WorldWideScience

Sample records for common genetic diseases

  1. Nutrition and genetic susceptibility to common diseases.

    Science.gov (United States)

    Motulsky, A G

    1992-06-01

    Genetic factors play a role in chronic disease and conditions such as coronary heart disease, hypertension, and obesity. Individual responses to nutritional factors involved in such conditions vary depending upon a person's genetic make-up. The role of individual genes is best understood for the hyperlipidemias that predispose to coronary heart disease. Until more and better information on gene-nutritional interactions is available, general population-wide recommendations regarding a prudent diet appear reasonable. At the same time, high risk screening for certain conditions such as the hyperlipidemias is appropriate.

  2. Genetics of Common Endocrine Disease: The Present and the Future.

    Science.gov (United States)

    Goodarzi, Mark O

    2016-03-01

    In honor of the 75th issue of the Journal of Clinical Endocrinology and Metabolism, the author was invited to present his perspectives on genetics in human endocrinology. This paper reviews what the field has achieved in the genetics of common endocrine disease, and offers predictions on where the field will move in the future and its impact on endocrine clinical practice. The October 2015 data release of the National Human Genome Research Institute-European Bioinformatics Institute (NHGRI-EBI) Catalog of Published Genome-wide Association Studies was queried regarding endocrinologic diseases and traits. PubMed searches were focused on genetic prediction of disease, genetic findings and drug targets, functional interrogation of genetic loci, use of genetics to subtype disease, missing heritability, systems genomics, and higher order chromatin structures as regulators of gene function. Nearly a quarter of genome wide association study findings concern endocrinologic diseases and traits. While these findings have not yet dramatically altered clinical care, genetics will have a major impact by providing the drug targets of tomorrow, facilitated by experimental and bioinformatic advances that will shorten the time from gene discovery to drug development. Use of genetic findings to subtype common endocrine disease will allow more precise prevention and treatment efforts. Future advances will allow us to move away from the common view of DNA as a string of letters, allowing exploration of higher order structure that likely explains much "missing heritability." The future will see a greater role of genetics at the bedside, with genetic epidemiologic discoveries leading not only to new treatments of endocrine disease, but also helping us prescribe the right drug to the right patients by allowing subclassification of common heterogeneous endocrine conditions. Future technological breakthroughs will reveal the heritable mysteries hidden in chromatin structure, leading to a

  3. New IBD genetics: common pathways with other diseases.

    Science.gov (United States)

    Lees, C W; Barrett, J C; Parkes, M; Satsangi, J

    2011-12-01

    Complex disease genetics has been revolutionised in recent years by the advent of genome-wide association (GWA) studies. The chronic inflammatory bowel diseases (IBDs), Crohn's disease and ulcerative colitis have seen notable successes culminating in the discovery of 99 published susceptibility loci/genes (71 Crohn's disease; 47 ulcerative colitis) to date. Approximately one-third of loci described confer susceptibility to both Crohn's disease and ulcerative colitis. Amongst these are multiple genes involved in IL23/Th17 signalling (IL23R, IL12B, JAK2, TYK2 and STAT3), IL10, IL1R2, REL, CARD9, NKX2.3, ICOSLG, PRDM1, SMAD3 and ORMDL3. The evolving genetic architecture of IBD has furthered our understanding of disease pathogenesis. For Crohn's disease, defective processing of intracellular bacteria has become a central theme, following gene discoveries in autophagy and innate immunity (associations with NOD2, IRGM, ATG16L1 are specific to Crohn's disease). Genetic evidence has also demonstrated the importance of barrier function to the development of ulcerative colitis (HNF4A, LAMB1, CDH1 and GNA12). However, when the data are analysed in more detail, deeper themes emerge including the shared susceptibility seen with other diseases. Many immune-mediated diseases overlap in this respect, paralleling the reported epidemiological evidence. However, in several cases the reported shared susceptibility appears at odds with the clinical picture. Examples include both type 1 and type 2 diabetes mellitus. In this review we will detail the presently available data on the genetic overlap between IBD and other diseases. The discussion will be informed by the epidemiological data in the published literature and the implications for pathogenesis and therapy will be outlined. This arena will move forwards very quickly in the next few years. Ultimately, we anticipate that these genetic insights will transform the landscape of common complex diseases such as IBD.

  4. Is there a Common Genetic Basis for Autoimmune Diseases?

    Directory of Open Access Journals (Sweden)

    Juan-Manuel Anaya

    2006-01-01

    Full Text Available Autoimmune diseases (ADs represent a diverse collection of diseases in terms of their demographic profile and primary clinical manifestations. The commonality between them however, is the damage to tissues and organs that arises from the response to self-antigens. The presence of shared pathophysiological mechanisms within ADs has stimulated searches for common genetic roots to these diseases. Two approaches have been undertaken to sustain the “common genetic origin” theory of ADs. Firstly, a clinical genetic analysis showed that autoimmunity aggregates within families of probands diagnosed with primary Sjögren's (pSS syndrome or type 1 diabetes mellitus (T1D. A literature review supported the establishment of a familiar cluster of ADs depending upon the proband's disease phenotype. Secondly, in a same and well-defined population, a large genetic association study indicated that a number of polymorphic genes (i.e. HLA-DRB1, TNF and PTPN22 influence the susceptibility for acquiring different ADs. Likewise, association and linkage studies in different populations have revealed that several susceptibility loci overlap in ADs, and clinical studies have shown that frequent clustering of several ADs occurs. Thus, the genetic factors for ADs consist of two types: those which are common to many ADs (acting in epistatic pleitropy and those that are specific to a given disorder. Their identification and functional characterization will allow us to predict their effect as well as to indicate potential new therapeutic interventions. Both autoimmunity family history and the co-occurrence of ADs in affected probands should be considered when performing genetic association and linkage studies.

  5. Genetics in Common Liver Diseases: From Pathophysiology to Precise Treatment.

    Science.gov (United States)

    Lammert, Frank

    In the past 2 decades, advances in genetics have improved our understanding of liver disease and physiology. Firstly, developments in genomic technologies drove the identification of genes responsible for monogenic (Mendelian) liver diseases. Over the last decade, genome-wide association studies allowed for the dissection of the genetic susceptibility to complex liver diseases such as fatty liver disease and drug-induced liver injury, in which environmental co-factors play critical roles. The findings have allowed the identification and elaboration of pathophysiological processes, have indicated the need for reclassification of liver diseases and risk factors and have already pointed to new disease treatments. This is illustrated by the interaction of alcohol, overnutrition and the PNPLA3 gene, which represents an 'infernal triangle' for the liver. In the future, genetics will allow further stratification of liver diseases and contribute to personalized (precision) medicine, offering novel opportunities for translational research and clinical care of our patients. © 2016 S. Karger AG, Basel.

  6. Genetic basis of common diseases: the general theory of Mendelian recessive genetics.

    Science.gov (United States)

    Hutchinson, Michael; Spanaki, Cleanthe; Lebedev, Sergey; Plaitakis, Andreas

    2005-01-01

    Common diseases tend to appear sporadically, i.e., they appear in an individual who has no first or second degree relatives with the disease. Yet diseases are often associated with a slight but definite increase in risk to the children of an affected individual. This weak pattern of inheritability cannot be explained by conventional interpretations of Mendelian genetics, and it is therefore commonly held that there is "incomplete penetrance" of a gene, or that there are polygenic, or multifactorial modes of inheritance. However, such arguments are heuristic and lack predictive power. Here, we explore the possibility that "incomplete penetrance" means the existence of a second, disease-related, gene. By examining in detail a specific common condition, Parkinson's disease (PD), we show that the sporadic form of the disease can be fully explained by a compact fully penetrant genotype involving an interaction between two, and only two, genes. In this model, therefore PD is fundamentally genetic. Our digenic model is complementary to Mendelian recessive genetics, but taken together with the latter forms a complete description for recessive genetics on one chromosome. It explains the slight increase in risk to the children if one parent has sporadic PD, and makes strict predictions where both parents coincidentally have sporadic PD. These predictions were verified in two large and carefully selected kindred, where the data also argue against other genetic models, including oligogenic and polygenic schemes. Since the inheritance patterns of sporadic PD are reminiscent of what is seen in many common diseases, it is plausible that similar genetic forms could apply to other diseases. Seen in this light, diseases wash in and out of every family, so that in a sense, over time every human family is equally at risk for most diseases.

  7. Premature birth and diseases in premature infants: common genetic background?

    Science.gov (United States)

    Hallman, Mikko

    2012-04-01

    It has been proposed that during human evolution, development of obligate bipedalism, narrow birth canal cross-sectional area and the large brain have forced an adjustment in duration of pregnancy (scaling of gestational age; Plunkett 2011). Children compared to other mammals are born with proportionally small brains (compared to adult brains), suggesting shortening of pregnancy duration during recent evolution. Prevalence of both obstructed delivery and premature birth is still exceptionally high. In near term infants, functional maturity and viability is high, and gene variants predisposing to respiratory distress syndrome (RDS) are rare. Advanced antenatal and neonatal treatment practices during the new era of medicine allowed survival of also very preterm infants (gestation premature birth. Specific genes associating with diseases in preterm infants may also contribute to the susceptibility to preterm birth. Understanding and applying the knowledge of genetic interactions in normal and abnormal perinatal-neonatal development requires large, well-structured population cohorts, studies involving the whole genome and international interdisciplinary collaboration.

  8. Shared genetic variants suggest common pathways in allergy and autoimmune diseases

    DEFF Research Database (Denmark)

    Kreiner-Møller, Eskil; Waage, Johannes; Standl, Marie

    2016-01-01

    Background: The relationship between allergy and autoimmune disorders is complex and poorly understood. Objective: To investigate commonalities in genetic loci and pathways between allergy and autoimmune diseases to elucidate shared disease mechanisms. Methods: We meta-analyzed two GWAS on self......-reported allergy and sensitization comprising a total of 62,330 individuals. These results were used to calculate enrichment for SNPs previously associated with autoimmune diseases. Furthermore, we probed for enrichment within genetic pathways and of transcription factor binding sites, and characterized...... commonalities in the variant burden on tissue-specific regulatory sites by calculating the enrichment of allergy SNPs falling in gene regulatory regions in various cells using Encode Roadmap DHS data, and compared the allergy data with all known diseases. Conclusion: Among 290 loci previously associated with 16...

  9. Genetics of diabetic nephropathy: are there clues to the understanding of common kidney diseases?

    Science.gov (United States)

    Conway, B R; Maxwell, A P

    2009-01-01

    Diabetic nephropathy is the most common cause of end-stage renal disease in the Western world. There is evidence for a genetic susceptibility to diabetic kidney disease, but despite intensive research efforts it has proved difficult to identify the causative genes. Improvements in genotyping technologies have made genome-wide association studies (GWAS), employing hundreds of thousands of single nucleotide polymorphisms, affordable. Recently, such scans have advanced understanding of the genetics of common complex diseases, finding more than 100 novel susceptibility variants for diverse disorders including type 1 and 2 diabetes, coronary heart disease, Crohn's disease and rheumatoid arthritis. In this review, type 2 diabetes is highlighted to illustrate how genome-wide association studies have been used to study the genetics of complex multifactorial conditions; in addition, diabetic nephropathy will be used to demonstrate how similar scans could be employed to detect genetic factors predisposing to kidney disease. The identification of such variants would permit early identification of atrisk patients, enabling targeting of therapy and a move towards primary prevention. In addition, these powerful research methodologies may identify genes that were not previously known to predispose to nephropathy, thereby enhancing our understanding of the pathophysiology of renal disorders and potentially leading to novel therapeutic approaches.

  10. Genetic evidence for common pathways in human age-related diseases.

    Science.gov (United States)

    Johnson, Simon C; Dong, Xiao; Vijg, Jan; Suh, Yousin

    2015-10-01

    Aging is the single largest risk factor for chronic disease. Studies in model organisms have identified conserved pathways that modulate aging rate and the onset and progression of multiple age-related diseases, suggesting that common pathways of aging may influence age-related diseases in humans as well. To determine whether there is genetic evidence supporting the notion of common pathways underlying age-related diseases, we analyzed the genes and pathways found to be associated with five major categories of age-related disease using a total of 410 genomewide association studies (GWAS). While only a small number of genes are shared among all five disease categories, those found in at least three of the five major age-related disease categories are highly enriched for apoliprotein metabolism genes. We found that a more substantial number of gene ontology (GO) terms are shared among the 5 age-related disease categories and shared GO terms include canonical aging pathways identified in model organisms, such as nutrient-sensing signaling, translation, proteostasis, stress responses, and genome maintenance. Taking advantage of the vast amount of genetic data from the GWAS, our findings provide the first direct evidence that conserved pathways of aging simultaneously influence multiple age-related diseases in humans as has been demonstrated in model organisms. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  11. Analysis of the human diseasome using phenotype similarity between common, genetic, and infectious diseases

    Science.gov (United States)

    Hoehndorf, Robert; Schofield, Paul N.; Gkoutos, Georgios V.

    2015-06-01

    Phenotypes are the observable characteristics of an organism arising from its response to the environment. Phenotypes associated with engineered and natural genetic variation are widely recorded using phenotype ontologies in model organisms, as are signs and symptoms of human Mendelian diseases in databases such as OMIM and Orphanet. Exploiting these resources, several computational methods have been developed for integration and analysis of phenotype data to identify the genetic etiology of diseases or suggest plausible interventions. A similar resource would be highly useful not only for rare and Mendelian diseases, but also for common, complex and infectious diseases. We apply a semantic text-mining approach to identify the phenotypes (signs and symptoms) associated with over 6,000 diseases. We evaluate our text-mined phenotypes by demonstrating that they can correctly identify known disease-associated genes in mice and humans with high accuracy. Using a phenotypic similarity measure, we generate a human disease network in which diseases that have similar signs and symptoms cluster together, and we use this network to identify closely related diseases based on common etiological, anatomical as well as physiological underpinnings.

  12. Analysis of the human diseasome using phenotype similarity between common, genetic, and infectious diseases

    KAUST Repository

    Hoehndorf, Robert

    2015-06-08

    Phenotypes are the observable characteristics of an organism arising from its response to the environment. Phenotypes associated with engineered and natural genetic variation are widely recorded using phenotype ontologies in model organisms, as are signs and symptoms of human Mendelian diseases in databases such as OMIM and Orphanet. Exploiting these resources, several computational methods have been developed for integration and analysis of phenotype data to identify the genetic etiology of diseases or suggest plausible interventions. A similar resource would be highly useful not only for rare and Mendelian diseases, but also for common, complex and infectious diseases. We apply a semantic text-mining approach to identify the phenotypes (signs and symptoms) associated with over 6,000 diseases. We evaluate our text-mined phenotypes by demonstrating that they can correctly identify known disease-associated genes in mice and humans with high accuracy. Using a phenotypic similarity measure, we generate a human disease network in which diseases that have similar signs and symptoms cluster together, and we use this network to identify closely related diseases based on common etiological, anatomical as well as physiological underpinnings.

  13. A HapMap harvest of insights into the genetics of common disease.

    Science.gov (United States)

    Manolio, Teri A; Brooks, Lisa D; Collins, Francis S

    2008-05-01

    The International HapMap Project was designed to create a genome-wide database of patterns of human genetic variation, with the expectation that these patterns would be useful for genetic association studies of common diseases. This expectation has been amply fulfilled with just the initial output of genome-wide association studies, identifying nearly 100 loci for nearly 40 common diseases and traits. These associations provided new insights into pathophysiology, suggesting previously unsuspected etiologic pathways for common diseases that will be of use in identifying new therapeutic targets and developing targeted interventions based on genetically defined risk. In addition, HapMap-based discoveries have shed new light on the impact of evolutionary pressures on the human genome, suggesting multiple loci important for adapting to disease-causing pathogens and new environments. In this review we examine the origin, development, and current status of the HapMap; its prospects for continued evolution; and its current and potential future impact on biomedical science.

  14. Common variation in ISL1 confers genetic susceptibility for human congenital heart disease.

    Directory of Open Access Journals (Sweden)

    Kristen N Stevens

    Full Text Available Congenital heart disease (CHD is the most common birth abnormality and the etiology is unknown in the overwhelming majority of cases. ISLET1 (ISL1 is a transcription factor that marks cardiac progenitor cells and generates diverse multipotent cardiovascular cell lineages. The fundamental role of ISL1 in cardiac morphogenesis makes this an exceptional candidate gene to consider as a cause of complex congenital heart disease. We evaluated whether genetic variation in ISL1 fits the common variant-common disease hypothesis. A 2-stage case-control study examined 27 polymorphisms mapping to the ISL1 locus in 300 patients with complex congenital heart disease and 2,201 healthy pediatric controls. Eight genic and flanking ISL1 SNPs were significantly associated with complex congenital heart disease. A replication study analyzed these candidate SNPs in 1,044 new cases and 3,934 independent controls and confirmed that genetic variation in ISL1 is associated with risk of non-syndromic congenital heart disease. Our results demonstrate that two different ISL1 haplotypes contribute to risk of CHD in white and black/African American populations.

  15. Common genetic variants associated with thyroid function may be risk alleles for Hashimoto's disease and Graves' disease.

    Science.gov (United States)

    Campbell, Purdey; Brix, Thomas H; Wilson, Scott G; Ward, Lynley C; Hui, Jennie; Beilby, John P; Hegedüs, Laszlo; Walsh, John P

    2015-02-14

    Recent studies have identified common genetic variants associated with TSH, free T4 and thyroid peroxidase antibodies, but it is unclear whether these differ between patients with Hashimoto's disease and Graves' disease. To examine whether 11 common genetic variants differ between Graves' disease and Hashimoto's disease. We genotyped 11 common variants in a discovery cohort of 203 Australian patients with autoimmune thyroid disease (AITD). Two variants with significant or suggestive associations were analysed in a replication cohort of 384 Danish patients. For rs753760 (PDE10A), the minor allele frequency in Graves' disease and Hashimoto's disease was 0·38 vs. 0·23, respectively, (P = 6·42 × 10(-4) ) in the discovery cohort, 0·29 vs. 0·24 (P = 0·147) in the replication cohort and 0·32 vs. 0·24 in combined analysis (P = 0·0021; all analyses adjusted for sex). In healthy controls from Busselton, the frequency was 0·29, significantly different from Hashimoto's disease but not Graves' disease. For rs4889009 (MAF gene region), the frequency of the minor G-allele in Graves' disease and Hashimoto's disease was 0·48 vs. 0·36 (P = 0·0156) in the discovery cohort, 0·48 vs. 0·34 (P = 1·83 × 10(-4) ) in the replication cohort and 0·48 vs. 0·35 in the combined analysis (P = 7·53 × 10(-6) ); in controls, the frequency was 0·38, significantly different from Graves' disease but not Hashimoto's disease. After further adjustment for smoking, associations with rs4889009 remained significant, whereas those with rs753760 were not. Common variants in PDE10A and MAF gene regions may influence whether patients with AITD develop Graves' disease or Hashimoto's disease. © 2015 John Wiley & Sons Ltd.

  16. DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases

    Science.gov (United States)

    Bettencourt, Conceição; Hensman‐Moss, Davina; Flower, Michael; Wiethoff, Sarah; Brice, Alexis; Goizet, Cyril; Stevanin, Giovanni; Koutsis, Georgios; Karadima, Georgia; Panas, Marios; Yescas‐Gómez, Petra; García‐Velázquez, Lizbeth Esmeralda; Alonso‐Vilatela, María Elisa; Lima, Manuela; Raposo, Mafalda; Traynor, Bryan; Sweeney, Mary; Wood, Nicholas; Giunti, Paola; Durr, Alexandra; Holmans, Peter; Houlden, Henry; Tabrizi, Sarah J.

