genetic cancer susceptibility testing

    NARCIS (Netherlands)

    van Oostrom, I.; Meijers-Heijboer, H.; Duivenvoorden, H. J.; Bröcker-Vriends, A. H. J. T.; van Asperen, C. J.; Sijmons, R. H.; Seynaeve, C.; van Gool, A. R.; Klijn, J. G. M.; Tibben, A.

    2006-01-01

    This study explores the effect of age at the time of parental cancer diagnosis or death on psychological distress and cancer risk perception in individuals undergoing genetic testing for a specific cancer susceptibility. Cancer-related distress, worry and risk perception were assessed in 271

  10. Reassessing insurers' access to genetic information: genetic privacy, ignorance, and injustice.

    Science.gov (United States)

    Feiring, Eli

    2009-06-01

    Many countries have imposed strict regulations on the genetic information to which insurers have access. Commentators have warned against the emerging body of legislation for different reasons. This paper demonstrates that, when confronted with the argument that genetic information should be available to insurers for health insurance underwriting purposes, one should avoid appeals to rights of genetic privacy and genetic ignorance. The principle of equality of opportunity may nevertheless warrant restrictions. A choice-based account of this principle implies that it is unfair to hold people responsible for the consequences of the genetic lottery, since we have no choice in selecting our genotype or the expression of it. However appealing, this view does not take us all the way to an adequate justification of inaccessibility of genetic information. A contractarian account, suggesting that health is a condition of opportunity and that healthcare is an essential good, seems more promising. I conclude that if or when predictive medical tests (such as genetic tests) are developed with significant actuarial value, individuals have less reason to accept as fair institutions that limit access to healthcare on the grounds of risk status. Given the assumption that a division of risk pools in accordance with a rough estimate of people's level of (genetic) risk will occur, fairness and justice favour universal health insurance based on solidarity.

  11. Diet, Cardiometabolic Factors and Type-2 Diabetes Mellitus: The Role of Genetics.

    Science.gov (United States)

    Marcadenti, Aline

    2016-01-01

    Type 2 diabetes mellitus (T2DM) is a highly prevalent condition and is associated with a number of metabolic risk factors such as excess of weight, impaired lipid profile and higher levels of blood pressure. As other complex diseases, it is strongly related to an environmental component such as sedentarism and unhealthy diet, and also to a genetic component. A cluster of variants (polymorphisms) in a large number of genes seem to interact with nutrients/dietary factors in modulating cardiometabolic parameters in healthy individuals. The role of total calories intake and also different kind of carbohydrates and dietary fats in worsening the excess of weight and/or metabolic profile in patients with diabetes is well known, but the extent to which genetic factors can modify these associations is not yet fully understood. Therefore, the aim of this mini-review is to discuss the interaction of genetics and diet in the T2DM setting, since both are strongly involved in the genesis and development of the disease.

  12. Genetic variation in the lymphotoxin-α (LTA)/tumour necrosis factor-α (TNFα) locus as a risk factor for idiopathic achalasia

    NARCIS (Netherlands)

    Wouters, Mira M.; Lambrechts, Diether; Becker, Jessica; Cleynen, Isabelle; Tack, Jan; Vigo, Ana G.; Ruiz de León, Antonio; Urcelay, Elena; Pérez de la Serna, Julio; Rohof, Wout; Annese, Vito; Latiano, Anna; Palmieri, Orazio; Mattheisen, Manuel; Mueller, Michaela; Lang, Hauke; Fumagalli, Uberto; Laghi, Luigi; Zaninotto, Giovanni; Cuomo, Rosario; Sarnelli, Giovanni; Nöthen, Markus M.; Vermeire, Séverine; Knapp, Michael; Gockel, Ines; Schumacher, Johannes; Boeckxstaens, Guy E.

    2014-01-01

    Idiopathic achalasia is a rare motor disorder of the oesophagus characterised by neuronal loss at the lower oesophageal sphincter. Achalasia is generally accepted as a multifactorial disorder with various genetic and environmental factors being risk-associated. Since genetic factors predisposing to

  13. Population-based familial aggregation of eosinophilic esophagitis suggests a genetic contribution.

    Science.gov (United States)

    Allen-Brady, Kristina; Firszt, Rafael; Fang, John C; Wong, Jathine; Smith, Ken R; Peterson, Kathryn A

    2017-10-01

    Prior familial clustering studies have observed an increased risk of eosinophilic esophagitis (EoE) mostly among first-degree relatives, suggesting a genetic contribution to EoE, and twin studies have suggested a powerful contribution from environmental factors. This study sought to clarify the contribution of genetic factors to EoE through estimation of familial aggregation and risk of EoE in extended relatives. The Utah Population Database, a population-based genealogy resource linked to electronic medical records for health care systems across the state of Utah, was used to identify EoE cases and age, sex, and birthplace-matched controls at a 5:1 ratio. Logistic regression was used to determine the odds of EoE among relatives of EoE probands compared with the odds of EoE among relatives of controls. There were 4,423 EoE cases and 24,322 controls. The population-attributable risk of EoE was 31% (95% CI, 28% to 34%), suggesting a relatively strong genetic contribution. Risks of EoE were significantly increased among first-degree relatives (odds ratio [OR], 7.19; 95% CI, 5.65-9.14), particularly first-degree relatives of EoE cases diagnosed <18 years of age (OR, 16.3; 95% CI, 9.4-28.3); second-degree relatives (OR, 1.99; 95% CI, 1.49-2.65); and first cousins (OR, 1.35; 95% CI, 1.03-1.77), providing evidence of a genetic contribution. However, spouses of EoE probands were observed to be at increased risk of EoE (OR, 2.86; 95% CI, 1.31-6.25), suggesting either positive assortative mating or a shared environmental contribution to EoE. This study supports a significant genetic contribution to EoE as evidenced by increased risk of EoE in distant relatives. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  14. Genetic variations in key inflammatory cytokines exacerbates the risk of diabetic nephropathy by influencing the gene expression.

    Science.gov (United States)

    Hameed, Iqra; Masoodi, Shariq R; Malik, Perveez A; Mir, Shahnaz A; Ghazanfar, Khalid; Ganai, Bashir A

    2018-06-30

    Diabetic nephropathy is the single strongest predictor of mortality in patients with diabetes. The development of overt nephropathy involves important inter-individual variations, even after adjusting for potential confounding influences of modifiable and non-modifiable risk factors. Genome-wide transcriptome studies have reported the activation of inflammatory signaling pathways and there is mounting indication of the role of genetic factors. We screened nine genetic variations in three cytokine genes (TNF-α, IL-6 and IL-β) in 1326 unrelated subjects comprising of healthy controls (n = 464), type 2 diabetics with nephropathy (DN, n = 448) and type 2 diabetes without nephropathy (T2D, n = 414) by sequence-specific amplification. Functional implication of SNPs was elucidated by correlation studies and relative gene expression using Realtime-Quantitative PCR (RT-qPCR). Individual SNP analysis showed highest association of IL-1β rs16944-TT genotype (OR = 3.51, 95%CI = 2.36-5.21, P = 0.001) and TNF-α rs1800629-AA genotype (OR = 2.75, 95% CI = 1.64-4.59, P = 0.001) with T2D and DN respectively. The haplotype frequency showed significant risk of seven combinations among T2D and four combinations among DN subjects. The highest risk of T2D and DN was associated with GGTGAGTTT (OR = 4.25, 95%CI = 3.3-14.20, P = 0.0016) and GACGACCTT (OR = 21.3, 95%CI = 15.1-28.33, P = 0.026) haplotypes respectively. Relative expression by RT-qPCR showed increased cytokine expression in cases as compared to controls. TNF-α expression was increased by more than four-folds (n-fold = 4.43 ± 1.11) in DN. TNF-α, IL-6 and IL-1β transcript levels were significantly modulated by promoter region SNPs. The present study implicates a strong association between cytokine TNF-α, IL-6 and IL-1β gene promoter polymorphisms and modulation of transcript levels with susceptibility to nephropathy in diabetes subjects. Copyright

  15. Myelin basic protein as a novel genetic risk factor in rheumatoid arthritis--a genome-wide study combined with immunological analyses.

    Directory of Open Access Journals (Sweden)

    Chikashi Terao

    Full Text Available Rheumatoid arthritis (RA is a major cause of adult chronic inflammatory arthritis and a typical complex trait. Although several genetic determinants have been identified, they account for only a part of the genetic susceptibility. We conducted a genome-wide association study of RA in Japanese using 225,079 SNPs genotyped in 990 cases and 1,236 controls from two independent collections (658 cases and 934 controls in collection1; 332 cases and 302 controls in collection2, followed by replication studies in two additional collections (874 cases and 855 controls in collection3; 1,264 cases and 948 controls in collection4. SNPs showing p<0.005 in the first two collections and p<10(-4 by meta-analysis were further genotyped in the latter two collections. A novel risk variant, rs2000811, in intron2 of the myelin basic protein (MBP at chromosome 18q23 showed strong association with RA (p = 2.7×10(-8, OR 1.23, 95% CI: 1.14-1.32. The transcription of MBP was significantly elevated with the risk allele compared to the alternative allele (p<0.001. We also established by immunohistochemistry that MBP was expressed in the synovial lining layer of RA patients, the main target of inflammation in the disease. Circulating autoantibody against MBP derived from human brain was quantified by ELISA between patients with RA, other connective tissue diseases and healthy controls. As a result, the titer of anti-MBP antibody was markedly higher in plasma of RA patients compared to healthy controls (p<0.001 and patients with other connective tissue disorders (p<0.001. ELISA experiment using citrullinated recombinant MBP revealed that a large fraction of anti-MBP antibody in RA patients recognized citrullinated MBP. This is the first report of a genetic study in RA implicating MBP as a potential autoantigen and its involvement in pathogenesis of the disease.

  16. Beyond dual systems: A genetically-informed, latent factor model of behavioral and self-report measures related to adolescent risk-taking

    Directory of Open Access Journals (Sweden)

    K. Paige Harden

    2017-06-01

    Full Text Available The dual systems model posits that adolescent risk-taking results from an imbalance between a cognitive control system and an incentive processing system. Researchers interested in understanding the development of adolescent risk-taking use a diverse array of behavioral and self-report measures to index cognitive control and incentive processing. It is currently unclear whether different measures commonly interpreted as indicators of the same psychological construct do, in fact, tap the same underlying dimension of individual differences. In a diverse sample of 810 adolescent twins and triplets (M age = 15.9 years, SD = 1.4 years from the Texas Twin Project, we investigated the factor structure of fifteen self-report and task-based measures relevant to adolescent risk-taking. These measures can be organized into four factors, which we labeled premeditation, fearlessness, cognitive dyscontrol, and reward seeking. Most behavioral measures contained large amounts of task-specific variance; however, most genetic variance in each measure was shared with other measures of the corresponding factor. Behavior genetic analyses further indicated that genetic influences on cognitive dyscontrol overlapped nearly perfectly with genetic influences on IQ (rA = −0.91. These findings underscore the limitations of using single laboratory tasks in isolation, and indicate that the study of adolescent risk taking will benefit from applying multimethod approaches.

  17. Genetically elevated non-fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction

    DEFF Research Database (Denmark)

    Jørgensen, Anders Berg; Frikke-Schmidt, Ruth; West, Anders Sode

    2012-01-01

    AimsElevated non-fasting triglycerides mark elevated levels of remnant cholesterol. Using a Mendelian randomization approach, we tested whether genetically increased remnant cholesterol in hypertriglyceridaemia due to genetic variation in the apolipoprotein A5 gene (APOA5) associates with an incr......AimsElevated non-fasting triglycerides mark elevated levels of remnant cholesterol. Using a Mendelian randomization approach, we tested whether genetically increased remnant cholesterol in hypertriglyceridaemia due to genetic variation in the apolipoprotein A5 gene (APOA5) associates...... with an increased risk of myocardial infarction (MI).Methods and resultsWe resequenced the core promoter and coding regions of APOA5 in individuals with the lowest 1% (n = 95) and highest 2% (n = 190) triglyceride levels in the Copenhagen City Heart Study (CCHS, n = 10 391). Genetic variants which differed...... in frequency between the two extreme triglyceride groups (c.-1131T > C, S19W, and c.*31C > T; P-value: 0.06 to...