    2016-01-01

    Objective The polyglutamine diseases, including Huntington's disease (HD) and multiple spinocerebellar ataxias (SCAs), are among the commonest hereditary neurodegenerative diseases. They are caused by expanded CAG tracts, encoding glutamine, in different genes. Longer CAG repeat tracts are associated with earlier ages at onset, but this does not account for all of the difference, and the existence of additional genetic modifying factors has been suggested in these diseases. A recent genome‐wide association study (GWAS) in HD found association between age at onset and genetic variants in DNA repair pathways, and we therefore tested whether the modifying effects of variants in DNA repair genes have wider effects in the polyglutamine diseases. Methods We assembled an independent cohort of 1,462 subjects with HD and polyglutamine SCAs, and genotyped single‐nucleotide polymorphisms (SNPs) selected from the most significant hits in the HD study. Results In the analysis of DNA repair genes as a group, we found the most significant association with age at onset when grouping all polyglutamine diseases (HD+SCAs; p = 1.43 × 10–5). In individual SNP analysis, we found significant associations for rs3512 in FAN1 with HD+SCAs (p = 1.52 × 10–5) and all SCAs (p = 2.22 × 10–4) and rs1805323 in PMS2 with HD+SCAs (p = 3.14 × 10–5), all in the same direction as in the HD GWAS. Interpretation We show that DNA repair genes significantly modify age at onset in HD and SCAs, suggesting a common pathogenic mechanism, which could operate through the observed somatic expansion of repeats that can be modulated by genetic manipulation of DNA repair in disease models. This offers novel therapeutic opportunities in multiple diseases. Ann Neurol 2016;79:983–990 PMID:27044000

  17. Identification of common genetic modifiers of neurodegenerative diseases from an integrative analysis of diverse genetic screens in model organisms

    Directory of Open Access Journals (Sweden)

    Chen Xi

    2012-02-01

    Full Text Available Abstract Background An array of experimental models have been developed in the small model organisms C. elegans, S. cerevisiae and D. melanogaster for the study of various neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and expanded polyglutamine diseases as exemplified by Huntington's disease (HD and related ataxias. Genetic approaches to determine the nature of regulators of the disease phenotypes have ranged from small scale to essentially whole genome screens. The published data covers distinct models in all three organisms and one important question is the extent to which shared genetic factors can be uncovered that affect several or all disease models. Surprisingly it has appeared that there may be relatively little overlap and that many of the regulators may be organism or disease-specific. There is, however, a need for a fully integrated analysis of the available genetic data based on careful comparison of orthologues across the species to determine the real extent of overlap. Results We carried out an integrated analysis using C. elegans as the baseline model organism since this is the most widely studied in this context. Combination of data from 28 published studies using small to large scale screens in all three small model organisms gave a total of 950 identifications of genetic regulators. Of these 624 were separate genes with orthologues in C. elegans. In addition, 34 of these genes, which all had human orthologues, were found to overlap across studies. Of the common genetic regulators some such as chaperones, ubiquitin-related enzymes (including the E3 ligase CHIP which directly links the two pathways and histone deacetylases were involved in expected pathways whereas others such as the peroxisomal acyl CoA-oxidase suggest novel targets for neurodegenerative disease therapy Conclusions We identified a significant number of overlapping regulators of neurodegenerative disease models. Since the diseases

  18. How genetics research in Parkinson's disease is enhancing understanding of the common idiopathic forms of the disease.

    Science.gov (United States)

    Cookson, Mark R; Xiromerisiou, Georgia; Singleton, Andrew

    2005-12-01

    Rapid progress in genetics has meant that there are now five genes identified for 'Parkinson's disease'. The detailed phenotypes vary, but generally the dominant genes cause a Lewy body disease spectrum whereas recessive genes cause a milder parkinsonism with variable inclusion body pathology. The subject of this review is to highlight these discoveries and to discuss their relationships to idiopathic Parkinson's disease. In January 2004, mutations in PINK1, coding for a mitochondrial kinase, were found to be causal for recessive parkinsonism. Subsequently, several studies have found additional mutations associated with early onset parkinsonism. Some cases have been described with a phenotype much closer to idiopathic Parkinson's disease, but it does not appear that PINK1 is a major risk factor for the sporadic disease. Later in the same year, the LRRK2 gene was shown to cause a dominant disease with a broader phenotype. The protein product was named dardarin and contains GTPase and kinase domains. Lewy bodies have been reported in LRRK2 cases, potentially linking this gene with sporadic Parkinson's disease. One mutation, G2019S, is found in a significant percentage of cases, including sporadic Parkinson's disease. Mutations in these two genes, along with previously described Mendelian variants, are beginning to yield important information about loss of specific neuronal groups or to protein inclusion pathology. How this relates to sporadic Parkinson's disease, however, is not yet fully defined. There are clear phenotypic overlaps with genetic and sporadic Parkinson's disease, especially for the dominant genes, suggesting that common facets of pathogenesis may exist.

  19. 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.

  20. Shared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants.

    Science.gov (United States)

    Dichgans, Martin; Malik, Rainer; König, Inke R; Rosand, Jonathan; Clarke, Robert; Gretarsdottir, Solveig; Thorleifsson, Gudmar; Mitchell, Braxton D; Assimes, Themistocles L; Levi, Christopher; O'Donnell, Christopher J; Fornage, Myriam; Thorsteinsdottir, Unnur; Psaty, Bruce M; Hengstenberg, Christian; Seshadri, Sudha; Erdmann, Jeanette; Bis, Joshua C; Peters, Annette; Boncoraglio, Giorgio B; März, Winfried; Meschia, James F; Kathiresan, Sekar; Ikram, M Arfan; McPherson, Ruth; Stefansson, Kari; Sudlow, Cathie; Reilly, Muredach P; Thompson, John R; Sharma, Pankaj; Hopewell, Jemma C; Chambers, John C; Watkins, Hugh; Rothwell, Peter M; Roberts, Robert; Markus, Hugh S; Samani, Nilesh J; Farrall, Martin; Schunkert, Heribert

    2014-01-01

    Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases. Genome-wide association data were obtained from the METASTROKE, Coronary Artery Disease Genome-wide Replication and Meta-analysis (CARDIoGRAM), and Coronary Artery Disease (C4D) Genetics consortia. We first analyzed common variants reaching a nominal threshold of significance (Pstroke (LAS) subtype. Common variants associated with CAD at Pgenetic risk of IS and particularly the LAS subtype with CAD.

  1. metabolicMine: an integrated genomics, genetics and proteomics data warehouse for common metabolic disease research.

    Science.gov (United States)

    Lyne, Mike; Smith, Richard N; Lyne, Rachel; Aleksic, Jelena; Hu, Fengyuan; Kalderimis, Alex; Stepan, Radek; Micklem, Gos

    2013-01-01

    Common metabolic and endocrine diseases such as diabetes affect millions of people worldwide and have a major health impact, frequently leading to complications and mortality. In a search for better prevention and treatment, there is ongoing research into the underlying molecular and genetic bases of these complex human diseases, as well as into the links with risk factors such as obesity. Although an increasing number of relevant genomic and proteomic data sets have become available, the quantity and diversity of the data make their efficient exploitation challenging. Here, we present metabolicMine, a data warehouse with a specific focus on the genomics, genetics and proteomics of common metabolic diseases. Developed in collaboration with leading UK metabolic disease groups, metabolicMine integrates data sets from a range of experiments and model organisms alongside tools for exploring them. The current version brings together information covering genes, proteins, orthologues, interactions, gene expression, pathways, ontologies, diseases, genome-wide association studies and single nucleotide polymorphisms. Although the emphasis is on human data, key data sets from mouse and rat are included. These are complemented by interoperation with the RatMine rat genomics database, with a corresponding mouse version under development by the Mouse Genome Informatics (MGI) group. The web interface contains a number of features including keyword search, a library of Search Forms, the QueryBuilder and list analysis tools. This provides researchers with many different ways to analyse, view and flexibly export data. Programming interfaces and automatic code generation in several languages are supported, and many of the features of the web interface are available through web services. The combination of diverse data sets integrated with analysis tools and a powerful query system makes metabolicMine a valuable research resource. The web interface makes it accessible to first

  2. [Sickle cell anemia causes varied symptoms and high morbidity. Serious prognosis in the most common genetic disease in the world].

    Science.gov (United States)

    Kjellander, Christian; Sennström, Maria K B; Stiller, Viveka; Ågren, Anna

    2015-03-03

    Sickle cell anemia is a life-threatening disease, and the most common genetic disease in the world. The prevalence of sickle cell anemia in Sweden is unknown. Sickle cell anemia is an important disease, because of its variable complications, in many medical and surgical specialties. The overview highlights common medical problems encountered in sickle cell anemia presented through a case report of a pregnant woman.

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

    NARCIS (Netherlands)

    Meurs, van J.B.J.; Pare, G.; Schwartz, S.M.; Hazra, A.; Tanaka, T.; Vermeulen, S.H.; Cotlarciuc, I.; Yuan, X.; Malarstig, A.; Bandinelli, S.; Bis, J.C.; Morn, H.; Brown, M.J.; Chen, C.; Chen, Y.D.; Clarke, R.J.; Dehghan, A.; Erdmann, J.; Ferrucci, L.; Hamsten, A.; Hofman, A.; Hunten, D.J.; Goel, A.; Johnson, A.D.; Kathiresan, S.; Kampman, E.; Kiel, D.P.; Kiemeney, L.A.; Chambers, J.C.; Kraft, P.; Lindemans, J.; McKnight, B.; Nelson, C.P.; O'Donnell, C.J.; Psaty, B.M.; Ridken, P.M.; Rivadeneira, F.; Rose, L.M.; Seedoif, U.; Siscovick, D.S.; Schunkert, H.; Selhub, J.; Ueland, P.M.; Vollenweiden, P.; Waeben, G.; Waterworth, D.M.; Watkins, H.; Witteman, J.C.M.; Heijen, den M.; Jacques, P.; Uitterlinden, A.G.; Koonet, J.S.; Rader, D.J.; Reilly, M.P.; Moose, 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 homocysteinelowering trials have prompted the need to identify genetic variants associated with homocysteine concentrations and

  4. Genetics and Genomics of Single-Gene Cardiovascular Diseases: Common Hereditary Cardiomyopathies as Prototypes of Single-Gene Disorders.

    Science.gov (United States)

    Marian, Ali J; van Rooij, Eva; Roberts, Robert

    2016-12-27

    This is the first of 2 review papers on genetics and genomics appearing as part of the series on "omics." Genomics pertains to all components of an organism's genes, whereas genetics involves analysis of a specific gene or genes in the context of heredity. The paper provides introductory comments, describes the basis of human genetic diversity, and addresses the phenotypic consequences of genetic variants. Rare variants with large effect sizes are responsible for single-gene disorders, whereas complex polygenic diseases are typically due to multiple genetic variants, each exerting a modest effect size. To illustrate the clinical implications of genetic variants with large effect sizes, 3 common forms of hereditary cardiomyopathies are discussed as prototypic examples of single-gene disorders, including their genetics, clinical manifestations, pathogenesis, and treatment. The genetic basis of complex traits is discussed in a separate paper. Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  5. Common and different genetic background for rheumatoid arthritis and coeliac disease

    NARCIS (Netherlands)

    Coenen, Marieke J H; Trynka, Gosia; Heskamp, Sandra; Franke, Barbara; van Diemen, Cleo C; Smolonska, Joanna; van Leeuwen, Maria; Brouwer, Elisabeth; Boezen, Hendrika; Postma, Dirkje S; Platteel, Mathieu; Zanen, Pieter; Lammers, Jan-Willem W J; Groen, Hendricus; Mali, Willem P T M; Mulder, Chris J; Tack, Greetje J; Verbeek, Wieke H M; Wolters, Victorien M; Houwen, Roderick H J; Mearin, M Luisa; van Heel, David A; Radstake, Timothy R D J; van Riel, Piet L C M; Wijmenga, Cisca; Barrera, Pilar; Zhernakova, Alexandra

    2009-01-01

    Recent genome-wide association studies (GWAS) have revealed genetic risk factors in autoimmune and inflammatory disorders. Several of the associated genes and underlying pathways are shared by various autoimmune diseases. Rheumatoid arthritis (RA) and coeliac disease (CD) are two autoimmune

  6. A common genetic background could explain early-onset Crohn's disease.

    Science.gov (United States)

    Bianco, Anna Monica; Zanin, Valentina; Girardelli, Martina; Magnolato, Andrea; Martelossi, Stefano; Martellossi, Stefano; Tommasini, Alberto; Marcuzzi, Annalisa; Crovella, Sergio

    2012-04-01

    Crohn's disease (CD) is a multifactorial disease, in which environmental, microbial and genetic factors play important roles. CD is characterized by a chronic granulomatous inflammation by necrotic scarring with aspects of full-thickness wall. In spite of affecting mainly young adults, sometimes, CD can be present in the first year of life (early onset Crohn disease, EOCD) showing an unpredictable course and being often more severe than at older ages. In this paper we propose the hypothesis that EOCD patients should be analyzed using a Mendelian approach with family studies aimed to identify new loci directly involved in the early onset Crohn's disease. So we will leave the classic association study approach used until now for the identification of genes responsible for susceptibility to CD and propose linkage family analysis as alternative and powerful tool for the identification of new genetic variants associated with familiar cases of EOCD.

  7. Commonalities and differences between Crohn's disease and ulcerative colitis: the genetic clues to their interpretation.

    Science.gov (United States)

    Actis, Giovanni C; Pellicano, Rinaldo; Tarallo, Sonia; Rosina, Floriano

    2011-12-01

    Traditional knowledge of clinical, laboratorial, and endoscopic orders regarding ulcerative colitis and Crohn's disease has begun to be implemented by the revolutionary data from genetic studies. Ever since many decades ago it has been clear that inflammatory bowel diseases are complex multifactorial disorders wherein gut-confined and/or environmental factors must synergize with genetic components to effect the full-blown disorder. The sequencing of the human genome and the generation of public resources of single nucleotide polymorphisms permitted the conduction of powerful population based genome-wide association studies. The latter have increased the number of the identified susceptibility loci to 99. In this review we touched on two pathways that make true susceptibility genes for inflammatory bowel diseases; gene loci that confer specific risk for ulcerative colitis and Crohn's disease were discussed in detail.

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

    NARCIS (Netherlands)

    J.B.J. van Meurs (Joyce); G. Paré (Guillaume); S.M. Schwartz (Stephen); A. Hazra (Aditi); T. Tanaka; S.H.H.M. Vermeulen (Sita); I. Cotlarciuc (Ioana); X. Yuan (Xin); A. Mälarstig (Anders); S. Bandinelli (Stefania); J.C. Bis (Joshua); H.J. Blom (Henk); M.J. Brown (Morris); C. Chen (Christopher); R. Clarke (Robert); A. Dehghan (Abbas); J. Erdmann (Jeanette); L. Ferrucci; A. Hamsten (Anders); A. Hofman (Albert); D. Hunter (David); A. Goel (Anuj); A.D. Johnson (Andrew); S. Kathiresan (Sekar); E. Kampman (Ellen); D.P. Kiel (Douglas); L.A.L.M. Kiemeney (Bart); J.C. Chambers (John); P. Kraft (Peter); J. Lindemans (Jan); B. McKnight (Barbara); C.P. Nelson (Christopher P.); C.J. O'Donnell (Christopher); B.M. Psaty (Bruce); P.M. Ridker (Paul); F. Rivadeneira Ramirez (Fernando); L.M. Rose (Lynda); U. Seedorf (Udo); D.S. Siscovick (David); H. Schunkert (Heribert); J. Selhub (Jacob); P.M. Ueland (Per); P. Vollenweider (Peter); G. Waeber (Gérard); D. Waterworth (Dawn); H. Watkins (Hugh); J.C.M. Witteman (Jacqueline); M. den Heijer (Martin); P.F. Jacques (Paul); A.G. Uitterlinden (André); J.S. Kooner (Jaspal); D.J. Rader (Daniel); M.P. Reilly (Muredach); V. Mooser (Vincent); D.I. Chasman (Daniel); N.J. Samani (Nilesh); K.R. Ahmadi (Kourosh)

    2013-01-01

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

  9. 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...

  10. Age at Onset in Two Common Neurodegenerative Diseases Is Genetically Controlled

    Science.gov (United States)

    Li, Yi-Ju; Scott, William K.; Hedges, Dale J.; Zhang, Fengyu; Gaskell, P. Craig; Nance, Martha A.; Watts, Ray L.; Hubble, Jean P.; Koller, William C.; Pahwa, Rajesh; Stern, Matthew B.; Hiner, Bradley C.; Jankovic, Joseph; Allen, Jr., Fred H.; Goetz, Christopher G.; Mastaglia, Frank; Stajich, Jeffrey M.; Gibson, Rachel A.; Middleton, Lefkos T.; Saunders, Ann M.; Scott, Burton L.; Small, Gary W.; Nicodemus, Kristin K.; Reed, Allison D.; Schmechel, Donald E.; Welsh-Bohmer, Kathleen A.; Conneally, P. Michael; Roses, Allen D.; Gilbert, John R.; Vance, Jeffery M.; Haines, Jonathan L.; Pericak-Vance, Margaret A.

    2002-01-01

    To identify genes influencing age at onset (AAO) in two common neurodegenerative diseases, a genomic screen was performed for AAO in families with Alzheimer disease (AD; n=449) and Parkinson disease (PD; n=174). Heritabilities between 40%–60% were found in both the AD and PD data sets. For PD, significant evidence for linkage to AAO was found on chromosome 1p (LOD = 3.41). For AD, the AAO effect of APOE (LOD = 3.28) was confirmed. In addition, evidence for AAO linkage on chromosomes 6 and 10 was identified independently in both the AD and PD data sets. Subsequent unified analyses of these regions identified a single peak on chromosome 10q between D10S1239 and D10S1237, with a maximum LOD score of 2.62. These data suggest that a common gene affects AAO in these two common complex neurodegenerative diseases. PMID:11875758

  11. Shared genetic susceptibility to ischemic stroke and coronary artery disease – a genome-wide analysis of common variants

    Science.gov (United States)

    Dichgans, Martin; Malik, Rainer; König, Inke R.; Rosand, Jonathan; Clarke, Robert; Gretarsdottir, Solveig; Thorleifsson, Gudmar; Mitchell, Braxton D.; Assimes, Themistocles L.; Levi, Christopher; O′Donnell, Christopher J.; Fornage, Myriam; Thorsteinsdottir, Unnur; Psaty, Bruce M.; Hengstenberg, Christian; Seshadri, Sudha; Erdmann, Jeanette; Bis, Joshua C.; Peters, Annette; Boncoraglio, Giorgio B.; März, Winfried; Meschia, James F.; Kathiresan, Sekar; Ikram, M. Arfan; McPherson, Ruth; Stefansson, Kari; Sudlow, Cathie; Reilly, Muredach P.; Thompson, John R.; Sharma, Pankaj; Hopewell, Jemma C.; Chambers, John C.; Watkins, Hugh; Rothwell, Peter M.; Roberts, Robert; Markus, Hugh S.; Samani, Nilesh J.; Farrall, Martin; Schunkert, Heribert

    2014-01-01

    Summary Background and Purpose Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each have a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases. Methods Genome-wide association data were obtained from the METASTROKE, CARDIoGRAM, and C4D consortia. We first analyzed common variants reaching a nominal threshold of significance (pstroke (LAS) subtype. Results Common variants associated with CAD at pgenetic risk of ischemic stroke and particularly the large artery stroke subtype with coronary artery disease. PMID:24262325

  12. Evaluating the contribution of genetics and familial shared environment to common disease using the UK Biobank.

    Science.gov (United States)

    Muñoz, María; Pong-Wong, Ricardo; Canela-Xandri, Oriol; Rawlik, Konrad; Haley, Chris S; Tenesa, Albert

    2016-09-01

    Genome-wide association studies have detected many loci underlying susceptibility to disease, but most of the genetic factors that contribute to disease susceptibility remain unknown. Here we provide evidence that part of the 'missing heritability' can be explained by an overestimation of heritability. We estimated the heritability of 12 complex human diseases using family history of disease in 1,555,906 individuals of white ancestry from the UK Biobank. Estimates using simple family-based statistical models were inflated on average by ∼47% when compared with those from structural equation modeling (SEM), which specifically accounted for shared familial environmental factors. In addition, heritabilities estimated using SNP data explained an average of 44.2% of the simple family-based estimates across diseases and an average of 57.3% of the SEM-estimated heritabilities, accounting for almost all of the SEM heritability for hypertension. Our results show that both genetics and familial environment make substantial contributions to familial clustering of disease.