  18. Genetic association of the KLK4 locus with risk of prostate cancer.

    Directory of Open Access Journals (Sweden)

    Felicity Lose

    Full Text Available The Kallikrein-related peptidase, KLK4, has been shown to be significantly overexpressed in prostate tumours in numerous studies and is suggested to be a potential biomarker for prostate cancer. KLK4 may also play a role in prostate cancer progression through its involvement in epithelial-mesenchymal transition, a more aggressive phenotype, and metastases to bone. It is well known that genetic variation has the potential to affect gene expression and/or various protein characteristics and hence we sought to investigate the possible role of single nucleotide polymorphisms (SNPs in the KLK4 gene in prostate cancer. Assessment of 61 SNPs in the KLK4 locus (± 10 kb in approximately 1300 prostate cancer cases and 1300 male controls for associations with prostate cancer risk and/or prostate tumour aggressiveness (Gleason score <7 versus ≥ 7 revealed 7 SNPs to be associated with a decreased risk of prostate cancer at the P(trend<0.05 significance level. Three of these SNPs, rs268923, rs56112930 and the HapMap tagSNP rs7248321, are located several kb upstream of KLK4; rs1654551 encodes a non-synonymous serine to alanine substitution at position 22 of the long isoform of the KLK4 protein, and the remaining 3 risk-associated SNPs, rs1701927, rs1090649 and rs806019, are located downstream of KLK4 and are in high linkage disequilibrium with each other (r(2 ≥ 0.98. Our findings provide suggestive evidence of a role for genetic variation in the KLK4 locus in prostate cancer predisposition.

  19. Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens

    Science.gov (United States)

    Kiryluk, Krzysztof; Li, Yifu; Scolari, Francesco; Sanna-Cherchi, Simone; Choi, Murim; Verbitsky, Miguel; Fasel, David; Lata, Sneh; Prakash, Sindhuri; Shapiro, Samantha; Fischman, Clara; Snyder, Holly J.; Appel, Gerald; Izzi, Claudia; Viola, Battista Fabio; Dallera, Nadia; Vecchio, Lucia Del; Barlassina, Cristina; Salvi, Erika; Bertinetto, Francesca Eleonora; Amoroso, Antonio; Savoldi, Silvana; Rocchietti, Marcella; Amore, Alessandro; Peruzzi, Licia; Coppo, Rosanna; Salvadori, Maurizio; Ravani, Pietro; Magistroni, Riccardo; Ghiggeri, Gian Marco; Caridi, Gianluca; Bodria, Monica; Lugani, Francesca; Allegri, Landino; Delsante, Marco; Maiorana, Mariarosa; Magnano, Andrea; Frasca, Giovanni; Boer, Emanuela; Boscutti, Giuliano; Ponticelli, Claudio; Mignani, Renzo; Marcantoni, Carmelita; Di Landro, Domenico; Santoro, Domenico; Pani, Antonello; Polci, Rosaria; Feriozzi, Sandro; Chicca, Silvana; Galliani, Marco; Gigante, Maddalena; Gesualdo, Loreto; Zamboli, Pasquale; Maixnerová, Dita; Tesar, Vladimir; Eitner, Frank; Rauen, Thomas; Floege, Jürgen; Kovacs, Tibor; Nagy, Judit; Mucha, Krzysztof; Pączek, Leszek; Zaniew, Marcin; Mizerska-Wasiak, Małgorzata; Roszkowska-Blaim, Maria; Pawlaczyk, Krzysztof; Gale, Daniel; Barratt, Jonathan; Thibaudin, Lise; Berthoux, Francois; Canaud, Guillaume; Boland, Anne; Metzger, Marie; Panzer, Ulf; Suzuki, Hitoshi; Goto, Shin; Narita, Ichiei; Caliskan, Yasar; Xie, Jingyuan; Hou, Ping; Chen, Nan; Zhang, Hong; Wyatt, Robert J.; Novak, Jan; Julian, Bruce A.; Feehally, John; Stengel, Benedicte; Cusi, Daniele; Lifton, Richard P.; Gharavi, Ali G.

    2014-01-01

    We performed a genome-wide association study (GWAS) of IgA nephropathy (IgAN), the most common form of glomerulonephritis, with discovery and follow-up in 20,612 individuals of European and East Asian ancestry. We identified six novel genome-wide significant associations, four in ITGAM-ITGAX, VAV3 and CARD9 and two new independent signals at HLA-DQB1 and DEFA. We replicated the nine previously reported signals, including known SNPs in the HLA-DQB1 and DEFA loci. The cumulative burden of risk alleles is strongly associated with age at disease onset. Most loci are either directly associated with risk of inflammatory bowel disease (IBD) or maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The geo-spatial distribution of risk alleles is highly suggestive of multi-locus adaptation and the genetic risk correlates strongly with variation in local pathogens, particularly helminth diversity, suggesting a possible role for host-intestinal pathogen interactions in shaping the genetic landscape of IgAN. PMID:25305756

  20. A Strong Case for Viral Genetic Factors in HIV Virulence

    Directory of Open Access Journals (Sweden)

    Joshua T. Herbeck

    2011-03-01

    Full Text Available HIV infections show great variation in the rate of progression to disease, and the role of viral genetic factors in this variation had remained poorly characterized until recently. Now a series of four studies [1–4] published within a year has filled this important gap and has demonstrated a robust effect of the viral genotype on HIV virulence.