  13. Statistical Colocalization of Genetic Risk Variants for Related Autoimmune Diseases in the Context of Common Controls

    Science.gov (United States)

    Fortune, Mary D.; Guo, Hui; Burren, Oliver; Schofield, Ellen; Walker, Neil M.; Ban, Maria; Sawcer, Stephen J.; Bowes, John; Worthington, Jane; Barton, Ann; Eyre, Steve; Todd, John A.; Wallace, Chris

    2015-01-01

    Identifying whether potential causal variants for related diseases are shared can identify overlapping etiologies of multifactorial disorders. Colocalization methods disentangle shared and distinct causal variants. However, existing approaches require independent datasets. Here we extend two colocalization methods to allow for the shared control design commonly used in comparison of genome-wide association study results across diseases. Our analysis of four autoimmune diseases, type 1 diabetes (T1D), rheumatoid arthritis, celiac disease and multiple sclerosis, revealed 90 regions that were associated with at least one disease, 33 (37%) of which with two or more disorders. Nevertheless, for 14 of these 33 shared regions there was evidence that causal variants differed. We identified novel disease associations in 11 regions previously associated with one or more of the other three disorders. Four of eight T1D-specific regions contained known type 2 diabetes candidate genes: COBL, GLIS3, RNLS and BCAR1, suggesting a shared cellular etiology. PMID:26053495

  14. Analysis of the cartilage proteome from three different mouse models of genetic skeletal diseases reveals common and discrete disease signatures

    Directory of Open Access Journals (Sweden)

    Peter A. Bell

    2013-06-01

    Pseudoachondroplasia and multiple epiphyseal dysplasia are genetic skeletal diseases resulting from mutations in cartilage structural proteins. Electron microscopy and immunohistochemistry previously showed that the appearance of the cartilage extracellular matrix (ECM in targeted mouse models of these diseases is disrupted; however, the precise changes in ECM organization and the pathological consequences remain unknown. Our aim was to determine the effects of matrilin-3 and COMP mutations on the composition and extractability of ECM components to inform how these detrimental changes might influence cartilage organization and degeneration. Cartilage was sequentially extracted using increasing denaturants and the extraction profiles of specific proteins determined using SDS-PAGE/Western blotting. Furthermore, the relative composition of protein pools was determined using mass spectrometry for a non-biased semi-quantitative analysis. Western blotting revealed changes in the extraction of matrilins, COMP and collagen IX in mutant cartilage. Mass spectrometry confirmed quantitative changes in the extraction of structural and non-structural ECM proteins, including proteins with roles in cellular processes such as protein folding and trafficking. In particular, genotype-specific differences in the extraction of collagens XII and XIV and tenascins C and X were identified; interestingly, increased expression of several of these genes has recently been implicated in susceptibility and/or progression of murine osteoarthritis. We demonstrated that mutation of matrilin-3 and COMP caused changes in the extractability of other cartilage proteins and that proteomic analyses of Matn3 V194D, Comp T585M and Comp DelD469 mouse models revealed both common and discrete disease signatures that provide novel insight into skeletal disease mechanisms and cartilage degradation.

  15. Commonalities in biological pathways, genetics, and cellular mechanism between Alzheimer Disease and other neurodegenerative diseases: An in silico-updated overview.

    Science.gov (United States)

    Ahmad, Khurshid; Baig, Mohammad Hassan; Mushtaq, Gohar; Kamal, Mohammad Amjad; Greig, Nigel H; Choi, Inho

    2017-02-03

    Alzheimer's disease (AD) is the most common and well-studied neurodegenerative disease (ND). Biological pathways, pathophysiology and genetics of AD show commonalities with other NDs viz. Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Prion Disease and Dentatorubral-pallidoluysian atrophy (DRPLA). Many of the NDs, sharing the common features and molecular mechanisms suggests that pathology may be directly comparable and be implicated in disease prevention and development of highly effective therapies. In this review, a brief description of pathophysiology, clinical symptoms and available treatment of various NDs have been explored with special emphasis on AD. Commonalities in these fatal NDs provide support for therapeutic advancements and enhance the understanding of disease manifestation. The studies concentrating on the commonalities in biological pathways, cellular mechanisms and genetics may provide the scope to researchers to identify few novel common target/s for disease prevention and development of effective common drugs for multi-neurodegenerative diseases. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  16. Genetics of complex diseases.

    Science.gov (United States)

    Motulsky, Arno G

    2006-02-01

    Approaches to the study of the genetic basis of common complex diseases and their clinical applications are considered. Monogenic Mendelian inheritance in such conditions is infrequent but its elucidation may help to detect pathogenic mechanisms in the more common variety of complex diseases. Involvement by multiple genes in complex diseases usually occurs but the isolation and identification of specific genes so far has been exceptional. The role of common polymorphisms as indicators of disease risk in various studies is discussed.

  17. 鲤抗病育种研究进展%Genetic improvement of disease resistance in common carp

    Institute of Scientific and Technical Information of China (English)

    贾智英; 石连玉; 孙效文

    2012-01-01

    尽管鲤养殖业取得了巨大成就,但病害问题仍然是其发展所面临的一个重要制约因素。病害防控方法,主要有环境防控、药物控制和疫苗法,而运用遗传改良来提高鲤抗病力被认为是一种切实可行的方法。虽然以提高生长为目的的多项鲤育种计划已经取得了成功,但有关抗病育种相关研究仍处于起步阶段。利用鲤群体所存在的有益遗传变异,选择合适的育种方法,积极开展抗病选育应该是今后鲤养殖业所必须关注的重要研究内容。从环境胁迫对抗病性状的影响、抗病性状的遗传学基础、抗病性状与其他性状的关系、抗病性状的测定、抗病育种具体方法等方面较系统地介绍了利用遗传改良来提高鲤抗病力的相关研究进展。研究亮点:抗病力是养殖鱼类一个重要经济性状,但由于基础研究薄弱、有效评价方法缺乏等原因,致使抗病选育工作远落后于以生长等性状为目标的育种研究。本文综述了鲤抗病育种相关研究进展,为鲤和其他鱼类的抗病育种工作提供了重要的参考。%Despite impressive progress in common carp farming during the last years, the impact of fish diseases is still an important problem in aquaculture. Current methods to control diseases consist, among others, of euhural environment control, medication or vaccination. Another alternative approach is to prevent diseases by improving the immune capacity of fish by or genetic selection. Selection breeding has made a great progress for common carp, but only limited to the growth characteristics, and resistance breeding research was only in the initial stage. In the future, common carp industry should focus on using of genetic variation, choosing suitable breeding methods, developing diseases resistance breeding program actively. In this review, stress effects on diseases resistance, genetic basis of diseases resistance, relationship between diseases

  18. Are there genetic paths common to obesity, cardiovascular disease outcomes, and cardiovascular risk factors?

    Science.gov (United States)

    Rankinen, Tuomo; Sarzynski, Mark A; Ghosh, Sujoy; Bouchard, Claude

    2015-02-27

    Clustering of obesity, coronary artery disease, and cardiovascular disease risk factors is observed in epidemiological studies and clinical settings. Twin and family studies have provided some supporting evidence for the clustering hypothesis. Loci nearest a lead single nucleotide polymorphism (SNP) showing genome-wide significant associations with coronary artery disease, body mass index, C-reactive protein, blood pressure, lipids, and type 2 diabetes mellitus were selected for pathway and network analyses. Eighty-seven autosomal regions (181 SNPs), mapping to 56 genes, were found to be pleiotropic. Most pleiotropic regions contained genes associated with coronary artery disease and plasma lipids, whereas some exhibited coaggregation between obesity and cardiovascular disease risk factors. We observed enrichment for liver X receptor (LXR)/retinoid X receptor (RXR) and farnesoid X receptor/RXR nuclear receptor signaling among pleiotropic genes and for signatures of coronary artery disease and hepatic steatosis. In the search for functionally interacting networks, we found that 43 pleiotropic genes were interacting in a network with an additional 24 linker genes. ENCODE (Encyclopedia of DNA Elements) data were queried for distribution of pleiotropic SNPs among regulatory elements and coding sequence variations. Of the 181 SNPs, 136 were annotated to ≥ 1 regulatory feature. An enrichment analysis found over-representation of enhancers and DNAse hypersensitive regions when compared against all SNPs of the 1000 Genomes pilot project. In summary, there are genomic regions exerting pleiotropic effects on cardiovascular disease risk factors, although only a few included obesity. Further studies are needed to resolve the clustering in terms of DNA variants, genes, pathways, and actionable targets.

  19. Defective folding and rapid degradation of mutant proteins is a common disease mechanism in genetic disorders

    DEFF Research Database (Denmark)

    Gregersen, N; Bross, P; Jørgensen, M M

    2000-01-01

    of such 'conformational disease' are illustrated by reference to cystic fibrosis, phenylketonuria and short-chain acyl-CoA dehydrogenase deficiency. Other cellular components such as chaperones and proteases, as well as environmental factors, may combine to modulate the phenotype of such disorders and this may open up...

  20. Common genetic variations in CLOCK transcription factor are associated with nonalcoholic fatty liver disease

    Institute of Scientific and Technical Information of China (English)

    Silvia Sookoian; Gustavo Casta(n)o; Carolina Gemma; Tomas Fernández Gianotti; Carlos Jose Pirola

    2007-01-01

    AIM: To investigate the role of gene variants and derived haplotypes of the CLOCK transcription factor in nonalcoholic fatty liver disease (NAFLD) and their relation with the disease severity.METHODS: A total of 136 patients with NAFLD and 64 healthy individuals were studied. Liver biopsy was performed in 91 patients. Six tag SNPs showing a minor allele frequency > 10% (rs1554483 C/G; rs11932595A/G; rs4580704 C/G; rs6843722 A/C; rs6850524 C/G and rs4864548 A/G) encompassing 117 kb of chromosome 4and representing 115 polymorphic sites (r2>0.8) were genotyped.RESULTS: rs11932595 and rs6843722 showed significant associations with NAFLD (empiric P = 0.0449and 0.023, respectively). A significant association was also observed between clinical or histologic spectrum of NAFLD and rs1554483 (empiric P = 0.0399), rs6843722(empiric P = 0.0229) and rs6850524 (empiric P =0.00899) and between fibrosis score and rs1554483(empiric P = 0.02697), rs6843722 (empiric P = 0.01898)and rs4864548 (empiric P = 0.02697). Test of haplotypic association showed that CLOCK gene variant haplotypes frequencies in NAFLD individuals significantly differed from those in controls (empiric P = 0.0097).CONCLUSION: Our study suggests a potential role of the CLOCK polymorphisms and their haplotypes in susceptibility to NAFLD and disease severity.

  1. Genetic diversity and disease susceptibility.

    OpenAIRE

    Bodmer, W F

    1997-01-01

    The range of genetic diversity within human populations is enormous. Genetic susceptibility to common chronic disease is a significant part of this genetic diversity, which also includes a variety of rare clear-cut inherited diseases. Modern DNA-based genomic analysis can now routinely lead to the identification of genes involved in disease susceptibility, provides the basis for genetic counselling in affected families, and more widely for a genetically targeted approach to disease prevention...

  2. Genetics and Rheumatic Disease

    Science.gov (United States)

    ... Well with Rheumatic Disease Genetics and Rheumatic Disease Genetics and Rheumatic Disease Fast Facts Studying twins has ... 70%, and for non-identical pairs, even lower. Genetics and ankylosing spondylitis Each rheumatic disease has its ...

  3. Genetics and Rheumatic Disease

    Science.gov (United States)

    ... Well with Rheumatic Disease Genetics and Rheumatic Disease Genetics and Rheumatic Disease Fast Facts Studying twins has ... 70%, and for non-identical pairs, even lower. Genetics and ankylosing spondylitis Each rheumatic disease has its ...

  4. Shared Genetic Susceptibility to Ischemic Stroke and Coronary Artery Disease A Genome-Wide Analysis of Common Variants

    OpenAIRE

    Dichgans, Martin; Malik, Rainer; König, Inke R.; Rosand, Jonathan; Clarke, Robert; Gretarsdottir, Solveig; Thorleifsson, Gudmar; Mitchell, Braxton D.; Assimes, Themistocles L.; Levi, Christopher; O′Donnell, Christopher J.; Fornage, Myriam; Thorsteinsdottir, Unnur; Psaty, Bruce M.; Hengstenberg, Christian

    2014-01-01

    To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases. Genome-wide association data were obtained from ...

  5. Genetic Mapping in Human Disease

    OpenAIRE

    Altshuler, David; Daly, Mark J; Lander, Eric S.

    2008-01-01

    Genetic mapping provides a powerful approach to identify genes and biological processes underlying any trait influenced by inheritance, including human diseases. We discuss the intellectual foundations of genetic mapping of Mendelian and complex traits in humans, examine lessons emerging from linkage analysis of Mendelian diseases and genome-wide association studies of common diseases, and discuss questions and challenges that lie ahead.

  6. Analysis of genome-wide association studies of Alzheimer disease and of Parkinson disease to determine if these 2 diseases share a common genetic risk.

    Science.gov (United States)

    Moskvina, Valentina; Harold, Denise; Russo, GianCarlo; Vedernikov, Alexey; Sharma, Manu; Saad, Mohamed; Holmans, Peter; Bras, Jose M; Bettella, Francesco; Keller, Margaux F; Nicolaou, Nayia; Simón-Sánchez, Javier; Gibbs, J Raphael; Schulte, Claudia; Durr, Alexandra; Guerreiro, Rita; Hernandez, Dena; Brice, Alexis; Stefánsson, Hreinn; Majamaa, Kari; Gasser, Thomas; Heutink, Peter; Wood, Nick; Martinez, Maria; Singleton, Andrew B; Nalls, Michael A; Hardy, John; Owen, Michael J; O'Donovan, Michael C; Williams, Julie; Morris, Huw R; Williams, Nigel M

    2013-10-01

    Despite Alzheimer disease (AD) and Parkinson disease (PD) being clinically distinct entities, there is a possibility of a pathological overlap, with some genome-wide association (GWA) studies suggesting that the 2 diseases represent a biological continuum. The application of GWA studies to idiopathic forms of AD and PD have identified a number of loci that contain genetic variants that increase the risk of these disorders. To assess the genetic overlap between PD and AD by testing for the presence of potentially pleiotropic loci in 2 recent GWA studies of PD and AD. Combined GWA analysis. Data sets from the United Kingdom, Germany, France, and the United States. Thousands of patients with AD or PD and their controls. Meta-analysis of GWA studies of AD and PD. To identify evidence for potentially pleiotropic alleles that increased the risk for both PD and AD, we performed a combined PD-AD meta-analysis and compared the results with those obtained in the primary GWA studies.We also tested for a net effect of potentially polygenic alleles that were shared by both disorders by performing a polygenic score analysis. Finally, we also performed a gene-based association analysis that was aimed at detecting genes that harbor multiple disease-causing single-nucleotide polymorphisms, some of which confer a risk of PD and some a risk of AD. Detailed interrogation of the single-nucleotide polymorphism, polygenic, and gene-based analyses resulted in no significant evidence that supported the presence of loci that increase the risk of both PD and AD. Our findings therefore imply that loci that increase the risk of both PD and AD are not widespread and that the pathological overlap could instead be “downstream” of the primary susceptibility genes that increase the risk of each disease.

  7. Report: Genetics of complex diseases

    Institute of Scientific and Technical Information of China (English)

    MOTULSKY Arno G.

    2006-01-01

    Approaches to the study of the genetic basis of common complex diseases and their clinical applications are considered. Monogenic Mendelian inheritance in such conditions is infrequent but its elucidation may help to detect pathogenic mechanisms in the more common variety of complex diseases. Involvement by multiple genes in complex diseases usually occurs but the isolation and identification of specific genes so far has been exceptional. The role of common polymorphisms as indicators of disease risk in various studies is discussed.

  8. Genetics of Parkinson's disease.

    Science.gov (United States)

    Gasser, Thomas

    2005-08-01

    Parkinson's disease is the second most common neurodegenerative disorder and affects 2% of the population over the age of 60 years. Due to the increasing proportion of elderly individuals in developed countries, Parkinson's disease and related neurodegenerative disorders represent a growing burden on the health care system. In the majority of cases, the cause of the disease is still unknown, and its elucidation remains one of the major challenges of the neurosciences. Recent findings in rare genetic forms of Parkinson's disease have allowed the development of novel animal models, providing a basis for a better understanding of the molecular pathogenesis of the disease, setting the stage for the development of novel treatment strategies. Several novel genes for monogenic forms of Parkinson's disease, such as PINK-1 for an autosomal-recessive early-onset variant, and LRRK2 for a relatively common late-onset autosomal-dominant form have recently been discovered, and several novel animal models have been generated on the basis of genes that had been found earlier. The combination of genetic, pathologic and molecular findings provide increasing evidence that the pathways identified through the cloning of different disease genes are interacting on different levels and share several major pathogenic mechanisms.

  9. Bioenergetics in human evolution and disease: implications for the origins of biological complexity and the missing genetic variation of common diseases.

    Science.gov (United States)

    Wallace, Douglas C

    2013-07-19

    Two major inconsistencies exist in the current neo-Darwinian evolutionary theory that random chromosomal mutations acted on by natural selection generate new species. First, natural selection does not require the evolution of ever increasing complexity, yet this is the hallmark of biology. Second, human chromosomal DNA sequence variation is predominantly either neutral or deleterious and is insufficient to provide the variation required for speciation or for predilection to common diseases. Complexity is explained by the continuous flow of energy through the biosphere that drives the accumulation of nucleic acids and information. Information then encodes complex forms. In animals, energy flow is primarily mediated by mitochondria whose maternally inherited mitochondrial DNA (mtDNA) codes for key genes for energy metabolism. In mammals, the mtDNA has a very high mutation rate, but the deleterious mutations are removed by an ovarian selection system. Hence, new mutations that subtly alter energy metabolism are continuously introduced into the species, permitting adaptation to regional differences in energy environments. Therefore, the most phenotypically significant gene variants arise in the mtDNA, are regional, and permit animals to occupy peripheral energy environments where rarer nuclear DNA (nDNA) variants can accumulate, leading to speciation. The neutralist-selectionist debate is then a consequence of mammals having two different evolutionary strategies: a fast mtDNA strategy for intra-specific radiation and a slow nDNA strategy for speciation. Furthermore, the missing genetic variation for common human diseases is primarily mtDNA variation plus regional nDNA variants, both of which have been missed by large, inter-population association studies.

  10. Genetic Disease Foundation

    Science.gov (United States)

    ... mission to help prevent, manage and treat inherited genetic diseases. View our latest News Brief here . You can ... contributions to the diagnosis, prevention and treatment of genetic diseases. Learn how advances at Mount Sinai have impacted ...

  11. Urinary metabolites along with common and rare genetic variations are associated with incident chronic kidney disease.

    Science.gov (United States)

    McMahon, Gearoid M; Hwang, Shih-Jen; Clish, Clary B; Tin, Adrienne; Yang, Qiong; Larson, Martin G; Rhee, Eugene P; Li, Man; Levy, Daniel; O'Donnell, Christopher J; Coresh, Josef; Young, J Hunter; Gerszten, Robert E; Fox, Caroline S

    2017-06-01

    We assessed the association between urinary metabolites, genetic variants, and incident chronic kidney disease (CKD) in the Framingham Offspring cohort. Among the participants, 193 individuals developed CKD (estimated glomerular filtration rate under 60 ml/min/1.73m(2)) between cohort examinations 6 (1995-1998) and 8 (2005-2008, mean follow-up 9.7 years). They were age- and sex-matched to 193 control individuals free of CKD. A total of 154 urinary metabolites were measured using mass spectrometry, and the association between metabolites and CKD was examined using logistic regression. Next, we tested the genetic associations of each metabolite with an Illumina exome chip. Urinary glycine and histidine were associated with a lower risk of incident CKD with an odds ratio of 0.59 (95% confidence interval [CI] 0.43-0.80) and 0.65 (0.50-0.85) respectively, per one standard deviation increase in metabolite concentration. Follow-up in the Atherosclerosis Risk in Communities cohort confirmed the association of urinary glycine with CKD. In exome chip analyses, 36 single nucleotide polymorphisms at 30 loci were significantly associated with 31 metabolites. We surveyed exome chip findings for associations with known renal function loci such as rs8101881 in SLC7A9 coding for an amino acid transporter, which has been associated with a lower risk of CKD. We found this polymorphism was significantly associated with higher levels of lysine and NG-monomethyl-L-arginine (NMMA). Increased urinary lysine and NMMA were associated with a lower risk of CKD (0.73 [0.50-0.90] and 0.66 [0.53-0.83], respectively) in the univariate model. Thus, low urinary glycine and histidine are associated with incident CKD. Furthermore, genomic association of urinary metabolomics identified lysine and NMMA as being linked with CKD and provided additional evidence for the association of SLC7A9 with kidney disease. Copyright © 2017 International Society of Nephrology. All rights reserved.

  12. Systems genetics : From GWAS to disease pathways

    NARCIS (Netherlands)

    van der Sijde, Marijke R.; Ng, Aylwin; Fu, Jingyuan

    2014-01-01

    Most common diseases are complex, involving multiple genetic and environmental factors and their interactions. In the past decade, genome-wide association studies (GWAS) have successfully identified thousands of genetic variants underlying susceptibility to complex diseases. However, the results fro

  13. Developing a framework for implementation of genetic services: learning from examples of testing for monogenic forms of common diseases.

    Science.gov (United States)

    Rigter, Tessel; Henneman, Lidewij; Broerse, Jacqueline E W; Shepherd, Maggie; Blanco, Ignacio; Kristoffersson, Ulf; Cornel, Martina C

    2014-10-01

    Genetics in health care is shifting, and responsibilities of genetic and nongenetic specialists are changing, requiring new guidance on how to adapt health care to advances in genetic services. This paper explores facilitators and barriers in the process of implementation of innovations in genetic health care. Furthermore, lessons learnt for optimizing development of new genetic services are summarized. Barriers and facilitators in transition processes were identified using mixed methods, including an online open-ended questionnaire among professionals and an international expert meeting. A multi-case study approach was used to explore recent experiences with innovations in genetic services in different phases of implementation. Barriers encountered in transitions in genetic service provision include the following: lack of genetic knowledge and skills among nongenetic health care providers, resistance to new divisions of responsibilities, and a need for more close collaboration and communication between geneticists and nongeneticists. Facilitating factors include the following: statutory registration of genetic specialists, availability of essential staff and equipment, and existence of registries and guidelines. Other challenges are experienced in the establishment of the appropriate legal and financial structures. A set of points to consider for genetic innovation processes is proposed, addressing, e.g., transition management and cooperation and communication strategies.

  14. Genetics of Parkinson Disease

    Science.gov (United States)

    Pankratz, Nathan; Foroud, Tatiana

    2004-01-01

    Summary: Parkinson disease (PD) is the second most common neurodegenerative disorder. Recent studies have consistently demonstrated that in some families, disease is attributable to a mutation in a single gene. To date, genetic analyses have detected linkage to six chromosomal regions and have identified three causative genes: PARK1 (alpha-synuclein), PARK2 (parkin), and PARK7 (DJ-1). In addition, mutations in several other genes have been implicated in familial PD. Identification of the mutations in these genes has led to the recognition that the ubiquitin-proteasome system is an important pathway that may be disrupted in PD. Studies are ongoing to identify additional genes that may contribute to PD susceptibility, particularly in late-onset families without a clear pattern of disease inheritance. With the identification of mutations in particular genes and the likely role of additional genes that are important in PD risk-susceptibility, appropriate protocols must be developed so that accurate and informative genetic counseling can be offered to families in which one or more members has PD. Further diagnostic testing should be delayed until more is learned about the frequency, penetrance, and risk assessment of certain gene mutations. Important lessons can be learned from the implementation of counseling protocols for other neurodegenerative disorders, such as Huntington disease and Alzheimer disease. PMID:15717024

  15. Genetics of Parkinson disease.

    Science.gov (United States)

    Pankratz, Nathan; Foroud, Tatiana

    2004-04-01

    Parkinson disease (PD) is the second most common neurodegenerative disorder. Recent studies have consistently demonstrated that in some families, disease is attributable to a mutation in a single gene. To date, genetic analyses have detected linkage to six chromosomal regions and have identified three causative genes: PARK1 (alpha-synuclein), PARK2 (parkin), and PARK7 (DJ-1). In addition, mutations in several other genes have been implicated in familial PD. Identification of the mutations in these genes has led to the recognition that the ubiquitin-proteasome system is an important pathway that may be disrupted in PD. Studies are ongoing to identify additional genes that may contribute to PD susceptibility, particularly in late-onset families without a clear pattern of disease inheritance. With the identification of mutations in particular genes and the likely role of additional genes that are important in PD risk-susceptibility, appropriate protocols must be developed so that accurate and informative genetic counseling can be offered to families in which one or more members has PD. Further diagnostic testing should be delayed until more is learned about the frequency, penetrance, and risk assessment of certain gene mutations. Important lessons can be learned from the implementation of counseling protocols for other neurodegenerative disorders, such as Huntington disease and Alzheimer disease.

  16. Genetic determinants of common epilepsies

    DEFF Research Database (Denmark)

    2014-01-01

    and insufficient power. We aimed to identify risk loci through meta-analyses of genome-wide association studies for all epilepsy and the two largest clinical subtypes (genetic generalised epilepsy and focal epilepsy). METHODS: We combined genome-wide association data from 12 cohorts of individuals with epilepsy...... and controls from population-based datasets. Controls were ethnically matched with cases. We phenotyped individuals with epilepsy into categories of genetic generalised epilepsy, focal epilepsy, or unclassified epilepsy. After standardised filtering for quality control and imputation to account for different...... genotyping platforms across sites, investigators at each site conducted a linear mixed-model association analysis for each dataset. Combining summary statistics, we conducted fixed-effects meta-analyses of all epilepsy, focal epilepsy, and genetic generalised epilepsy. We set the genome-wide significance...

  17. Genetics and Genomics of Single-Gene Cardiovascular Diseases : Common Hereditary Cardiomyopathies as Prototypes of Single-Gene Disorders

    NARCIS (Netherlands)

    Marian, Ali J; van Rooij, Eva; Roberts, Robert

    2016-01-01

    This is the first of 2 review papers on genetics and genomics appearing as part of the series on "omics." Genomics pertains to all components of an organism's genes, whereas genetics involves analysis of a specific gene or genes in the context of heredity. The paper provides introductory comments,

  18. Genetics and Genomics of Single-Gene Cardiovascular Diseases : Common Hereditary Cardiomyopathies as Prototypes of Single-Gene Disorders

    NARCIS (Netherlands)

    Marian, Ali J.; van Rooij, Eva; Roberts, Robert

    2016-01-01

    This is the first of 2 review papers on genetics and genomics appearing as part of the series on “omics.” Genomics pertains to all components of an organism's genes, whereas genetics involves analysis of a specific gene or genes in the context of heredity. The paper provides introductory comments,

  19. Genetics of complex diseases

    DEFF Research Database (Denmark)

    Mellerup, Erling; Møller, Gert Lykke; Koefoed, Pernille

    2012-01-01

    A complex disease with an inheritable component is polygenic, meaning that several different changes in DNA are the genetic basis for the disease. Such a disease may also be genetically heterogeneous, meaning that independent changes in DNA, i.e. various genotypes, can be the genetic basis...... for the disease. Each of these genotypes may be characterized by specific combinations of key genetic changes. It is suggested that even if all key changes are found in genes related to the biology of a certain disease, the number of combinations may be so large that the number of different genotypes may be close...

  20. Genetics of Parkinson's disease

    National Research Council Canada - National Science Library

    Klein, Christine; Westenberger, Ana

    2012-01-01

    Fifteen years of genetic research in Parkinson's disease (PD) have led to the identification of several monogenic forms of the disorder and of numerous genetic risk factors increasing the risk to develop PD...

  1. Genetic diseases in adults.

    Science.gov (United States)

    Kolettis, Peter N

    2003-02-01

    Genetic diseases that do not primarily affect the genitourinary tract may have urologic manifestations. These urologic manifestations range from benign and malignant renal disease to infertility. Thus, the practicing urologist may be involved in the care of these patients and should have knowledge of these diseases. Continued improvements in the diagnosis and treatment of these genetic diseases will likely result in improved survival and will increase the number of patients who may develop urologic manifestations of these diseases.

  2. [The genetics of Parkinson disease].

    Science.gov (United States)

    Toft, Mathias; Aasly, Jan

    2004-04-01

    Parkinson's disease, PD, is the second most common neurodegenerative disorder. A genetic component in Parkinson's disease was long thought to be unlikely, but recent genetic studies have identified several genes associated with the disease. A review of the literature and personal experiences from genetic studies in central Norway are presented. Nine loci on the human genome have been linked to Parkinson's disease. Mutations in the alfa-synuclein, parkin, DJ-1, and arguably UCH-L1 genes are identified for familial PD. Recently a locus on chromosome 1 was linked to common late-onset PD in the Icelandic population. Iceland's population is primarily of Norse descent. This locus may be of significant importance to Norwegian PD patients. The genes and loci identified have improved our understanding of the pathogenesis in PD significantly. This knowledge may help to create new treatment strategies for PD.

  3. Parkinson's disease and genetics.

    Science.gov (United States)

    Lester, Jacobo; Otero-Siliceo, Enrique

    2006-09-01

    Idiopathic Parkinson disease (IPD) is a condition of unknown cause. Several factors are believed to contribute to its onset, and many studies have been conducted in search of the possible etiology of Parkinson disease. Genetic factors have become relevant when trying to explain the onset of Parkinson disease. The studies are divided into 2 categories: epidemiological and studies that analyze twins from families with members suffering from Parkinson disease, thus looking for the responsible genetic mutations. In this article we address this controversial topic, reviewing some of the most significant studies trying to provide evidence which relates genetics to Parkinson disease. We present current epidemiological studies and the most important genetic factors related to Parkinson disease, including the latest information currently available on each issue.

  4. Common genetic variants near the Brittle Cornea Syndrome locus ZNF469 influence the blinding disease risk factor central corneal thickness.

    Directory of Open Access Journals (Sweden)

    Yi Lu

    2010-05-01

    Full Text Available Central corneal thickness (CCT, one of the most highly heritable human traits (h(2 typically>0.9, is important for the diagnosis of glaucoma and a potential risk factor for glaucoma susceptibility. We conducted genome-wide association studies in five cohorts from Australia and the United Kingdom (total N = 5058. Three cohorts were based on individually genotyped twin collections, with the remaining two cohorts genotyped on pooled samples from singletons with extreme trait values. The pooled sample findings were validated by individual genotyping the pooled samples together with additional samples also within extreme quantiles. We describe methods for efficient combined analysis of the results from these different study designs. We have identified and replicated quantitative trait loci on chromosomes 13 and 16 for association with CCT. The locus on chromosome 13 (nearest gene FOXO1 had an overall meta-analysis p-value for all the individually genotyped samples of 4.6x10(-10. The locus on chromosome 16 was associated with CCT with p = 8.95x10(-11. The nearest gene to the associated chromosome 16 SNPs was ZNF469, a locus recently implicated in Brittle Cornea Syndrome (BCS, a very rare disorder characterized by abnormal thin corneas. Our findings suggest that in addition to rare variants in ZNF469 underlying CCT variation in BCS patients, more common variants near this gene may contribute to CCT variation in the general population.

  5. Common genetic variants near the Brittle Cornea Syndrome locus ZNF469 influence the blinding disease risk factor central corneal thickness.

    Directory of Open Access Journals (Sweden)

    Yi Lu

    2010-05-01

    Full Text Available Central corneal thickness (CCT, one of the most highly heritable human traits (h(2 typically>0.9, is important for the diagnosis of glaucoma and a potential risk factor for glaucoma susceptibility. We conducted genome-wide association studies in five cohorts from Australia and the United Kingdom (total N = 5058. Three cohorts were based on individually genotyped twin collections, with the remaining two cohorts genotyped on pooled samples from singletons with extreme trait values. The pooled sample findings were validated by individual genotyping the pooled samples together with additional samples also within extreme quantiles. We describe methods for efficient combined analysis of the results from these different study designs. We have identified and replicated quantitative trait loci on chromosomes 13 and 16 for association with CCT. The locus on chromosome 13 (nearest gene FOXO1 had an overall meta-analysis p-value for all the individually genotyped samples of 4.6x10(-10. The locus on chromosome 16 was associated with CCT with p = 8.95x10(-11. The nearest gene to the associated chromosome 16 SNPs was ZNF469, a locus recently implicated in Brittle Cornea Syndrome (BCS, a very rare disorder characterized by abnormal thin corneas. Our findings suggest that in addition to rare variants in ZNF469 underlying CCT variation in BCS patients, more common variants near this gene may contribute to CCT variation in the general population.

  6. Genetic Aspects of Alzheimer Disease

    Science.gov (United States)

    Williamson, Jennifer; Goldman, Jill; Marder, Karen S.

    2011-01-01

    Background Alzheimer disease (AD) is a genetically complex disorder. Mutations in 3 genes, presenilin 1, amyloid precursor protein, and presenilin 2, lead to early-onset familial AD in rare families with onset of disease occurring prior to age 65. Specific polymorphisms in apolipoprotein E are associated with the more common, late-onset AD occurring after age 65. In this review, we discuss current advances in AD genetics, the implications of the known AD genes, presenilin 1, presenilin 2, amyloid precursor protein, and apolipoprotein E, and other possible genes on the clinical diagnosis, treatment, and genetic counseling of patients and families with early- and late-onset AD. Review Summary In addition to the mutations in 4 known genes associated with AD, mutations in other genes may be implicated in the pathogenesis of the disease. Most recently, 2 different research groups have reported genetic association between 2 genes, sortilin-related receptor and GAB2, and AD. These associations have not changed the diagnostic and medical management of AD. Conclusions New research in the genetics of AD have implicated novel genes as having a role in the disease, but these findings have not been replicated nor have specific disease causing mutations been identified. To date, clinical genetic testing is limited to familial early-onset disease for symptomatic individuals and asymptomatic relatives and, although not recommended, amyloid precursor protein apolipoprotein E testing as an adjunct to diagnosis of symptomatic individuals. PMID:19276785

  7. Genetics Home Reference: Ollier disease

    Science.gov (United States)

    ... Information & Resources MedlinePlus (1 link) Health Topic: Bone Diseases Genetic and Rare Diseases Information Center (1 link) Ollier disease Educational Resources (5 links) Atlas of Genetics and Cytogenetics in Oncology and Haematology Disease InfoSearch: ...

  8. Common genetic variants influence human subcortical brain structures

    OpenAIRE

    Hibar, Derrek P.; Stein, Jason L.; Renteria, Miguel E.; Arias-Vasquez, Alejandro,; Desrivieres, Sylvane; Jahanshad, Neda; Toro, Roberto; Wittfeld, Katharina; Abramovic, Lucija; Andersson, Micael; Aribisala, Benjamin S.; Armstrong, Nicola J.; Bernard, Manon; Bohlken, Marc M.; Boks, Marco P

    2015-01-01

    The highly complex structure of the human brain is strongly shaped by genetic influences(1). Subcortical brain regions form circuits with cortical areas to coordinate movement(2), learning, memory(3) and motivation(4), and altered circuits can lead to abnormal behaviour and disease(5). To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume de...

  9. Genetics of gallstone disease.

    Directory of Open Access Journals (Sweden)

    Mittal B

    2002-04-01

    Full Text Available Gallstone disease is a complex disorder where both environmental and genetic factors contribute towards susceptibility to the disease. Epidemiological and family studies suggest a strong genetic component in the causation of this disease. Several genetically derived phenotypes in the population are responsible for variations in lipoprotein types, which in turn affect the amount of cholesterol available in the gall bladder. The genetic polymorphisms in various genes for apo E, apo B, apo A1, LDL receptor, cholesteryl ester transfer and LDL receptor-associated protein have been implicated in gallstone formation. However, presently available information on genetic differences is not able to account for a large number of gallstone patients. The molecular studies in the animal models have not only confirmed the present paradigm of gallstone formation but also helped in identification of novel genes in humans, which might play an important role in pathogenesis of the disease. Precise understanding of such genes and their molecular mechanisms may provide the basis of new targets for rational drug designs and dietary interventions.

  10. Genetics Home Reference: polycystic kidney disease

    Science.gov (United States)

    ... links) Genetic Testing Registry: Autosomal recessive polycystic kidney disease Genetic Testing Registry: Polycystic kidney disease 2 Genetic Testing Registry: Polycystic kidney disease 3 Genetic Testing ...