  1. Congenital and genetic cerebrovascular anomalies as risk factors for stroke in Saudi Arabia

    International Nuclear Information System (INIS)

    Salih, Mustafa A.; Al-Jarallah, Ahmed A.; Kentab, Amal Y.; Murshid, Waleed R.; Zahraa, Jihad N.; Abdel-Gader, Abdel-Galil M.; Alorainy, Ibrahim A.; Hassan, Hamdy H.; Tjan, G. T.

    2006-01-01

    To explore the role of and report congenital and genetic cerebrovascular anomalies as risk factors for stroke in a prospective and retrospective cohort of Saudi children. Children with stroke were evaluated at the Division of Pediatric Neurology (Dpn), or were seen as inpatients in the Pediatric Wards at King Khalid University Hospital (KKUH), Riyadh, Kingdom of Saudi Arabia during the periods July 1992 to February 2001 (retrospective study) and February 2001 to March 2003 (prospective study). Stroke work-up for each suspected case included hemostatic assays, serological, biochemical and neurophysiological tests. Neuroimaging modalities included routine skill x-rays, CT, MRI, magnetic resonance angiography (MRA) and conventional cerebral angiography. Of 104 children with stroke, congenital and genetic cerebrovascular anomalies were the underlying risk factor in 7 (6.7%). The patients were evaluated at the DPN at a mean age of 66 months (range = 8 months to 11 years, median = 6 years); and they had stroke at a mean age of 48 months (range = 2 months to 10 years, median = 8 months). Four patients had stroke in association with neurocutaneous syndromes. Two had Sturge-Weber syndrome (SWS), one had Klippel-Trenaunay syndrome associated with SWS, and the fourth had neurofibromatosis type 1. Two patients had intracranial hemorrhage secondary to ruptured aneurysm. A girl (aged 9 years and 4 months) had left posterior cerebral artery aneurysm. She was diagnosed to have autosomal dominant polycystic kidney disease following renal ultrasonography. She died 5 months later despite surgical intervention (clipping of aneurysm). The second child was an 8-months-old boy who presented with subarachnoid and intraventricular hemorrhage (IVH) following ruptured anterior communicating artery aneurysm. He recovered with no residual symptoms following successful clipping of the aneurysm. Arteriovenous malformation (AVM) caused IVH in a 7-year-old boy who reported to hospital 5 hours

  2. Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers

    Science.gov (United States)

    Peterlongo, Paolo; Chang-Claude, Jenny; Moysich, Kirsten B.; Rudolph, Anja; Schmutzler, Rita K.; Simard, Jacques; Soucy, Penny; Eeles, Rosalind A.; Easton, Douglas F.; Hamann, Ute; Wilkening, Stefan; Chen, Bowang; Rookus, Matti A.; Schmidt, Marjanka K; van der Baan, Frederieke H.; Spurdle, Amanda B.; Walker, Logan C.; Lose, Felicity; Maia, Ana-Teresa; Montagna, Marco; Matricardi, Laura; Lubinski, Jan; Jakubowska, Anna; Gómez Garcia, Encarna B.; Olopade, Olufunmilayo I.; Nussbaum, Robert L.; Nathanson, Katherine L.; Domchek, Susan M.; Rebbeck, Timothy R.; Arun, Banu K.; Karlan, Beth Y.; Orsulic, Sandra; Lester, Jenny; Chung, Wendy K.; Miron, Alex; Southey, Melissa C.; Goldgar, David E.; Buys, Saundra S.; Janavicius, Ramunas; Dorfling, Cecilia M.; van Rensburg, Elizabeth J.; Ding, Yuan Chun; Neuhausen, Susan L.; Hansen, Thomas V. O.; Gerdes, Anne-Marie; Ejlertsen, Bent; Jønson, Lars; Osorio, Ana; Martínez-Bouzas, Cristina; Benitez, Javier; Conway, Edye E.; Blazer, Kathleen R.; Weitzel, Jeffrey N.; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Scuvera, Giulietta; Barile, Monica; Ficarazzi, Filomena; Mariette, Frederique; Fortuzzi, Stefano; Viel, Alessandra; Giannini, Giuseppe; Papi, Laura; Martayan, Aline; Tibiletti, Maria Grazia; Radice, Paolo; Vratimos, Athanassios; Fostira, Florentia; Garber, Judy E.; Donaldson, Alan; Brewer, Carole; Foo, Claire; Evans, D. Gareth R.; Frost, Debra; Eccles, Diana; Brady, Angela; Cook, Jackie; Tischkowitz, Marc; Adlard, Julian; Barwell, Julian; Walker, Lisa; Izatt, Louise; Side, Lucy E.; Kennedy, M. John; Rogers, Mark T.; Porteous, Mary E.; Morrison, Patrick J.; Platte, Radka; Davidson, Rosemarie; Hodgson, Shirley V.; Ellis, Steve; Cole, Trevor; Godwin, Andrew K.; Claes, Kathleen; Van Maerken, Tom; Meindl, Alfons; Gehrig, Andrea; Sutter, Christian; Engel, Christoph; Niederacher, Dieter; Steinemann, Doris; Plendl, Hansjoerg; Kast, Karin; Rhiem, Kerstin; Ditsch, Nina; Arnold, Norbert; Varon-Mateeva, Raymonda; Wappenschmidt, Barbara; Wang-Gohrke, Shan; Bressac-de Paillerets, Brigitte; Buecher, Bruno; Delnatte, Capucine; Houdayer, Claude; Stoppa-Lyonnet, Dominique; Damiola, Francesca; Coupier, Isabelle; Barjhoux, Laure; Venat-Bouvet, Laurence; Golmard, Lisa; Boutry-Kryza, Nadia; Sinilnikova, Olga M.; Caron, Olivier; Pujol, Pascal; Mazoyer, Sylvie; Belotti, Muriel; Piedmonte, Marion; Friedlander, Michael L.; Rodriguez, Gustavo C.; Copeland, Larry J; de la Hoya, Miguel; Segura, Pedro Perez; Nevanlinna, Heli; Aittomäki, Kristiina; van Os, Theo A.M.; Meijers-Heijboer, Hanne E.J.; van der Hout, Annemarie H.; Vreeswijk, Maaike P.G.; Hoogerbrugge, Nicoline; Ausems, Margreet G.E.M.; van Doorn, Helena C.; Collée, J. Margriet; Olah, Edith; Diez, Orland; Blanco, Ignacio; Lazaro, Conxi; Brunet, Joan; Feliubadalo, Lidia; Cybulski, Cezary; Gronwald, Jacek; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Sukiennicki, Grzegorz; Arason, Adalgeir; Chiquette, Jocelyne; Teixeira, Manuel R.; Olswold, Curtis; Couch, Fergus J.; Lindor, Noralane M.; Wang, Xianshu; Szabo, Csilla I.; Offit, Kenneth; Corines, Marina; Jacobs, Lauren; Robson, Mark E.; Zhang, Liying; Joseph, Vijai; Berger, Andreas; Singer, Christian F.; Rappaport, Christine; Kaulich, Daphne Geschwantler; Pfeiler, Georg; Tea, Muy-Kheng M.; Phelan, Catherine M.; Greene, Mark H.; Mai, Phuong L.; Rennert, Gad; Mulligan, Anna Marie; Glendon, Gord; Tchatchou, Sandrine; Andrulis, Irene L.; Toland, Amanda Ewart; Bojesen, Anders; Pedersen, Inge Sokilde; Thomassen, Mads; Jensen, Uffe Birk; Laitman, Yael; Rantala, Johanna; von Wachenfeldt, Anna; Ehrencrona, Hans; Askmalm, Marie Stenmark; Borg, Åke; Kuchenbaecker, Karoline B.; McGuffog, Lesley; Barrowdale, Daniel; Healey, Sue; Lee, Andrew; Pharoah, Paul D.P.; Chenevix-Trench, Georgia; Antoniou, Antonis C.; Friedman, Eitan

    2014-01-01

    Background BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and non-genetic modifying factors. In this study we evaluated the putative role of variants in many candidate modifier genes. Methods Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n=3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results The observed p-values of association ranged between 0.005-1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies. PMID:25336561

  3. Detection of Genetically Modified Food: Has Your Food Been Genetically Modified?

    Science.gov (United States)

    Brandner, Diana L.

    2002-01-01

    Explains the benefits and risks of genetically-modified foods and describes methods for genetically modifying food. Presents a laboratory experiment using a polymerase chain reaction (PCR) test to detect foreign DNA in genetically-modified food. (Contains 18 references.) (YDS)

  4. Genetic sharing with cardiovascular disease risk factors and diabetes reveals novel bone mineral density loci

    NARCIS (Netherlands)

    S. Reppe (Sjur); Y. Wang (Yunpeng); W.K. Thompson (Wesley K.); L.K. McEvoy (Linda K.); N.J. Schork (Nicholas); V. Zuber (Verena); M. Leblanc (Marissa); F. Bettella (Francesco); I.G. Mills (Ian G.); R.S. Desikan (Rahul S.); S. Djurovic (Srdjan); K.M. Gautvik (Kaare); A.M. Dale (Anders); O.A. Andreassen (Ole); K. Estrada Gil (Karol); U. Styrkarsdottir (Unnur); E. Evangelou (Evangelos); Y.-H. Hsu (Yi-Hsiang); E.L. Duncan (Emma); E.E. Ntzani (Evangelia); L. Oei (Ling); O.M.E. Albagha (Omar M.); N. Amin (Najaf); J.P. Kemp (John); D.L. Koller (Daniel); G. Li (Guo); C.-T. Liu (Ching-Ti); R.L. Minster (Ryan); A. Moayyeri (Alireza); L. Vandenput (Liesbeth); D. Willner (Dana); S.-M. Xiao (Su-Mei); L.M. Yerges-Armstrong (Laura); H.-F. Zheng (Hou-Feng); N. Alonso (Nerea); J. Eriksson (Joel); C.M. Kammerer (Candace); S. Kaptoge (Stephen); P.J. Leo (Paul); G. Thorleifsson (Gudmar); S.G. Wilson (Scott); J.F. Wilson (James F); V. Aalto (Ville); M. Alen (Markku); A.K. Aragaki (Aaron); T. Aspelund (Thor); J.R. Center (Jacqueline); Z. Dailiana (Zoe); C. Duggan; M. Garcia (Melissa); N. Garcia-Giralt (Natàlia); S. Giroux (Sylvie); G. Hallmans (Göran); L.J. Hocking (Lynne); L.B. Husted (Lise Bjerre); K. Jameson (Karen); R. Khusainova (Rita); G.S. Kim (Ghi Su); C. Kooperberg (Charles); T. Koromila (Theodora); M. Kruk (Marcin); M. Laaksonen (Marika); A.Z. Lacroix (Andrea Z.); S.H. Lee (Seung Hun); P.C. Leung (Ping C.); J.R. Lewis (Joshua); L. Masi (Laura); S. Mencej-Bedrac (Simona); T.V. Nguyen (Tuan); X. Nogues (Xavier); M.S. Patel (Millan); J. Prezelj (Janez); L.M. Rose (Lynda); S. Scollen (Serena); K. Siggeirsdottir (Kristin); G.D. Smith; O. Svensson (Olle); S. Trompet (Stella); O. Trummer (Olivia); N.M. van Schoor (Natasja); J. Woo (Jean); K. Zhu (Kun); S. Balcells (Susana); M.L. Brandi; B.M. Buckley (Brendan M.); S. Cheng (Sulin); C. Christiansen; C. Cooper (Charles); G.V. Dedoussis (George); I. Ford (Ian); M. Frost (Morten); D. Goltzman (David); J. González-Macías (Jesús); M. Kähönen (Mika); M. Karlsson (Magnus); E.K. Khusnutdinova (Elza); J.-M. Koh (Jung-Min); P. Kollia (Panagoula); B.L. Langdahl (Bente); W.D. Leslie (William D.); P. Lips (Paul); O. Ljunggren (Östen); R. Lorenc (Roman); J. Marc (Janja); D. Mellström (Dan); B. Obermayer-Pietsch (Barbara); D. Olmos (David); U. Pettersson-Kymmer (Ulrika); D.M. Reid (David); J.A. Riancho (José); P.M. Ridker (Paul); M.F. Rousseau (Francois); P.E. Slagboom (Eline); N.L.S. Tang (Nelson L.S.); R. Urreizti (Roser); W. Van Hul (Wim); J. Viikari (Jorma); M.T. Zarrabeitia (María); Y.S. Aulchenko (Yurii); M.C. Castaño Betancourt (Martha); E. Grundberg (Elin); L. Herrera (Lizbeth); T. Ingvarsson (Torvaldur); H. Johannsdottir (Hrefna); T. Kwan (Tony); R. Li (Rui); R.N. Luben (Robert); M.C. Medina-Gomez (Carolina); S.T. Palsson (Stefan Th); J.I. Rotter (Jerome