  11. Common genetic variants influence human subcortical brain structures

    NARCIS (Netherlands)

    Hibar, D.P.; Stein, J.L.; Renteria, M.E.; Arias Vasquez, A.; Desrivieres, S.; Jahanshad, N.; Toro, R.; Wittfeld, K.; Abramovic, L.; Andersson, M.; Aribisala, B.S.; Armstrong, N.J.; Bernard, M.; Bohlken, M.M.; Boks, M.P.; Bralten, J.; Brown, A.A.; Chakravarty, M.M.; Chen, Q.; Ching, C.R.; Cuellar-Partida, G.; Braber, A.; Giddaluru, S.; Goldman, A.L.; Grimm, O.; Guadalupe, T.; Hass, J.; Woldehawariat, G.; Holmes, A.J.; Hoogman, M.; Janowitz, D.; Jia, T.; Kim, S.; Klein, M.; Kraemer, B.; Lee, P.H.; Olde Loohuis, L.M.; Luciano, M.; Macare, C.; Mather, K.A.; Mattheisen, M.; Milaneschi, Y.; Nho, K.; Papmeyer, M.; Ramasamy, A.; Risacher, S.L.; Roiz-Santianez, R.; Rose, E.J.; Salami, A.; Samann, P.G.; Schmaal, L.; Schork, A.J.; Shin, J.; Strike, L.T.; Teumer, A.; Donkelaar, M.M.J. van; Eijk, K.R. van; Walters, R.K.; Westlye, L.T.; Whelan, C.D.; Winkler, A.M.; Zwiers, M.P.; Alhusaini, S.; Athanasiu, L.; Ehrlich, S.; Hakobjan, M.M.; Hartberg, C.B.; Haukvik, U.K.; Heister, A.J.; Hoehn, D.; Kasperaviciute, D.; Liewald, D.C.; Lopez, L.M.; Makkinje, R.R.; Matarin, M.; Naber, M.; McKay, D.R.; Needham, M.; Nugent, A.C.; Putz, B.; Royle, N.A.; Shen, L.; Sprooten, E.; Trabzuni, D.; Marel, S.S. van der; Hulzen, K.J.E. van; Walton, E.; Wolf, C.; Almasy, L.; Ames, D.; Arepalli, S.; Assareh, A.A.; Bastin, M.E.; Brodaty, H.; Bulayeva, K.B.; Carless, M.A.; Cichon, S.; Corvin, A.; Curran, J.E.; Czisch, M.; Fisher, S.E.

    2015-01-01

    The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common

  12. Genetics of celiac disease

    NARCIS (Netherlands)

    Ricano-Ponce, Isis; Wijmenga, Cisca; Gutierrez-Achury, Javier

    2015-01-01

    New insights into the underlying molecular pathophysiology of celiac disease (CeD) over the last few years have been guided by major advances in the fields of genetics and genomics. The development and use of the Immunochip genotyping platform paved the way for the discovery of 39 non-HLA loci assoc

  13. Genetics of Parkinson disease.

    Science.gov (United States)

    Pankratz, Nathan; Foroud, Tatiana

    2007-12-01

    During the past decade five genes have been identified that are important in autosomal dominant and autosomal recessive forms of Parkinson disease. The identification of these genes has increased our understanding of the likely pathogenic mechanisms resulting in disease. However, mutations in these genes likely contribute to disease in fewer than 5% of all cases of Parkinson disease. Thus, researchers have continued to search for genes that may influence disease susceptibility. Molecular diagnostic testing is currently available for four of the genes mutated in Parkinson disease. Evidence for reduced penetrance, possible effects of haploinsufficiency, and the identification of nondisease causing polymorphisms within several of these genes has made genetic counseling challenging. Current recommendations are to limit molecular testing only to those individuals who are symptomatic. Furthermore, because treatment is unaltered by the presence or absence of mutations in these genes, restraint is recommended when considering the value of screening for mutations in a clinical setting.

  14. The Association between Pediatric NAFLD and Common Genetic Variants

    Directory of Open Access Journals (Sweden)

    Giuseppina Rosaria Umano

    2017-06-01

    Full Text Available Non-alcoholic fatty liver disease (NAFLD is one of the most common complications of obesity. Several studies have shown that genetic predisposition probably plays an important role in its pathogenesis. In fact, in the last few years a large number of genetic studies have provided compelling evidence that some gene variants, especially those in genes encoding proteins regulating lipid metabolism, are associated with intra-hepatic fat accumulation. Here we provide a comprehensive review of the gene variants that have affected the natural history of the disease.

  15. Genetics of Proteasome Diseases

    Directory of Open Access Journals (Sweden)

    Aldrin V. Gomes

    2013-01-01

    Full Text Available The proteasome is a large, multiple subunit complex that is capable of degrading most intracellular proteins. Polymorphisms in proteasome subunits are associated with cardiovascular diseases, diabetes, neurological diseases, and cancer. One polymorphism in the proteasome gene PSMA6 (−8C/G is associated with three different diseases: type 2 diabetes, myocardial infarction, and coronary artery disease. One type of proteasome, the immunoproteasome, which contains inducible catalytic subunits, is adapted to generate peptides for antigen presentation. It has recently been shown that mutations and polymorphisms in the immunoproteasome catalytic subunit PSMB8 are associated with several inflammatory and autoinflammatory diseases including Nakajo-Nishimura syndrome, CANDLE syndrome, and intestinal M. tuberculosis infection. This comprehensive review describes the disease-related polymorphisms in proteasome genes associated with human diseases and the physiological modulation of proteasome function by these polymorphisms. Given the large number of subunits and the central importance of the proteasome in human physiology as well as the fast pace of detection of proteasome polymorphisms associated with human diseases, it is likely that other polymorphisms in proteasome genes associated with diseases will be detected in the near future. While disease-associated polymorphisms are now readily discovered, the challenge will be to use this genetic information for clinical benefit.

  16. Genetics, Disease Prevention and Treatment

    Science.gov (United States)

    ... the genetic terms used on this page Genetics, Disease Prevention and Treatment Overview How can learning about my family's health history help me prevent disease? How can I learn about my family's health ...

  17. Coeliac disease : investigation of the genetic factors underlying coeliac disease

    NARCIS (Netherlands)

    Belzen, M.J. (Martine Juliana) van

    2003-01-01

    Coeliac disease is a common food intolerance with a complex genetic aetiology. It is caused by ingestion of gluten peptides from wheat and related proteins from barley and rye in genetically susceptible individuals. The disease affects the small intestine and leads to abnormalities ranging from the

  18. Coeliac disease : investigation of the genetic factors underlying coeliac disease

    NARCIS (Netherlands)

    Belzen, M.J. (Martine Juliana) van

    2004-01-01

    Coeliac disease is a common food intolerance with a complex genetic aetiology. It is caused by ingestion of gluten peptides from wheat and related proteins from barley and rye in genetically susceptible individuals. The disease affects the small intestine and leads to abnormalities ranging from the

  19. A common genetic factor underlies hypertension and other cardiovascular disorders

    Directory of Open Access Journals (Sweden)

    Spector Tim D

    2004-11-01

    Full Text Available Abstract Background Certain conditions characterised by blood vessel occlusion or vascular spasm have been found to cluster together in epidemiological studies. However the biological causes for these associations remain controversial. This study used a classical twin design to examine whether these conditions are linked through shared environmental exposures or by a common underlying genetic propensity to vasospasm. Methods We investigated the association between hypertension, migraine, Raynaud's phenomenon and coronary artery disease in twins from a national register. Phenotype status was determined using a questionnaire and the genetic and environmental association between phenotypes was estimated through variance components analysis. Results Responses were obtained from 2,204 individuals comprising 525 monozygotic and 577 dizygotic pairs. There was a significant genetic contribution to all four traits with heritabilities ranging from 0.34 to 0.64. Multivariate model-fitting demonstrated that a single common genetic factor underlies the four conditions. Conclusions We have confirmed an association between hypertension, migraine, Raynaud's phenomenon and coronary artery disease, and shown that a single genetic factor underlies them. The demonstration of a shared genetic factor explains the association between them and adds weight to the theory of an inherited predisposition to vasospasm.

  20. Genetics Home Reference: Alzheimer disease

    Science.gov (United States)

    ... Me Understand Genetics Home Health Conditions Alzheimer disease Alzheimer disease Enable Javascript to view the expand/collapse boxes. Download PDF Open All Close All Description Alzheimer disease is a degenerative disease of the brain ...

  1. Genetics in psychiatry: common variant association studies

    Directory of Open Access Journals (Sweden)

    Buxbaum Joseph D

    2010-03-01

    Full Text Available Abstract Many psychiatric conditions and traits are associated with significant heritability. Genetic risk for psychiatric conditions encompass rare variants, identified due to major effect, as well as common variants, the latter analyzed by association analyses. We review guidelines for common variant association analyses, undertaking after assessing evidence of heritability. We highlight the importance of: suitably large sample sizes; an experimental design that controls for ancestry; careful data cleaning; correction for multiple testing; small P values for positive findings; assessment of effect size for positive findings; and, inclusion of an independent replication sample. We also note the importance of a critical discussion of any prior findings, biological follow-up where possible, and a means of accessing the raw data.

  2. How important are rare variants in common disease?

    Science.gov (United States)

    Saint Pierre, Aude; Génin, Emmanuelle

    2014-09-01

    Genome-wide association studies have uncovered hundreds of common genetic variants involved in complex diseases. However, for most complex diseases, these common genetic variants only marginally contribute to disease susceptibility. It is now argued that rare variants located in different genes could in fact play a more important role in disease susceptibility than common variants. These rare genetic variants were not captured by genome-wide association studies using single nucleotide polymorphism-chips but with the advent of next-generation sequencing technologies, they have become detectable. It is now possible to study their contribution to common disease by resequencing samples of cases and controls or by using new genotyping exome arrays that cover rare alleles. In this review, we address the question of the contribution of rare variants in common disease by taking the examples of different diseases for which some resequencing studies have already been performed, and by summarizing the results of simulation studies conducted so far to investigate the genetic architecture of complex traits in human. So far, empirical data have not allowed the exclusion of many models except the most extreme ones involving only a small number of rare variants with large effects contributing to complex disease. To unravel the genetic architecture of complex disease, case-control data will not be sufficient, and alternative study designs need to be proposed together with methodological developments.

  3. Genetics Home Reference: maple syrup urine disease

    Science.gov (United States)

    ... links) Genetic Testing Registry: Classical maple syrup urine disease Genetic Testing Registry: Intermediate maple syrup urine disease Genetic Testing Registry: Maple syrup urine disease Other Diagnosis ...

  4. Genetics of Inflammatory Bowel Diseases.

    Science.gov (United States)

    McGovern, Dermot P B; Kugathasan, Subra; Cho, Judy H

    2015-10-01

    In this review, we provide an update on genome-wide association studies (GWAS) in inflammatory bowel disease (IBD). In addition, we summarize progress in defining the functional consequences of associated alleles for coding and noncoding genetic variation. In the small minority of loci where major association signals correspond to nonsynonymous variation, we summarize studies defining their functional effects and implications for therapeutic targeting. Importantly, the large majority of GWAS-associated loci involve noncoding variation, many of which modulate levels of gene expression. Recent expression quantitative trait loci (eQTL) studies have established that the expression of most human genes is regulated by noncoding genetic variations. Significant advances in defining the epigenetic landscape have demonstrated that IBD GWAS signals are highly enriched within cell-specific active enhancer marks. Studies in European ancestry populations have dominated the landscape of IBD genetics studies, but increasingly, studies in Asian and African-American populations are being reported. Common variation accounts for only a modest fraction of the predicted heritability and the role of rare genetic variation of higher effects (ie, odds ratios markedly deviating from 1) is increasingly being identified through sequencing efforts. These sequencing studies have been particularly productive in more severe very early onset cases. A major challenge in IBD genetics will be harnessing the vast array of genetic discovery for clinical utility through emerging precision medical initiatives. In this article, we discuss the rapidly evolving area of direct-to-consumer genetic testing and the current utility of clinical exome sequencing, especially in very early onset, severe IBD cases. We summarize recent progress in the pharmacogenetics of IBD with respect to partitioning patient responses to anti-TNF and thiopurine therapies. Highly collaborative studies across research centers and

  5. Common errors in disease mapping

    Directory of Open Access Journals (Sweden)

    Ricardo Ocaña-Riola

    2010-05-01

    Full Text Available Many morbid-mortality atlases and small-area studies have been carried out over the last decade. However, the methods used to draw up such research, the interpretation of results and the conclusions published are often inaccurate. Often, the proliferation of this practice has led to inefficient decision-making, implementation of inappropriate health policies and negative impact on the advancement of scientific knowledge. This paper reviews the most frequent errors in the design, analysis and interpretation of small-area epidemiological studies and proposes a diagnostic evaluation test that should enable the scientific quality of published papers to be ascertained. Nine common mistakes in disease mapping methods are discussed. From this framework, and following the theory of diagnostic evaluation, a standardised test to evaluate the scientific quality of a small-area epidemiology study has been developed. Optimal quality is achieved with the maximum score (16 points, average with a score between 8 and 15 points, and low with a score of 7 or below. A systematic evaluation of scientific papers, together with an enhanced quality in future research, will contribute towards increased efficacy in epidemiological surveillance and in health planning based on the spatio-temporal analysis of ecological information.

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

    Science.gov (United States)

    ... July 20, 2014 Common gene variants account for most genetic risk for autism Roles of heritability, mutations, ... factors. Population-Based Autism Genetics and Environment Study Most of the genetic risk for autism comes from ...

  7. Stem cells and genetic diseases

    Directory of Open Access Journals (Sweden)

    Irshad S.

    2012-09-01

    Full Text Available In this review, we have discussed a role of stem cells in the treatment of genetic diseases including cochlear and retinal regeneration. The most perceptive use of stem cells at the genetic diseases is cellular repair of tissues affected by a genetic mutation when stem cells without such mutation are transplanted to restore normal tissue function.

  8. Genetics Home Reference: Crohn disease

    Science.gov (United States)

    ... Me Understand Genetics Home Health Conditions Crohn disease Crohn disease Enable Javascript to view the expand/collapse boxes. Download PDF Open All Close All Description Crohn disease is a complex, chronic disorder that primarily affects ...

  9. Genetics Home Reference: Parkinson disease

    Science.gov (United States)

    ... on Aging National Institutes of Neurological Disorders and Stroke: Parkinson's Disease Research Web Educational Resources (9 links) Centre for Genetics Education (Australia) Disease InfoSearch: Parkinson Disease MalaCards: lrrk2- ...

  10. Genetics Home Reference: moyamoya disease

    Science.gov (United States)

    ... as neurofibromatosis type 1 , sickle cell disease , or Graves disease . These individuals are said to have moyamoya syndrome. ... Achrol AS, Guzman R, Lee M, Steinberg GK. Pathophysiology and genetic factors in moyamoya disease. Neurosurg Focus. ...

  11. Genetic variants in periodontal health and disease

    Energy Technology Data Exchange (ETDEWEB)

    Dumitrescu, Alexandrina L. [Tromsoe Univ. (Norway). Inst. of Clinical Dentistry; Kobayashi, Junya [Kyoto Univ. (Japan). Dept. of Genome Repair Dynamics

    2010-07-01

    Periodontitis is a complex, multifactorial disease and its susceptibility is genetically determined. The present book systematically reviews the evidence of the association between the genetic variants and periodontitis progression and/or treatment outcomes. Genetic syndromes known to be associated with periodontal disease, the candidate gene polymorphisms investigated in relation to periodontitis, the heritability of chronic and aggressive periodontitis, as well as common guidelines for association studies are described. This growing understanding of the role of genetic variation in inflammation and periodontal chronic disease presents opportunities to identify healthy persons who are at increased risk of disease and to potentially modify the trajectory of disease to prolong healthy aging. The book represents a new concept in periodontology with its pronounced focus on understanding through knowledge rather than presenting the presently valid answers. Connections between genetics and periodontology are systematically reviewed and covered in detail. (orig.)

  12. Genetic epidemiology of Scheuermann's disease

    DEFF Research Database (Denmark)

    Damborg, Frank; Engell, Vilhelm; Nielsen, Jan

    2011-01-01

    The genetic/environmental etiology of Scheuermann's disease is unclear. We estimated the heritability of the disease using an etiological model adjusted for sex and time of diagnosis, and examined whether the prevalence of Scheuermann's disease was constant over time.......The genetic/environmental etiology of Scheuermann's disease is unclear. We estimated the heritability of the disease using an etiological model adjusted for sex and time of diagnosis, and examined whether the prevalence of Scheuermann's disease was constant over time....

  13. Genetics of Coronary Artery Disease

    DEFF Research Database (Denmark)

    McPherson, Ruth; Tybjærg-Hansen, Anne

    2016-01-01

    Genetic factors contribute importantly to the risk of coronary artery disease (CAD), and in the past decade, there has been major progress in this area. The tools applied include genome-wide association studies encompassing >200,000 individuals complemented by bioinformatic approaches, including...... factors and identify those individuals who will benefit most from statin therapy. Such information also has important applications in clinical medicine and drug discovery by using a Mendelian randomization approach to interrogate the causal nature of many factors found to associate with CAD risk...... have led to a broader understanding of the genetic architecture of CAD and demonstrate that it largely derives from the cumulative effect of multiple common risk alleles individually of small effect size rather than rare variants with large effects on CAD risk. Despite this success, there has been...

  14. Pediatric genetic diseases causing glaucoma

    Science.gov (United States)

    Ichhpujani, Parul; Singh, Rohan B.

    2014-01-01

    Glaucomatous optic neuropathy may be considered as an endpoint of multiple systemic factors. Genetic conditions commonly causing glaucoma in children and adolescents include Axenfeld-Reiger syndrome, aniridia, Marfan syndrome, Weill-Marchessani syndrome, Sturge-Weber syndrome, Rubinstein-Taybi syndrome, nevus of Ota, congenital rubella and neurofibromatosis type 1. In the recent years, with the advancements in genetic research our understanding of the fundamental causes of glaucoma associated with inherited disorders has improved. In addition to intraocular pressure reduction, it is important for the clinician to be familiar with the multiple systemic associations with glaucoma, to re-evaluate treatment frequently, and to target the underlying disease process, if present. PMID:27625878

  15. The role of common genetic variants in atrial fibrillation

    DEFF Research Database (Denmark)

    Paludan-Muller, Christian; Svendsen, Jesper H.; Olesen, Morten S.

    2016-01-01

    this approach. Highly penetrant variants in lone AF have also been described in a number of cases. Furthermore, familial AF, although rare, have been recognized for many years. Variants associated with AF have been identified in more than 40 genes, including cardiac gap junction proteins, ion channels and beta......This review focuses on the genetic basis of atrial fibrillation (AF) and the role of variants in the susceptibility of developing the disease. AF is the most common cardiac arrhythmia affecting 1-2% of the general population. Studies in the last decade have demonstrated that AF, and in particular...... and non-cardiac diseases....

  16. Identifying Common Genetic Risk Factors of Diabetic Neuropathies

    Science.gov (United States)

    Witzel, Ini-Isabée; Jelinek, Herbert F.; Khalaf, Kinda; Lee, Sungmun; Khandoker, Ahsan H.; Alsafar, Habiba

    2015-01-01

    Type 2 diabetes mellitus (T2DM) is a global public health problem of epidemic proportions, with 60–70% of affected individuals suffering from associated neurovascular complications that act on multiple organ systems. The most common and clinically significant neuropathies of T2DM include uremic neuropathy, peripheral neuropathy, and cardiac autonomic neuropathy. These conditions seriously impact an individual’s quality of life and significantly increase the risk of morbidity and mortality. Although advances in gene sequencing technologies have identified several genetic variants that may regulate the development and progression of T2DM, little is known about whether or not the variants are involved in disease progression and how these genetic variants are associated with diabetic neuropathy specifically. Significant missing heritability data and complex disease etiologies remain to be explained. This article is the first to provide a review of the genetic risk variants implicated in the diabetic neuropathies and to highlight potential commonalities. We thereby aim to contribute to the creation of a genetic-metabolic model that will help to elucidate the cause of diabetic neuropathies, evaluate a patient’s risk profile, and ultimately facilitate preventative and targeted treatment for the individual. PMID:26074879

  17. Pervasive Sharing of Genetic Effects in Autoimmune Disease

    NARCIS (Netherlands)

    Cotsapas, Chris; Voight, Benjamin F.; Rossin, Elizabeth; Lage, Kasper; Neale, Benjamin M.; Wallace, Chris; Abecasis, Goncalo R.; Barrett, Jeffrey C.; Behrens, Timothy; Cho, Judy; De Jager, Philip L.; Elder, James T.; Graham, Robert R.; Gregersen, Peter; Klareskog, Lars; Siminovitch, Katherine A.; van Heel, David A.; Wijmenga, Cisca; Worthington, Jane; Todd, John A.; Hafler, David A.; Rich, Stephen S.; Daly, Mark J.