I.); G. Sigurdsson (Gunnar); J.B.J. van Meurs (Joyce); D.J. Verlaan (Dominique); F.M. Williams (Frances); A.R. Wood (Andrew); Y. Zhou (Yanhua); T. Pastinen (Tomi); S. Raychaudhuri (Soumya); J.A. Cauley (Jane); D.I. Chasman (Daniel); G.R. Clark (Graeme); S.R. Cummings (Steven R.); P. Danoy (Patrick); E.M. Dennison (Elaine); R. Eastell (Richard); J.A. Eisman (John); V. Gudnason (Vilmundur); A. Hofman (Albert); R.D. Jackson (Rebecca); G. Jones (Graeme); J.W. Jukema (Jan Wouter); K.T. Khaw; T. Lehtimäki (Terho); Y. Liu (YongMei); M. Lorentzon (Mattias); E. McCloskey (Eugene); B.D. Mitchell (Braxton); K. Nandakumar (Kannabiran); G.C. Nicholson (Geoffrey); B.A. Oostra (Ben); M. Peacock (Munro); H.A.P. Pols (Huib); R.L. Prince (Richard); O. Raitakari (Olli); I.R. Reid (Ian); J. Robbins (John); P.N. Sambrook (Philip); P.C. Sham (Pak Chung); A.R. Shuldiner (Alan); F.A. Tylavsky (Frances); C.M. van Duijn (Cornelia); N.J. Wareham (Nicholas J.); L.A. Cupples (Adrienne); M.J. Econs (Michael); D.M. Evans (David); T.B. Harris (Tamara B.); A.W.C. Kung (Annie Wai Chee); B.M. Psaty (Bruce); J. Reeve (Jonathan); T.D. Spector (Timothy); E.A. Streeten (Elizabeth); M.C. Zillikens (Carola); U. Thorsteinsdottir (Unnur); C. Ohlsson (Claes); D. Karasik (David); J.B. Richards (Brent); M.A. Brown (Matthew); J-A. Zwart (John-Anker); A.G. Uitterlinden (André); S.H. Ralston (Stuart); J.P.A. Ioannidis (John P.A.); D.P. Kiel (Douglas P.); F. Rivadeneira Ramirez (Fernando)

    2015-01-01

    textabstractBone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown.

  5. Modes of risk explanation in telephone consultations between nurses and parents for a genetic condition

    DEFF Research Database (Denmark)

    Zayts, Olga; Sarangi, Srikant

    2013-01-01

    as warrants for advice-giving and providing reassurance. We then examine how the genetic nurses interactionally orient themselves to the parents’ existing knowledge regarding G6PD deficiency while delivering these risk explanations. The differences in explanation trajectories are linked to the presence...

  6. Health-related direct-to-consumer genetic tests: a public health assessment and analysis of practices related to Internet-based tests for risk of thrombosis.

    Science.gov (United States)

    Goddard, K A B; Robitaille, J; Dowling, N F; Parrado, A R; Fishman, J; Bradley, L A; Moore, C A; Khoury, M J

    2009-01-01

    Recent years have seen increased concern about direct-to-consumer (DTC) genetic testing (i.e., the sale and use of genetic tests without involving a health care provider). Numerous professional organizations have developed policies in this area. However, little systematic evidence exists to inform public policy about these tests. We conducted a systematic search to identify genetic tests that are sold DTC without involving a health care provider. We evaluated the practices of companies offering DTC genetic tests for risk of thrombosis using criteria from multiple sources and a minimal set of key practices. We identified 84 instances of currently available health-related DTC genetic tests sold on 27 Web sites; the most common were for pharmacogenomics (12), risk of thrombosis (10), and nutrigenomics (10). For the DTC genetic tests for risk of thrombosis, we found low adherence to recommendations. Online information was frequently incomplete and had low agreement with professional recommendations. Our findings document the rapid growth in the availability of health-related DTC genetic tests and highlight the need to improve the delivery of DTC genetic tests. A major implication of this study is the need for the scientific and medical community to develop consistent recommendations to increase their impact. Copyright 2008 S. Karger AG, Basel.

  7. Genome-Wide Interaction Analyses between Genetic Variants and Alcohol Consumption and Smoking for Risk of Colorectal Cancer.