    2011-01-01

    Genome-wide association (GWA) studies have identified numerous, replicable, genetic associations between common single nucleotide polymorphisms (SNPs) and risk of common autoimmune and inflammatory (immune-mediated) diseases, some of which are shared between two diseases. Along with epidemiological

  18. Genetic variants associated with Crohn's disease

    Directory of Open Access Journals (Sweden)

    Michail S

    2013-07-01

    Full Text Available Sonia Michail,1 Gilberto Bultron,1 R William DePaolo2 1The University of Southern California, Children's Hospital of Los Angeles, Los Angeles, CA, USA; 2Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Abstract: Crohn's disease is an immune-related disorder characterized by inflammation of the gastrointestinal mucosa, which can occur in any area throughout the digestive tract. This life-long disease commonly presents with abdominal pain, diarrhea, vomiting, and weight loss. While the exact etiology of this disease is largely unknown, it is thought to arise from an interaction between microbial, immunological, and environmental factors in a genetically susceptible host, whereby the immune system attacks the intestine as it cross reacts against gut microbial antigens. The study of genetic variants associated with Crohn's disease has shed light on our understanding of disease pathophysiology. A large number of genetic variants identified in Crohn's disease are related to genes targeting microbial recognition and bacterial wall sensing, the most common being NOD2/CARD15 gene. This review will discuss the recent advance in our knowledge of genetic variants of this disease and how they influence the disease course and prognosis. Keywords: Crohn's disease, genetics, autophagy

  19. Genetics Home Reference: Canavan disease

    Science.gov (United States)

    ... Information Page National Institute of Neurological Disorders and Stroke: Leukodystrophy Information Page Educational Resources (7 links) Center for Jewish Genetic Diseases, Mount Sinai School of Medicine Disease InfoSearch: ...

  20. Genetics Home Reference: Gaucher disease

    Science.gov (United States)

    ... Help Me Understand Genetics Home Health Conditions Gaucher disease Gaucher disease Enable Javascript to view the expand/collapse ... cerebroside lipidosis syndrome Gaucher splenomegaly Gaucher syndrome Gaucher's ... deficiency glucocerebrosidosis glucosyl cerebroside lipidosis ...

  1. Genetics of Parkinson's disease and parkinsonism.

    Science.gov (United States)

    Douglas, Michael R; Lewthwaite, Alistair J; Nicholl, David J

    2007-06-01

    The past 10 years has seen a shift in our etiological concepts of Parkinson's disease, moving from a nearly exclusively environmentally mediated disease towards a complex disorder with important genetic contributors. The identification of responsible mutations in certain genes, particularly alpha-synuclein, Parkin, PINK1, DJ-1 and LRRK2, has increased our understanding of the clinical and pathological changes underlying Parkinson's disease, with implications for patient diagnosis, management and future research. This review will outline the specific genetic advances, discuss their implications for clinical practice and hint at future directions for research into this common and disabling disease.

  2. Rabbit haemorrhagic disease virus 2 (RHDV2) outbreak in Azores: Disclosure of common genetic markers and phylogenetic segregation within the European strains.

    Science.gov (United States)

    Duarte, Margarida; Carvalho, Carina; Bernardo, Susana; Barros, Sílvia Vanessa; Benevides, Sandra; Flor, Lídia; Monteiro, Madalena; Marques, Isabel; Henriques, Margarida; Barros, Sílvia C; Fagulha, Teresa; Ramos, Fernanda; Luís, Tiago; Fevereiro, Miguel

    2015-10-01

    Rabbit haemorrhagic disease virus 2 (RHDV2) is widespread in several countries of Western Europe, but it has not been introduced to other continents. However, between late 2014 and early 2015, the presence of RHDV2 was confirmed outside of the European continent, in the Azores, initially in the islands of Graciosa, Flores, S. Jorge and Terceira. In this study we report the subsequent detection of RHDV2 in wild rabbits from the islands of Faial, St. Maria and S. Miguel, and display the necropsy and microscopic examination data obtained, which showed lesions similar to those induced by classical strains of RHDV, with severe affection of lungs and liver. We also disclose the result of a genetic investigation carried out with RHDV2 positive samples from wild rabbits found dead in the seven islands. Partial vp60 sequences were amplified from 27 tissue samples. Nucleotide analysis showed that the Azorean strains are closely related to each other, sharing a high genetic identity (>99.15%). None of the obtained sequences were identical to any RHDV2 sequence publically known, hampering a clue for the source of the outbreaks. However, Bayesian and maximum likelihood phylogenetic analyses disclosed that Azorean strains are more closely related to a few strains from Southern Portugal than with any others presently known. In the analysed region comprising the terminal 942 nucleotides of the vp60 gene, four new single nucleotide polymorphisms (SNP) were identified. Based on the present data, these four SNPs, which are unique in the strains from Azores, may constitute putative molecular geographic markers for Azorean RHDV2 strains, if they persist in the future. One of these variations is a non-synonymous substitution that involves the replacement of one amino acid in a hypervariable region of the capsid protein.

  3. Identifying genetics and genomics nursing competencies common among published recommendations.

    Science.gov (United States)

    Greco, Karen E; Salveson, Catherine

    2009-10-01

    The purpose of this article is to identify published recommendations for genetics and genomics competencies or curriculum for nurses in the United States and to summarize genetic and genomic nursing competencies based on common themes among these documents. A review of the literature between January 1998 and June 2008 was conducted. Efforts were also made to access the gray literature. Five consensus documents describing recommendations for genetics and genomics competencies for nurses meeting inclusion criteria were analyzed. Twelve genetics and genomics competencies were created based on common themes among the recommendations. These competencies include: demonstrate an understanding of basic genetic and genomic concepts, provide and explain genetic and genomic information, refer to appropriate genetics professionals and services, and identify the limits of one's own genetics and genomics expertise. The competencies represent fundamental genetics and genomics competencies for nurses on the basis of common themes among several consensus recommendations identified in the literature.

  4. Clinical feature and genetic characteristics in common mitochondrial diseases of children%儿童常见线粒体病的临床表现和遗传特征

    Institute of Scientific and Technical Information of China (English)

    方方

    2014-01-01

    线粒体病是儿童时期常见的遗传代谢性疾病之一,遗传方式复杂,既有孟德尔遗传,又有线粒体母系遗传.尽管临床表现多样,诊断困难,但随着分子生物学的进步,一些线粒体综合征的临床表现和遗传特征被逐步认识,现介绍几个儿童常见线粒体综合征临床表现和遗传特征.%Mitochondrial diseases is one of the common genetic metabolic diseases in children.The inheritance patterns are complex,both mendelian inheritance and mitochondrial maternal inheritance.Although the clinical feature is various and the diagnosis is difficult,but with the development of molecular biology,some clinical and genetic features in mitochondrial syndrome were gradually clear.This paper introduced the clinical feature and genetic characteristics in several common mitochondrial syndrome of children.

  5. Genetic testing in cardiovascular diseases.

    Science.gov (United States)

    Arndt, Anne-Karin; MacRae, Calum A

    2014-05-01

    The review is designed to outline the major developments in genetic testing in the cardiovascular arena in the past year or so. This is an exciting time in genetic testing as whole exome and whole genome approaches finally reach the clinic. These new approaches offer insight into disease causation in families in which this might previously have been inaccessible, and also bring a wide range of interpretative challenges. Among the most significant recent findings has been the extent of physiologic rare coding variation in the human genome. New disease genes have been identified through whole exome studies in neonatal arrhythmia, congenital heart disease and coronary artery disease that were simply inaccessible with other techniques. This has not only shed light on the challenges of genetic testing at this scale, but has also sharply defined the limits of prior gene-panel focused testing. As novel therapies targeting specific genetic subsets of disease become available, genetic testing will become a part of routine clinical care. The pace of change in sequencing technologies has begun to transform clinical medicine, and cardiovascular disease is no exception. The complexity of such studies emphasizes the importance of real-time communication between the genetics laboratory and genetically informed clinicians. New efforts in data and knowledge management will be central to the continued advancement of genetic testing.

  6. Genetics of autoimmune diseases: insights from population genetics.

    Science.gov (United States)

    Ramos, Paula S; Shedlock, Andrew M; Langefeld, Carl D

    2015-11-01

    Human genetic diversity is the result of population genetic forces. This genetic variation influences disease risk and contributes to health disparities. Autoimmune diseases (ADs) are a family of complex heterogeneous disorders with similar underlying mechanisms characterized by immune responses against self. Collectively, ADs are common, exhibit gender and ethnic disparities, and increasing incidence. As natural selection is an important influence on human genetic variation, and immune function genes are enriched for signals of positive selection, it is thought that the prevalence of AD risk alleles seen in different population is partially the result of differing selective pressures (for example, due to pathogens). With the advent of high-throughput technologies, new analytical methodologies and large-scale projects, evidence for the role of natural selection in contributing to the heritable component of ADs keeps growing. This review summarizes the genetic regions associated with susceptibility to different ADs and concomitant evidence for selection, including known agents of selection exerting selective pressure in these regions. Examples of specific adaptive variants with phenotypic effects are included as an evidence of natural selection increasing AD susceptibility. Many of the complexities of gene effects in different ADs can be explained by population genetics phenomena. Integrating AD susceptibility studies with population genetics to investigate how natural selection has contributed to genetic variation that influences disease risk will help to identify functional variants and elucidate biological mechanisms. As such, the study of population genetics in human population holds untapped potential for elucidating the genetic causes of human disease and more rapidly focusing to personalized medicine.

  7. Assessment of the clinical utility of adding common single nucleotide polymorphism genetic scores to classical risk factor algorithms in coronary heart disease risk prediction in UK men.

    Science.gov (United States)

    Beaney, Katherine E; Cooper, Jackie A; Drenos, Fotios; Humphries, Steve E

    2017-08-28

    Risk prediction algorithms for coronary heart disease (CHD) are recommended for clinical use. However, their predictive ability remains modest and the inclusion of genetic risk may improve their performance. QRISK2 was used to assess CHD risk using conventional risk factors (CRFs). The performance of a 19 single nucleotide polymorphism (SNP) gene score (GS) for CHD including variants identified by genome-wide association study and candidate gene studies (weighted using the results from the CARDIoGRAMplusC4D meta-analysis) was assessed using the second Northwick Park Heart Study (NPHSII) of 2775 healthy UK men (284 cases). To improve the GS, five SNPs with weak evidence of an association with CHD were removed and replaced with seven robustly associated SNPs - giving a 21-SNP GS. The weighted 19 SNP GS was associated with lipid traits (p<0.05) and CHD after adjustment for CRFs, (OR=1.31 per standard deviation, p=0.03). Addition of the 19 SNP GS to QRISK2 showed improved discrimination (area under the receiver operator characteristic curve 0.68 vs. 0.70 p=0.02), a positive net reclassification index (0.07, p=0.04) compared to QRISK2 alone and maintained good calibration (p=0.17). The 21-SNP GS was also associated with CHD after adjustment for CRFs (OR=1.39 per standard deviation, 1.42×10-3), but the combined QRISK2 plus GS score was poorly calibrated (p=0.03) and showed no improvement in discrimination (p=0.55) or reclassification (p=0.10) compared to QRISK2 alone. The 19-SNP GS is robustly associated with CHD and showed potential clinical utility in the UK population.

  8. Genetics and Common Disorders: Implications for Primary Care and Public Health Providers

    Energy Technology Data Exchange (ETDEWEB)

    McInerney, Joseph D.; Greendale, Karen; Peay, Holly L.

    2005-06-01

    We developed this program for primary care providers (PCPs) and public health professionals (PHPs) who are interested in increasing their understanding of the genetics of common chronic diseases and of the implications of genetics and genomics for their fields. The program differs from virtually all previous educational efforts in genetics for health professionals in that it focuses on the genetics of common chronic disease and on the broad principles that emerge when one views disease from the perspectives of variation and individuality, which are at the heart of thinking genetically. The CD-ROM introduces users to content that will improve their understanding of topics such as: • A framework for genetics and common disease; • Basic information on genetics, genomics, genetic medicine, and public health genetics, all in the context of common chronic disease; • The status of research on genetic contributions to specific common diseases, including a review of research methods; • Genetic/environmental interaction as the new “central dogma” of public health genetics; • The importance of taking and analyzing a family history; • The likely impact of potential gene discovery and genetic testing on genetic counseling and risk assessment and on the practices of PCPs and PHPs; • Stratification of populations into low-, moderate-, and high-risk categories; • The potential role of PCPs and PHPs in identifying high-risk individuals and families, in providing limited genetics services, and in referring to clinical genetics specialists; the potential for standard referral algorithms; • Implications of genetic insights for diagnosis and treatment; • Ethical, legal, and social issues that arise from genetic testing for common chronic diseases; and • Specific prevention strategies based on understanding of genetics and genetic/ environmental interactions. The interactive content – developed by experts in genetics, primary care, and public health – is

  9. Common genetic variants influence human subcortical brain structures.

    Science.gov (United States)

    Hibar, Derrek P; Stein, Jason L; Renteria, Miguel E; Arias-Vasquez, Alejandro; Desrivières, Sylvane; Jahanshad, Neda; Toro, Roberto; Wittfeld, Katharina; Abramovic, Lucija; Andersson, Micael; Aribisala, Benjamin S; Armstrong, Nicola J; Bernard, Manon; Bohlken, Marc M; Boks, Marco P; Bralten, Janita; Brown, Andrew A; Chakravarty, M Mallar; Chen, Qiang; Ching, Christopher R K; Cuellar-Partida, Gabriel; den Braber, Anouk; Giddaluru, Sudheer; Goldman, Aaron L; Grimm, Oliver; Guadalupe, Tulio; Hass, Johanna; Woldehawariat, Girma; Holmes, Avram J; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H; Olde Loohuis, Loes M; Luciano, Michelle; Macare, Christine; Mather, Karen A; Mattheisen, Manuel; Milaneschi, Yuri; Nho, Kwangsik; Papmeyer, Martina; Ramasamy, Adaikalavan; Risacher, Shannon L; Roiz-Santiañez, Roberto; Rose, Emma J; Salami, Alireza; Sämann, Philipp G; Schmaal, Lianne; Schork, Andrew J; Shin, Jean; Strike, Lachlan T; Teumer, Alexander; van Donkelaar, Marjolein M J; van Eijk, Kristel R; Walters, Raymond K; Westlye, Lars T; Whelan, Christopher D; Winkler, Anderson M; Zwiers, Marcel P; Alhusaini, Saud; Athanasiu, Lavinia; Ehrlich, Stefan; Hakobjan, Marina M H; Hartberg, Cecilie B; Haukvik, Unn K; Heister, Angelien J G A M; Hoehn, David; Kasperaviciute, Dalia; Liewald, David C M; Lopez, Lorna M; Makkinje, Remco R R; Matarin, Mar; Naber, Marlies A M; McKay, D Reese; Needham, Margaret; Nugent, Allison C; Pütz, Benno; Royle, Natalie A; Shen, Li; Sprooten, Emma; Trabzuni, Daniah; van der Marel, Saskia S L; van Hulzen, Kimm J E; Walton, Esther; Wolf, Christiane; Almasy, Laura; Ames, David; Arepalli, Sampath; Assareh, Amelia A; Bastin, Mark E; Brodaty, Henry; Bulayeva, Kazima B; Carless, Melanie A; Cichon, Sven; Corvin, Aiden; Curran, Joanne E; Czisch, Michael; de Zubicaray, Greig I; Dillman, Allissa; Duggirala, Ravi; Dyer, Thomas D; Erk, Susanne; Fedko, Iryna O; Ferrucci, Luigi; Foroud, Tatiana M; Fox, Peter T; Fukunaga, Masaki; Gibbs, J Raphael; Göring, Harald H H; Green, Robert C; Guelfi, Sebastian; Hansell, Narelle K; Hartman, Catharina A; Hegenscheid, Katrin; Heinz, Andreas; Hernandez, Dena G; Heslenfeld, Dirk J; Hoekstra, Pieter J; Holsboer, Florian; Homuth, Georg; Hottenga, Jouke-Jan; Ikeda, Masashi; Jack, Clifford R; Jenkinson, Mark; Johnson, Robert; Kanai, Ryota; Keil, Maria; Kent, Jack W; Kochunov, Peter; Kwok, John B; Lawrie, Stephen M; Liu, Xinmin; Longo, Dan L; McMahon, Katie L; Meisenzahl, Eva; Melle, Ingrid; Mohnke, Sebastian; Montgomery, Grant W; Mostert, Jeanette C; Mühleisen, Thomas W; Nalls, Michael A; Nichols, Thomas E; Nilsson, Lars G; Nöthen, Markus M; Ohi, Kazutaka; Olvera, Rene L; Perez-Iglesias, Rocio; Pike, G Bruce; Potkin, Steven G; Reinvang, Ivar; Reppermund, Simone; Rietschel, Marcella; Romanczuk-Seiferth, Nina; Rosen, Glenn D; Rujescu, Dan; Schnell, Knut; Schofield, Peter R; Smith, Colin; Steen, Vidar M; Sussmann, Jessika E; Thalamuthu, Anbupalam; Toga, Arthur W; Traynor, Bryan J; Troncoso, Juan; Turner, Jessica A; Valdés Hernández, Maria C; van 't Ent, Dennis; van der Brug, Marcel; van der Wee, Nic J A; van Tol, Marie-Jose; Veltman, Dick J; Wassink, Thomas H; Westman, Eric; Zielke, Ronald H; Zonderman, Alan B; Ashbrook, David G; Hager, Reinmar; Lu, Lu; McMahon, Francis J; Morris, Derek W; Williams, Robert W; Brunner, Han G; Buckner, Randy L; Buitelaar, Jan K; Cahn, Wiepke; Calhoun, Vince D; Cavalleri, Gianpiero L; Crespo-Facorro, Benedicto; Dale, Anders M; Davies, Gareth E; Delanty, Norman; Depondt, Chantal; Djurovic, Srdjan; Drevets, Wayne C; Espeseth, Thomas; Gollub, Randy L; Ho, Beng-Choon; Hoffmann, Wolfgang; Hosten, Norbert; Kahn, René S; Le Hellard, Stephanie; Meyer-Lindenberg, Andreas; Müller-Myhsok, Bertram; Nauck, Matthias; Nyberg, Lars; Pandolfo, Massimo; Penninx, Brenda W J H; Roffman, Joshua L; Sisodiya, Sanjay M; Smoller, Jordan W; van Bokhoven, Hans; van Haren, Neeltje E M; Völzke, Henry; Walter, Henrik; Weiner, Michael W; Wen, Wei; White, Tonya; Agartz, Ingrid; Andreassen, Ole A; Blangero, John; Boomsma, Dorret I; Brouwer, Rachel M; Cannon, Dara M; Cookson, Mark R; de Geus, Eco J C; Deary, Ian J; Donohoe, Gary; Fernández, Guillén; Fisher, Simon E; Francks, Clyde; Glahn, David C; Grabe, Hans J; Gruber, Oliver; Hardy, John; Hashimoto, Ryota; Hulshoff Pol, Hilleke E; Jönsson, Erik G; Kloszewska, Iwona; Lovestone, Simon; Mattay, Venkata S; Mecocci, Patrizia; McDonald, Colm; McIntosh, Andrew M; Ophoff, Roel A; Paus, Tomas; Pausova, Zdenka; Ryten, Mina; Sachdev, Perminder S; Saykin, Andrew J; Simmons, Andy