    Directory of Open Access Journals (Sweden)

    Jian Gong

    2016-10-01

    Full Text Available Genome-wide association studies (GWAS have identified many genetic susceptibility loci for colorectal cancer (CRC. However, variants in these loci explain only a small proportion of familial aggregation, and there are likely additional variants that are associated with CRC susceptibility. Genome-wide studies of gene-environment interactions may identify variants that are not detected in GWAS of marginal gene effects. To study this, we conducted a genome-wide analysis for interaction between genetic variants and alcohol consumption and cigarette smoking using data from the Colon Cancer Family Registry (CCFR and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO. Interactions were tested using logistic regression. We identified interaction between CRC risk and alcohol consumption and variants in the 9q22.32/HIATL1 (Pinteraction = 1.76×10-8; permuted p-value 3.51x10-8 region. Compared to non-/occasional drinking light to moderate alcohol consumption was associated with a lower risk of colorectal cancer among individuals with rs9409565 CT genotype (OR, 0.82 [95% CI, 0.74-0.91]; P = 2.1×10-4 and TT genotypes (OR,0.62 [95% CI, 0.51-0.75]; P = 1.3×10-6 but not associated among those with the CC genotype (p = 0.059. No genome-wide statistically significant interactions were observed for smoking. If replicated our suggestive finding of a genome-wide significant interaction between genetic variants and alcohol consumption might contribute to understanding colorectal cancer etiology and identifying subpopulations with differential susceptibility to the effect of alcohol on CRC risk.

  8. Belief and disbelief in the existence of genetic risk factors for suicide: cross-cultural comparisons.

    Science.gov (United States)

    Voracek, Martin

    2007-12-01

    There is evidence for widespread disbelief in the genetics of suicide, despite recent research progress in this area and convergent evidence supporting a role for genetic factors. This study analyzed the beliefs held in 8 samples (total N = 1224) of various types (psychology, medical, and various undergraduates, psychology graduates, and the general population) from 6 countries located on 3 continents (Austria, Canada, Malaysia, Romania, United Kingdom, and the USA). Endorsement rates for the existence of genetic risk factors for suicide ranged from 26% and 30% (Austrian psychology undergraduates and general population) to around 50% (psychology undergraduates in the USA and United Kingdom). In the 8 samples, respondents' sex, age, religiosity, political orientation, and other demographic variables were, for the most part, unrelated, but overall knowledge about suicide throughout was related positively to endorsement rates. Consistent with previous research, across a considerable variety of sample types and cultural settings there was no evidence for a clear majority believing in genetic bases for suicide.

  9. Genetic impact of low-level ionizing radiation: risk estimates for first and subsequent generations

    International Nuclear Information System (INIS)

    Abrahamson, S.

    1985-01-01

    This presentation is summarized as follows: (1) a discussion of the induced mutation rates/rad employed to derive central estimates for five major classes of genetic disease; (2) the expected first generation yield of mutations per million liveborn when both parents have received a gonadal exposure of 1 rad; (3) the expected yield of mutant offspring through all time from a single rad of parental exposure; (4) the impact in terms of effective years of life lost; and (5) a prediction of how many induced genetic disorders of each class should be found among the offspring of the A-bomb survivors using the risk estimates presented. 15 references, 6 tables

  10. The Tourette International Collaborative Genetics (TIC Genetics) study, finding the genes causing Tourette syndrome: objectives and methods.

    Science.gov (United States)

    Dietrich, Andrea; Fernandez, Thomas V; King, Robert A; State, Matthew W; Tischfield, Jay A; Hoekstra, Pieter J; Heiman, Gary A

    2015-02-01

    Tourette syndrome (TS) is a neuropsychiatric disorder characterized by recurrent motor and vocal tics, often accompanied by obsessive-compulsive disorder and/or attention-deficit/hyperactivity disorder. While the evidence for a genetic contribution is strong, its exact nature has yet to be clarified fully. There is now mounting evidence that the genetic risks for TS include both common and rare variants and may involve complex multigenic inheritance or, in rare cases, a single major gene. Based on recent progress in many other common disorders with apparently similar genetic architectures, it is clear that large patient cohorts and open-access repositories will be essential to further advance the field. To that end, the large multicenter Tourette International Collaborative Genetics (TIC Genetics) study was established. The goal of the TIC Genetics study is to undertake a comprehensive gene discovery effort, focusing both on familial genetic variants with large effects within multiply affected pedigrees and on de novo mutations ascertained through the analysis of apparently simplex parent-child trios with non-familial tics. The clinical data and biomaterials (DNA, transformed cell lines, RNA) are part of a sharing repository located within the National Institute for Mental Health Center for Collaborative Genomics Research on Mental Disorders, USA, and will be made available to the broad scientific community. This resource will ultimately facilitate better understanding of the pathophysiology of TS and related disorders and the development of novel therapies. Here, we describe the objectives and methods of the TIC Genetics study as a reference for future studies from our group and to facilitate collaboration between genetics consortia in the field of TS.

  11. Genetic analysis of the isolated Faroe Islands reveals SORCS3 as a potential multiple sclerosis risk gene

    DEFF Research Database (Denmark)

    Binzer, Stefanie; Stenager, Egon; Binzer, Michael

    2016-01-01

    BACKGROUND: In search of the missing heritability in multiple sclerosis (MS), additional approaches adding to the genetic discoveries of large genome-wide association studies are warranted. OBJECTIVE: The objective of this research paper is to search for rare genetic MS risk variants...... in the genetically homogenous population of the isolated Faroe Islands. METHODS: Twenty-nine Faroese MS cases and 28 controls were genotyped with the HumanOmniExpressExome-chip. The individuals make up 1596 pair-combinations in which we searched for identical-by-descent shared segments using the PLINK...... of neurotrophin factors and involvement in glutamate homeostasis. Although additional work is needed to scrutinise the genetic effect of the SORCS3-covering haplotype, this study suggests that SORCS3 may also be important in MS pathogenesis....

  12. Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium

    DEFF Research Database (Denmark)

    Pearce, C L; Near, A M; Van Den Berg, D J

    2009-01-01

    The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had...... been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P... and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted....

  13. Recent advances in the estimation of genetic risks of exposure to ionizing radiation

    International Nuclear Information System (INIS)

    Sankaranarayanan, K.

    2002-01-01

    This paper reviews the major advances that have occurred during the last few years in the estimation of genetic risks of exposure of human populations to ionizing radiation. Among these are: (i) an upward revision of the estimates of the baseline frequencies of Mendelian diseases (from 1.25% to 2.4%); (ii) the conceptual change to the use of a doubling dose based on human data on spontaneous mutation rates and mouse data on induced mutation rates (from the one based entirely on mouse data on spontaneous and induced mutation rates, which was the case thus far); (iii) the fuller development of the concept of mutation component (MC) and its application to predict the responsiveness of Mendelian and chronic multi factorial diseases to induced mutations; (iv) the introduction of the concept that the major adverse effects of radiation exposure of human germ cells are likely to be manifest as multi-system developmental abnormalities and (v) the introduction of concept of potential recoverability correction factor (PRCF) to bridge the gap between induced mutations studied in mice and the risk of genetic disease in humans are reviewed

  14. Communicating the risks and benefits of genetically engineered food products to the public: The view of experts from four European countries

    DEFF Research Database (Denmark)

    Scholderer, Joachim; Balderjahn, Ingo; Will, Simone

    Executive summary 1. Previous research on the risks and benefits of genetically engineered food products has not accounted for risk communication issues. The introductory part of this paper develops a more comprehensive model. Risks and benefits enter the model as the input of a risk communication...

  15. Portfolio management using value at risk: A comparison between genetic algorithms and particle swarm optimization

    NARCIS (Netherlands)

    V.A.F. Dallagnol (V. A F); J.H. van den Berg (Jan); L. Mous (Lonneke)

    2009-01-01

    textabstractIn this paper, it is shown a comparison of the application of particle swarm optimization and genetic algorithms to portfolio management, in a constrained portfolio optimization problem where no short sales are allowed. The objective function to be minimized is the value at risk

  16. Usefulness of Genetic Polymorphisms and Conventional Risk Factors to Predict Coronary Heart Disease in Patients With Familial Hypercholesterolemia

    NARCIS (Netherlands)

    van der Net, Jeroen B.; Janssens, A. Cecile J. W.; Defesche, Joep C.; Kastelein, John J. P.; Sijbrands, Eric J. G.; Steyerberg, Ewout W.

    2009-01-01

    Familial hypercholesterolemia (FH) is an autosomal dominant disorder with an associated high risk of coronary heart disease (CHD). The considerable variation in age of onset of CHD in patients with FH is believed to arise from conventional risk factors, as well as genetic variation other than in the

  17. Estimating the risks of cancer mortality and genetic defects resulting from exposures to low levels of ionizing radiation

    International Nuclear Information System (INIS)

    Buhl, T.E.; Hansen, W.R.

    1984-05-01

    Estimators for calculating the risk of cancer and genetic disorders induced by exposure to ionizing radiation have been recommended by the US National Academy of Sciences Committee on the Biological Effects of Ionizing Radiations, the UN Scientific Committee on the Effects of Atomic Radiation, and the International Committee on Radiological Protection. These groups have also considered the risks of somatic effects other than cancer. The US National Council on Radiation Protection and Measurements has discussed risk estimate procedures for radiation-induced health effects. The recommendations of these national and international advisory committees are summarized and compared in this report. Based on this review, two procedures for risk estimation are presented for use in radiological assessments performed by the US Department of Energy under the National Environmental Policy Act of 1969 (NEPA). In the first procedure, age- and sex-averaged risk estimators calculated with US average demographic statistics would be used with estimates of radiation dose to calculate the projected risk of cancer and genetic disorders that would result from the operation being reviewed under NEPA. If more site-specific risk estimators are needed, and the demographic information is available, a second procedure is described that would involve direct calculation of the risk estimators using recommended risk-rate factors. The computer program REPCAL has been written to perform this calculation and is described in this report. 25 references, 16 tables

  18. Estimating the risks of cancer mortality and genetic defects resulting from exposures to low levels of ionizing radiation

    Energy Technology Data Exchange (ETDEWEB)

    Buhl, T.E.; Hansen, W.R.

    1984-05-01

    Estimators for calculating the risk of cancer and genetic disorders induced by exposure to ionizing radiation have been recommended by the US National Academy of Sciences Committee on the Biological Effects of Ionizing Radiations, the UN Scientific Committee on the Effects of Atomic Radiation, and the International Committee on Radiological Protection. These groups have also considered the risks of somatic effects other than cancer. The US National Council on Radiation Protection and Measurements has discussed risk estimate procedures for radiation-induced health effects. The recommendations of these national and international advisory committees are summarized and compared in this report. Based on this review, two procedures for risk estimation are presented for use in radiological assessments performed by the US Department of Energy under the National Environmental Policy Act of 1969 (NEPA). In the first procedure, age- and sex-averaged risk estimators calculated with US average demographic statistics would be used with estimates of radiation dose to calculate the projected risk of cancer and genetic disorders that would result from the operation being reviewed under NEPA. If more site-specific risk estimators are needed, and the demographic information is available, a second procedure is described that would involve direct calculation of the risk estimators using recommended risk-rate factors. The computer program REPCAL has been written to perform this calculation and is described in this report. 25 references, 16 tables.

  19. What Is Genetic Ancestry Testing?

    Science.gov (United States)

    ... consumer genetic testing? What kinds of direct-to-consumer genetic tests are available? What is genetic ancestry testing? What are the benefits and risks of direct-to-consumer genetic testing? ...

  20. Genetic and modifying factors that determine the risk of brain tumors

    DEFF Research Database (Denmark)

    Montelli, Terezinha de Cresci Braga; Peraçoli, Maria Terezinha Serrão; Rogatto, Silvia Regina

    2011-01-01

    of tumor escape, CNS tumor immunology, immune defects that impair anti-tumor systemic immunity in brain tumor patients and local immuno-suppressive factors within CNS are also reviewed. New hope to treatment perspectives, as dendritic-cell-based vaccines is summarized too. Concluding, it seems well...... responses can alert immune system. However, it is necessary to clarify if individuals with both constitutional defects in immune functions and genetic instability have higher risk of developing brain tumors. Cytogenetic prospective studies and gene copy number variations analysis also must be performed...