    2015-04-01

    The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

  10. Common genetic variants influence human subcortical brain structures

    Science.gov (United States)

    Hibar, Derrek P.; Stein, Jason L.; Renteria, Miguel E.; Arias-Vasquez, Alejandro; Desrivières, Sylvane; Jahanshad, Neda; Toro, Roberto; Wittfeld, Katharina; Abramovic, Lucija; Andersson, Micael; Aribisala, Benjamin S.; Armstrong, Nicola J.; Bernard, Manon; Bohlken, Marc M.; Boks, Marco P.; Bralten, Janita; Brown, Andrew A.; Chakravarty, M. Mallar; Chen, Qiang; Ching, Christopher R. K.; Cuellar-Partida, Gabriel; den Braber, Anouk; Giddaluru, Sudheer; Goldman, Aaron L.; Grimm, Oliver; Guadalupe, Tulio; Hass, Johanna; Woldehawariat, Girma; Holmes, Avram J.; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H.; Olde Loohuis, Loes M.; Luciano, Michelle; Macare, Christine; Mather, Karen A.; Mattheisen, Manuel; Milaneschi, Yuri; Nho, Kwangsik; Papmeyer, Martina; Ramasamy, Adaikalavan; Risacher, Shannon L.; Roiz-Santiañez, Roberto; Rose, Emma J.; Salami, Alireza; Sämann, Philipp G.; Schmaal, Lianne; Schork, Andrew J.; Shin, Jean; Strike, Lachlan T.; Teumer, Alexander; van Donkelaar, Marjolein M. J.; van Eijk, Kristel R.; Walters, Raymond K.; Westlye, Lars T.; Whelan, Christopher D.; Winkler, Anderson M.; Zwiers, Marcel P.; Alhusaini, Saud; Athanasiu, Lavinia; Ehrlich, Stefan; Hakobjan, Marina M. H.; Hartberg, Cecilie B.; Haukvik, Unn K.; Heister, Angelien J. G. A. M.; Hoehn, David; Kasperaviciute, Dalia; Liewald, David C. M.; Lopez, Lorna M.; Makkinje, Remco R. R.; Matarin, Mar; Naber, Marlies A. M.; McKay, D. Reese; Needham, Margaret; Nugent, Allison C.; Pütz, Benno; Royle, Natalie A.; Shen, Li; Sprooten, Emma; Trabzuni, Daniah; van der Marel, Saskia S. L.; van Hulzen, Kimm J. E.; Walton, Esther; Wolf, Christiane; Almasy, Laura; Ames, David; Arepalli, Sampath; Assareh, Amelia A.; Bastin, Mark E.; Brodaty, Henry; Bulayeva, Kazima B.; Carless, Melanie A.; Cichon, Sven; Corvin, Aiden; Curran, Joanne E.; Czisch, Michael; de Zubicaray, Greig I.; Dillman, Allissa; Duggirala, Ravi; Dyer, Thomas D.; Erk, Susanne; Fedko, Iryna O.; Ferrucci, Luigi; Foroud, Tatiana M.; Fox, Peter T.; Fukunaga, Masaki; Gibbs, J. Raphael; Göring, Harald H. H.; Green, Robert C.; Guelfi, Sebastian; Hansell, Narelle K.; Hartman, Catharina A.; Hegenscheid, Katrin; Heinz, Andreas; Hernandez, Dena G.; Heslenfeld, Dirk J.; Hoekstra, Pieter J.; Holsboer, Florian; Homuth, Georg; Hottenga, Jouke-Jan; Ikeda, Masashi; Jack, Clifford R.; Jenkinson, Mark; Johnson, Robert; Kanai, Ryota; Keil, Maria; Kent, Jack W.; Kochunov, Peter; Kwok, John B.; Lawrie, Stephen M.; Liu, Xinmin; Longo, Dan L.; McMahon, Katie L.; Meisenzahl, Eva; Melle, Ingrid; Mohnke, Sebastian; Montgomery, Grant W.; Mostert, Jeanette C.; Mühleisen, Thomas W.; Nalls, Michael A.; Nichols, Thomas E.; Nilsson, Lars G.; Nöthen, Markus M.; Ohi, Kazutaka; Olvera, Rene L.; Perez-Iglesias, Rocio; Pike, G. Bruce; Potkin, Steven G.; Reinvang, Ivar; Reppermund, Simone; Rietschel, Marcella; Romanczuk-Seiferth, Nina; Rosen, Glenn D.; Rujescu, Dan; Schnell, Knut; Schofield, Peter R.; Smith, Colin; Steen, Vidar M.; Sussmann, Jessika E.; Thalamuthu, Anbupalam; Toga, Arthur W.; Traynor, Bryan J.; Troncoso, Juan; Turner, Jessica A.; Valdés Hernández, Maria C.; van ’t Ent, Dennis; van der Brug, Marcel; van der Wee, Nic J. A.; van Tol, Marie-Jose; Veltman, Dick J.; Wassink, Thomas H.; Westman, Eric; Zielke, Ronald H.; Zonderman, Alan B.; Ashbrook, David G.; Hager, Reinmar; Lu, Lu; McMahon, Francis J.; Morris, Derek W.; Williams, Robert W.; Brunner, Han G.; Buckner, Randy L.; Buitelaar, Jan K.; Cahn, Wiepke; Calhoun, Vince D.; Cavalleri, Gianpiero L.; Crespo-Facorro, Benedicto; Dale, Anders M.; Davies, Gareth E.; Delanty, Norman; Depondt, Chantal; Djurovic, Srdjan; Drevets, Wayne C.; Espeseth, Thomas; Gollub, Randy L.; Ho, Beng-Choon; Hoffmann, Wolfgang; Hosten, Norbert; Kahn, René S.; Le Hellard, Stephanie; Meyer-Lindenberg, Andreas; Müller-Myhsok, Bertram; Nauck, Matthias; Nyberg, Lars; Pandolfo, Massimo; Penninx, Brenda W. J. H.; Roffman, Joshua L.; Sisodiya, Sanjay M.; Smoller, Jordan W.; van Bokhoven, Hans; van Haren, Neeltje E. M.; Völzke, Henry; Walter, Henrik; Weiner, Michael W.; Wen, Wei; White, Tonya; Agartz, Ingrid; Andreassen, Ole A.; Blangero, John; Boomsma, Dorret I.; Brouwer, Rachel M.; Cannon, Dara M.; Cookson, Mark R.; de Geus, Eco J. C.; Deary, Ian J.; Donohoe, Gary; Fernández, Guillén; Fisher, Simon E.; Francks, Clyde; Glahn, David C.; Grabe, Hans J.; Gruber, Oliver; Hardy, John; Hashimoto, Ryota; Hulshoff Pol, Hilleke E.; Jönsson, Erik G.; Kloszewska, Iwona; Lovestone, Simon; Mattay, Venkata S.; Mecocci, Patrizia; McDonald, Colm; McIntosh, Andrew M.; Ophoff, Roel A.; Paus, Tomas; Pausova, Zdenka; Ryten, Mina; Sachdev, Perminder S.; Saykin, Andrew J.; Simmons, Andy; Singleton, Andrew; Soininen, Hilkka; Wardlaw, Joanna M.; Weale, Michael E.; Weinberger, Daniel R.; Adams, Hieab H. H.; Launer, Lenore J.; Seiler, Stephan; Schmidt, Reinhold; Chauhan, Ganesh; Satizabal, Claudia L.; Becker, James T.; Yanek, Lisa; van der Lee, Sven J.; Ebling, Maritza; Fischl, Bruce; Longstreth, W. T.; Greve, Douglas; Schmidt, Helena; Nyquist, Paul; Vinke, Louis N.; van Duijn, Cornelia M.; Xue, Luting; Mazoyer, Bernard; Bis, Joshua C.; Gudnason, Vilmundur; Seshadri, Sudha; Ikram, M. Arfan; Martin, Nicholas G.; Wright, Margaret J.; Schumann, Gunter; Franke, Barbara; Thompson, Paul M.; Medland, Sarah E.

    2015-01-01

    The highly complex structure of the human brain is strongly shaped by genetic influences1. Subcortical brain regions form circuits with cortical areas to coordinate movement2, learning, memory3 and motivation4, and altered circuits can lead to abnormal behaviour and disease2. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume5 and intracranial volume6. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10−33; 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability inhuman brain development, and may help to determine mechanisms of neuropsychiatric dysfunction. PMID:25607358

  11. Genetics Home Reference: Graves disease

    Science.gov (United States)

    ... Most of the genetic variations that have been discovered are thought to have a small impact on ... Treatment Options MedlinePlus Encyclopedia: TSI National Institute of Diabetes and Digestive and Kidney Diseases: Thyroid Function Tests ...

  12. Common mechanisms of autoimmune diseases (the autoimmune tautology).

    Science.gov (United States)

    Anaya, Juan-Manuel

    2012-09-01

    The fact that autoimmune diseases share subphenotypes, physiopathological mechanisms and genetic factors has been called autoimmune tautology, and indicates that they have a common origin. The autoimmune phenotypes vary depending on the target cell and the affected organ, gender, ancestry, trigger factors and age at onset. Ten shared characteristics supporting this logical theory are herein reviewed.

  13. Quantitative genetics of disease traits.

    Science.gov (United States)

    Wray, N R; Visscher, P M

    2015-04-01

    John James authored two key papers on the theory of risk to relatives for binary disease traits and the relationship between parameters on the observed binary scale and an unobserved scale of liability (James Annals of Human Genetics, 1971; 35: 47; Reich, James and Morris Annals of Human Genetics, 1972; 36: 163). These two papers are John James' most cited papers (198 and 328 citations, November 2014). They have been influential in human genetics and have recently gained renewed popularity because of their relevance to the estimation of quantitative genetics parameters for disease traits using SNP data. In this review, we summarize the two early papers and put them into context. We show recent extensions of the theory for ascertained case-control data and review recent applications in human genetics.

  14. Common acquired kidney diseases in children

    African Journals Online (AJOL)

    5. Common acquired kidney diseases in children. Examination of the urine is probably the most ... rheumatic fever and APSGN should not ... remains unknown. ... Volume overload may also cause ..... systematic review of observational studies.

  15. [Genetics of congenital heart diseases].

    Science.gov (United States)

    Bonnet, Damien

    2017-06-01

    Developmental genetics of congenital heart diseases has evolved from analysis of serial slices in embryos towards molecular genetics of cardiac morphogenesis with a dynamic view of cardiac development. Genetics of congenital heart diseases has also changed from formal genetic analysis of familial recurrences or population-based analysis to screening for mutations in candidates genes identified in animal models. Close cooperation between molecular embryologists, pathologists involved in heart development and pediatric cardiologists is crucial for further increase of knowledge in the field of cardiac morphogenesis and genetics of cardiac defects. The genetic model for congenital heart disease has to be revised to favor a polygenic origin rather than a monogenic one. The main mechanism is altered genic dosage that can account for heart diseases in chromosomal anomalies as well as in point mutations in syndromic and isolated congenital heart diseases. The use of big data grouping information from cardiac development, interactions between genes and proteins, epigenetic factors such as chromatin remodeling or DNA methylation is the current source for improving our knowledge in the field and to give clues for future therapies. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  16. Unifying diseases from a genetic point of view: the example of the genetic theory of infectious diseases.

    Science.gov (United States)

    Darrason, Marie

    2013-08-01

    In the contemporary biomedical literature, every disease is considered genetic. This extension of the concept of genetic disease is usually interpreted either in a trivial or genocentrist sense, but it is never taken seriously as the expression of a genetic theory of disease. However, a group of French researchers defend the idea of a genetic theory of infectious diseases. By identifying four common genetic mechanisms (Mendelian predisposition to multiple infections, Mendelian predisposition to one infection, and major gene and polygenic predispositions), they attempt to unify infectious diseases from a genetic point of view. In this article, I analyze this explicit example of a genetic theory, which relies on mechanisms and is applied only to a specific category of diseases, what we call "a regional genetic theory." I have three aims: to prove that a genetic theory of disease can be devoid of genocentrism, to consider the possibility of a genetic theory applied to every disease, and to introduce two hypotheses about the form that such a genetic theory could take by distinguishing between a genetic theory of diseases and a genetic theory of Disease. Finally, I suggest that network medicine could be an interesting framework for a genetic theory of Disease.

  17. Genetics Home Reference: common variable immune deficiency

    Science.gov (United States)

    ... or Free article on PubMed Central Park JH, Resnick ES, Cunningham-Rundles C. Perspectives on common variable ... on PubMed or Free article on PubMed Central Resnick ES, Cunningham-Rundles C. The many faces of ...

  18. Lipedema: A Relatively Common Disease with Extremely Common Misconceptions

    Science.gov (United States)

    Herbst, Karen L.

    2016-01-01

    Lipedema, or adiposis dolorosa, is a common adipose tissue disorder that is believed to affect nearly 11% of adult women worldwide. It is characterized most commonly by disproportionate adipocyte hypertrophy of the lower extremities, significant tenderness to palpation, and a failure to respond to extreme weight loss modalities. Women with lipedema report a rapid growth of the lipedema subcutaneous adipose tissue in the setting of stress, surgery, and/or hormonal changes. Women with later stages of lipedema have a classic “column leg” appearance, with masses of nodular fat, easy bruising, and pain. Despite this relatively common disease, there are few physicians who are aware of it. As a result, patients are often misdiagnosed with lifestyle-induced obesity, and/or lymphedema, and subjected to unnecessary medical interventions and fat-shaming. Diagnosis is largely clinical and based on criteria initially established in 1951. Treatment of lipedema is effective and includes lymphatic support, such as complete decongestive therapy, and specialized suction lipectomy to spare injury to lymphatic channels and remove the diseased lipedema fat. With an incidence that may affect nearly 1 in 9 adult women, it is important to generate appropriate awareness, conduct additional research, and identify better diagnostic and treatment modalities for lipedema so these women can obtain the care that they need and deserve.

  19. Neurodegenerative diseases: a common etiology and a common therapy.

    Science.gov (United States)

    Pierpaoli, Walter

    2005-12-01

    The variety of names of neurodegenerative diseases (NDDs) does not indicate that there is a wide variety of causes and a multiple number of cures. In fact NDDs derive from a common and repetitive, almost monotonous multicausal origin. NDDs are initiated invariably by a sudden or silent insidious decrease in immunologic resistance of the T cell-dependent or delayed type, produced by a large variety of psychological-emotional and/or environmental "stressors" (e.g., social, family-domestic, economic, alimentary, traumatic, and professional). These stressors increase the vulnerability of tissues (in this case, a section of the central or peripheral nervous system) to attack by a common virus (e.g., adenoviruses and herpesviruses). This attack creates a vicious circle leading to emergence of virus-generated tissue autoantigens and then to formation of autoantibodies. Use of corticosteroids and immunosuppressive drugs dramatically worsen and "eternalize" the diseases with further immunosuppression. Invariably, onset of NDDs is anticipated by a clear-cut alteration of the hormonal cyclicity, which closely controls immunity. My experience with patients in the last five years indicates a new approach to prevent and cure NDDs, based on a system totally divergent from present therapies. In fact "resetting the hormonal cyclicity clock" results in restoration of hormone-dependent antiviral immunity, arrest of disease progression, and at least partial recovery of neural functions, whatever the origin, anatomic location, and course of pathology.

  20. Genetics Home Reference: juvenile Paget disease

    Science.gov (United States)

    ... Information & Resources MedlinePlus (1 link) Health Topic: Bone Diseases Genetic and Rare Diseases Information Center (1 link) Juvenile ... on PubMed Daroszewska A, Ralston SH. Mechanisms of disease: genetics of Paget's disease of bone and related disorders. ...

  1. Genetics Home Reference: Alexander disease

    Science.gov (United States)

    ... up study of 22 Chinese children with Alexander disease and analysis of parental origin of de novo GFAP mutations. J Hum Genet. 2013 Apr;58(4):183-8. doi: 10.1038/jhg.2012.152. Epub 2013 Jan 31. Citation on ... GS. Alexander disease: ventricular garlands and abnormalities of the medulla and ...

  2. Reflections on the Field of Human Genetics: A Call for Increased Disease Genetics Theory.

    Science.gov (United States)

    Schrodi, Steven J

    2016-01-01

    Development of human genetics theoretical models and the integration of those models with experiment and statistical evaluation are critical for scientific progress. This perspective argues that increased effort in disease genetics theory, complementing experimental, and statistical efforts, will escalate the unraveling of molecular etiologies of complex diseases. In particular, the development of new, realistic disease genetics models will help elucidate complex disease pathogenesis, and the predicted patterns in genetic data made by these models will enable the concurrent, more comprehensive statistical testing of multiple aspects of disease genetics predictions, thereby better identifying disease loci. By theoretical human genetics, I intend to encompass all investigations devoted to modeling the heritable architecture underlying disease traits and studies of the resulting principles and dynamics of such models. Hence, the scope of theoretical disease genetics work includes construction and analysis of models describing how disease-predisposing alleles (1) arise, (2) are transmitted across families and populations, and (3) interact with other risk and protective alleles across both the genome and environmental factors to produce disease states. Theoretical work improves insight into viable genetic models of diseases consistent with empirical results from linkage, transmission, and association studies as well as population genetics. Furthermore, understanding the patterns of genetic data expected under realistic disease models will enable more powerful approaches to discover disease-predisposing alleles and additional heritable factors important in common diseases. In spite of the pivotal role of disease genetics theory, such investigation is not particularly vibrant.

  3. Optimal screening for genetic diseases.

    Science.gov (United States)

    Nævdal, Eric

    2014-12-01

    Screening for genetic diseases is performed in many regions and/or ethnic groups where there is a high prevalence of possibly malign genes. The propagation of such genes can be considered a dynamic externality. Given that many of these diseases are untreatable and give rise to truly tragic outcomes, they are a source of societal concern, and the screening process should perhaps be regulated. This paper incorporates a standard model of genetic propagation into an economic model of dynamic management to derive cost benefit rules for optimal screening. The highly non-linear nature of genetic dynamics gives rise to perhaps surprising results that include discontinuous controls and threshold effects. One insight is that any screening program that is in place for any amount of time should screen all individuals in a target population. The incorporation of genetic models may prove to be useful to several emerging fields in economics such as genoeconomics, neuroeconomics and paleoeconomics.

  4. Genetic diversity and population structure of common bean ...

    African Journals Online (AJOL)

    fire7-

    2016-12-28

    Dec 28, 2016 ... markers to assess the genetic diversity within and between common bean landraces, classifying them based on ... since the 1980's from continuous introduction of new ... control genotypes for the Andean and Mesoamerican gene pools, ... http://biology.anu.edu.au/GenAlEx/) was used to calculate genetic.

  5. Genetic influences in caries and periodontal diseases.

    Science.gov (United States)

    Hassell, T M; Harris, E L

    1995-01-01

    Deciphering the relative roles of heredity and environmental factors ("nature vs. nurture") in the pathogenesis of dental caries and diseases of the periodontium has occupied clinical and basic researchers for decades. Success in the endeavor has come more easily in the case of caries; the complex interactions that occur between host-response mechanisms and putative microbiologic pathogens in periodontal disease have made elucidation of genetic factors in disease susceptibility more difficult. In addition, during the 30-year period between 1958 and 1987, only meager resources were targeted toward the "nature" side of the nature/nurture dipole in periodontology. In this article, we present a brief history of the development of genetic epistemology, then describe the three main research mechanisms by which questions about the hereditary component of diseases in humans can be addressed. A critical discussion of the evidence for a hereditary component in caries susceptibility is next presented, also from a historical perspective. The evolution of knowledge concerning possible genetic ("endogenous", "idiotypic") factors in the pathogenesis of inflammatory periodontal disease is initiated with an analysis of some foreign-language (primarily German) literature that is likely to be unfamiliar to the reader. We identify a turning point at about 1960, when the periodontal research community turned away from genetics in favor of microbiology research. During the past five years, investigators have re-initiated the search for the hereditary component in susceptibility to common adult periodontal disease; this small but growing body of literature is reviewed. Recent applications of in vitro methods for genetic analyses in periodontal research are presented, with an eye toward a future in which persons who are at risk--genetically predisposed--to periodontal disease may be identified and targeted for interventive strategies. Critical is the realization that genes and environment

  6. Genetics Home Reference: chylomicron retention disease

    Science.gov (United States)

    ... a rare condition with approximately 40 cases described worldwide. Related Information What information about a genetic condition can statistics provide? Why are some genetic conditions more common ...

  7. Periodontal disease: a genetic perspective

    Directory of Open Access Journals (Sweden)

    Mario Taba Jr

    2012-01-01

    Full Text Available Periodontitis is a multifactorial disease that causes tooth loss. The complex pathogenesis of periodontitis implies the involvement of a susceptible host and a bacterial challenge. Many studies have provided a valuable contribution to understanding the genetic basis of periodontal disease, but the specific candidate genes of susceptibility are still unknown. In fact, genome-wide studies and screening of single-nucleotide polymorphisms have yielded new genetic information without a definitive solution for the management of periodontal disease. In this manuscript, we provide an overview of the most relevant literature, presenting the main concepts and insights of the strategies that have been emerging to better diagnose and treat periodontal disease based on biomarker analysis and host modulation.

  8. Genetics of valvular heart disease.

    Science.gov (United States)

    LaHaye, Stephanie; Lincoln, Joy; Garg, Vidu

    2014-01-01

    Valvular heart disease is associated with significant morbidity and mortality and often the result of congenital malformations. However, the prevalence is increasing in adults not only because of the growing aging population, but also because of improvements in the medical and surgical care of children with congenital heart valve defects. The success of the Human Genome Project and major advances in genetic technologies, in combination with our increased understanding of heart valve development, has led to the discovery of numerous genetic contributors to heart valve disease. These have been uncovered using a variety of approaches including the examination of familial valve disease and genome-wide association studies to investigate sporadic cases. This review will discuss these findings and their implications in the treatment of valvular heart disease.

  9. Polymylagia rheumatica: common disease, elusive diagnosis.

    Science.gov (United States)

    Mager, Diana R

    2015-03-01

    Polymyalgia rheumatica (PMR) is a common inflammatory rheumatic disease with little known about its etiology or incidence. Frequently found in older adult women, this disease can be debilitating, painful, and dangerous. Diagnosing PMR can be elusive due to lack of specific laboratory tests, and treatment with use of long-term glucocorticoids can be difficult due to side effects. The following article describes the pathophysiology, diagnosis, signs and symptoms, and treatment of PMR, as well as implications for home healthcare.

  10. Genetic polymorphisms in Kawasaki disease

    Institute of Scientific and Technical Information of China (English)

    Ho-chang KUO; Wei-chiao CHANG

    2011-01-01

    Kawasaki disease (KD) is an acute febrile systemic vasculitis,and the cause of KD is not well understood.It is likely due to multiple interactions between genes and environmental factors.The development of genetic association and genome-wide association studies (GWAS) has opened an avenue to better understanding the molecular mechanisms underlying KD.A novel ITPKC signaling pathway was recently found to be responsible for the susceptibility to KD.Furthermore,the GWAS demonstrated the functionally related susceptibility loci for KD in the Caucasian population.In the last decade,the identification of several genomic regions linked to the pathogenesis of KD has made a major breakthrough in understanding the genetics of KD.This review will focus on genetic polymorphisms associated with KD and describe some of the possible clinical implications and molecular mechanisms that can be used to explain how genetic variants regulate the pathogenesis in KD.

  11. Genetic counseling in mitochondrial disease.

    Science.gov (United States)

    Vento, Jodie M; Pappa, Belen

    2013-04-01

    Mitochondrial diseases are a genetically and clinically diverse group of disorders that arise as a result of dysfunction of the mitochondria. Mitochondrial disorders can be caused by alterations in nuclear DNA and/or mitochondrial DNA. Although some mitochondrial syndromes have been described clearly in the literature many others present as challenging clinical cases with multisystemic involvement at variable ages of onset. Given the clinical variability and genetic heterogeneity of these conditions, patients and their families often experience a lengthy and complicated diagnostic process. The diagnostic journey may be characterized by heightened levels of uncertainty due to the delayed diagnosis and the absence of a clear prognosis, among other factors. Uncertainty surrounding issues of family planning and genetic testing may also affect the patient. The role of the genetic counselor is particularly important to help explain these complexities and support the patient and family's ability to achieve effective coping strategies in dealing with increased levels of uncertainty.

  12. Genetic predisposition to Parkinson's disease

    DEFF Research Database (Denmark)

    Halling, Jónrit; Petersen, Maria Skaalum; Grandjean, Philippe

    2008-01-01

    OBJECTIVE: To investigate whether the genetic variants of CYP2D6 and HFE are more frequent in Parkinson's disease (PD) patients compared with controls in a population where the prevalence of these variants and PD are increased. METHODS: Blood samples were collected from 79 PD patients and 154...

  13. Genetic predisposition to Parkinson's disease

    DEFF Research Database (Denmark)

    Halling, Jónrit; Petersen, Maria Skaalum; Grandjean, Philippe

    2008-01-01

    OBJECTIVE: To investigate whether the genetic variants of CYP2D6 and HFE are more frequent in Parkinson's disease (PD) patients compared with controls in a population where the prevalence of these variants and PD are increased. METHODS: Blood samples were collected from 79 PD patients and 154...

  14. Determination of common genetic variants within the non-structural proteins of foot-and-mouth disease viruses isolated in sub-Saharan Africa.

    Science.gov (United States)

    Nsamba, P; de Beer, T A P; Chitray, M; Scott, K; Vosloo, W; Maree, F F

    2015-05-15

    The non-structural proteins of foot-and-mouth disease virus (FMDV) are responsible for RNA replication, proteolytic processing of the viral polyprotein precursor, folding and assembly of the structural proteins and modification of the cellular translation apparatus. Investigation of the amino acid heterogeneity of the non-structural proteins of seventy-nine FMDV isolates of SAT1, SAT2, SAT3, A and O serotypes revealed between 29 and 62% amino acid variability. The Leader protease (L(pro)) and 3A proteins were the most variable whilst the RNA-dependent RNA polymerase (3D(pol)) the most conserved. Phylogeny based on the non-structural protein-coding regions showed separate clusters for southern African viruses for both the L(pro) and 3C protease (3C(pro)) and sequences unique to this group of viruses, e.g. in the 2C and 3C(pro) proteins. These groupings were unlike serotype groupings based on structural protein-coding regions. The amino acid substitutions and the nature of the naturally occurring substitutions provide insight into the functional domains and regions of the non-structural proteins that are critical for structure-function. The L(pro) of southern African SAT type isolates differed from A, O and SAT isolates in northern Africa, particularly in the auto-processing region. Three-dimensional structures of the 3C protease (3C(pro)) and 3D(pol) showed that the observed variation does not affect the enzymatic active sites or substrate binding sites. Variation in the 3C(pro) cleavage sites demonstrates broad substrate specificity.

  15. Genetic modifiers of Huntington's disease.

    Science.gov (United States)

    Gusella, James F; MacDonald, Marcy E; Lee, Jong-Min

    2014-09-15

    Huntington's disease (HD) is a devastating neurodegenerative disorder that directly affects more than 1 in 10,000 persons in Western societies but, as a family disorder with a long, costly, debilitating course, it has an indirect impact on a far greater proportion of the population. Although some palliative treatments are used, no effective treatment exists for preventing clinical onset of the disorder or for delaying its inevitable progression toward premature death, approximately 15 years after diagnosis. Huntington's disease involves a movement disorder characterized by chorea, as well as a variety of psychiatric disturbances and intellectual decline, with a gradual loss of independence. A dire need exists for effective HD therapies to alleviate the suffering and costs to the individual, family, and health care system. In past decades, genetics, the study of DNA sequence variation and its consequences, provided the tools to map the HD gene to chromosome 4 and ultimately to identify its mutation as an expanded CAG trinucleotide repeat in the coding sequence of a large protein, dubbed huntingtin. Now, advances in genetic technology offer an unbiased route to the identification of genetic factors that are disease-modifying agents in human patients. Such genetic modifiers are expected to highlight processes capable of altering the course of HD and therefore to provide new, human-validated targets for traditional drug development, with the goal of developing rational treatments to delay or prevent onset of HD clinical signs.

  16. The Link Between Lysosomal Storage Disorders and More Common Diseases

    Directory of Open Access Journals (Sweden)

    Michael Beck MD

    2016-12-01

    Full Text Available In the last decades, it has become more and more evident that lysosomal storage disorders and common neurodegenerative diseases such as Alzheimer and Parkinson diseases have clinical, neuropathological, and genetic features in common, including lysosomal dysfunction and impaired autophagy. Patients with Gaucher and even carriers of Gaucher disease have an increased risk to develop Parkinson disease. Likewise, individuals who are heterozygous for a mutation of a gene that causes an adult form of neuronal ceroid lipofuscinosis are more likely to be affected by a form of frontotemporal dementia in their later life. A further example is the gene NAGLU encoding the enzyme α- N -acetylglucosaminidase, which is deficient in patients with mucopolysaccharidosis type IIIB. Mutations of the NAGLU gene have been observed in patients affected by an axonal neuropathy. An interesting unexpected finding was the link between stuttering and genes that are essential for the function of all lysosomal enzymes. This review will present some example of the association of lysosomal storage disorders and neurodegenerative disease and discuss possible pathogenic mechanisms that are common to both conditions. The understanding of the pathophysiology of the endosomal–lysosomal–autophagic system may help to develop drugs, which might provide benefit not only for patients with rare lysosomal storage disorders but also for individuals affected by more common diseases.

  17. The Link Between Lysosomal Storage Disorders and More Common Diseases

    Directory of Open Access Journals (Sweden)

    Michael Beck MD

    2016-12-01

    Full Text Available In the last decades, it has become more and more evident that lysosomal storage disorders and common neurodegenerative diseases such as Alzheimer and Parkinson diseases have clinical, neuropathological, and genetic features in common, including lysosomal dysfunction and impaired autophagy. Patients with Gaucher and even carriers of Gaucher disease have an increased risk to develop Parkinson disease. Likewise, individuals who are heterozygous for a mutation of a gene that causes an adult form of neuronal ceroid lipofuscinosis are more likely to be affected by a form of frontotemporal dementia in their later life. A further example is the gene NAGLU encoding the enzyme α-N-acetylglucosaminidase, which is deficient in patients with mucopolysaccharidosis type IIIB. Mutations of the NAGLU gene have been observed in patients affected by an axonal neuropathy. An interesting unexpected finding was the link between stuttering and genes that are essential for the function of all lysosomal enzymes. This review will present some example of the association of lysosomal storage disorders and neurodegenerative disease and discuss possible pathogenic mechanisms that are common to both conditions. The understanding of the pathophysiology of the endosomal–lysosomal–autophagic system may help to develop drugs, which might provide benefit not only for patients with rare lysosomal storage disorders but also for individuals affected by more common diseases.

  18. Nonmotor symptoms in genetic Parkinson disease

    DEFF Research Database (Denmark)

    Kasten, Meike; Kertelge, Lena; Brüggemann, Norbert

    2010-01-01

    To review current knowledge on nonmotor symptoms (NMS), particularly psychiatric features, in genetic Parkinson disease (PD) and to provide original data for genetic and idiopathic PD.......To review current knowledge on nonmotor symptoms (NMS), particularly psychiatric features, in genetic Parkinson disease (PD) and to provide original data for genetic and idiopathic PD....

  19. Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD.

    Science.gov (United States)

    Sun, Wei; Kechris, Katerina; Jacobson, Sean; Drummond, M Bradley; Hawkins, Gregory A; Yang, Jenny; Chen, Ting-Huei; Quibrera, Pedro Miguel; Anderson, Wayne; Barr, R Graham; Basta, Patricia V; Bleecker, Eugene R; Beaty, Terri; Casaburi, Richard; Castaldi, Peter; Cho, Michael H; Comellas, Alejandro; Crapo, James D; Criner, Gerard; Demeo, Dawn; Christenson, Stephanie A; Couper, David J; Curtis, Jeffrey L; Doerschuk, Claire M; Freeman, Christine M; Gouskova, Natalia A; Han, MeiLan K; Hanania, Nicola A; Hansel, Nadia N; Hersh, Craig P; Hoffman, Eric A; Kaner, Robert J; Kanner, Richard E; Kleerup, Eric C; Lutz, Sharon; Martinez, Fernando J; Meyers, Deborah A; Peters, Stephen P; Regan, Elizabeth A; Rennard, Stephen I; Scholand, Mary Beth; Silverman, Edwin K; Woodruff, Prescott G; O'Neal, Wanda K; Bowler, Russell P

    2016-08-01

    Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p 10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10-392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the

  20. Are there common genetic and environmental factors behind the endophenotypes associated with the metabolic syndrome?

    DEFF Research Database (Denmark)

    Benyamin, B.; Sørensen, T.I.A.; Schousboe, K.

    2007-01-01

    AIMS/HYPOTHESIS: The cluster of obesity, insulin resistance, dyslipidaemia and hypertension, called the metabolic syndrome, has been suggested as a risk factor for cardiovascular disease and type 2 diabetes. The aim of the present study was to evaluate whether there are common genetic...... and environmental factors influencing this cluster in a general population of twin pairs. MATERIALS AND METHODS: A multivariate genetic analysis was performed on nine endophenotypes associated with the metabolic syndrome from 625 adult twin pairs of the GEMINAKAR study of the Danish Twin Registry. RESULTS: All......, the endophenotypes associated with the metabolic syndrome apparently do not share a substantial common genetic or familial environmental background....

  1. Advances in the genetics of eye diseases.

    Science.gov (United States)

    Chan, Stephanie; Freund, Paul R; MacDonald, Ian

    2013-12-01

    An update on heritable eye disease will allow informed patient counseling and improved patient care. New loci and genes have been associated with identifiable heritable ocular traits. Molecular genetic analysis is available for many of these genes either as part of research or for clinical testing. The advent of gene array technologies has enabled screening of samples for known mutations in genes linked to various disorders. Exomic sequencing has proven to be particularly successful in research protocols in identifying the genetic causation of rare genetic traits by pooling patient resources and discovering new genes. Further, genetic analysis has led improvement in patient care and counselling, as exemplified by the continued advances in our treatment of retinoblastoma. Patients and families are commonly eager to participate in either research or clinical testing to improve their understanding of the cause and heritability of an ocular condition. Many patients hope that testing will then lead to appropriate treatments or cures. The success of gene therapy in the RPE65 form of Leber congenital amaurosis has provided a brilliant example of this hope; that a similar trial may become available to other patients and families burdened by genetic disease.

  2. Contribution of rare and common variants determine complex diseases-Hirschsprung disease as a model.

    Science.gov (United States)

    Alves, Maria M; Sribudiani, Yunia; Brouwer, Rutger W W; Amiel, Jeanne; Antiñolo, Guillermo; Borrego, Salud; Ceccherini, Isabella; Chakravarti, Aravinda; Fernández, Raquel M; Garcia-Barcelo, Maria-Mercè; Griseri, Paola; Lyonnet, Stanislas; Tam, Paul K; van Ijcken, Wilfred F J; Eggen, Bart J L; te Meerman, Gerard J; Hofstra, Robert M W

    2013-10-01

    Finding genes for complex diseases has been the goal of many genetic studies. Most of these studies have been successful by searching for genes and mutations in rare familial cases, by screening candidate genes and by performing genome wide association studies. However, only a small fraction of the total genetic risk for these complex genetic diseases can be explained by the identified mutations and associated genetic loci. In this review we focus on Hirschsprung disease (HSCR) as an example of a complex genetic disorder. We describe the genes identified in this congenital malformation and postulate that both common 'low penetrant' variants in combination with rare or private 'high penetrant' variants determine the risk on HSCR, and likely, on other complex diseases. We also discuss how new technological advances can be used to gain further insights in the genetic background of complex diseases. Finally, we outline a few steps to develop functional assays in order to determine the involvement of these variants in disease development.

  3. Common diseases as determinants of menopausal age.

    Science.gov (United States)

    Li, Jingmei; Eriksson, Mikael; Czene, Kamila; Hall, Per; Rodriguez-Wallberg, Kenny A

    2016-12-01

    Can the diagnosis of common diseases before menopause influence age at natural menopause (ANM) onset? Polycystic ovary syndrome (PCOS) and depression were observed to delay menopause. It has been observed that women who undergo early menopause experience a higher burden of health problems related to metabolic syndromes, heart disease and depression, but whether ANM can be influenced by common adult diseases has not been studied extensively. All women attending mammography screening or clinical mammography at four hospitals in Sweden were invited to participate in the Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA) study. Between January 2011 and March 2013, 70 877 women were recruited. Information from the baseline questionnaire filled out upon enrollment was used in this cross-sectional analysis on predictors of ANM onset. We limited our analyses to 61 936 women with complete data on ANM and covariates and a follow-up time (from birth to menopause or censoring) of at least 35 years. Premenopausal diagnoses of depression, anorexia, bulimia, PCOS, ovarian cyst, heart failure, myocardial infarction, angina pectoris, stroke, preeclampsia, diabetes, hypertension and hyperlipidemia were examined as time-dependent variables in multivariable Cox regression analyses, adjusting for reproductive factors (age at menarche, menstrual cycle regularity in adult life, number of children and premenopausal oral contraceptive use) and risk factors of common diseases (education, physical activity at 18 years and information at the time of questionnaire including BMI, ever smoking and alcohol consumption). Women with PCOS and depression were independently associated with later menopause (hazard ratio (95% CI): 0.44 (0.28-0.71) and 0.95 (0.91-1.00), respectively), compared to women with no such histories. The associations remained significant in a subset of women who had never received gynecological surgery or hormone treatment (n = 32313, 0.21 (0

  4. Worldwide genetic differentiation in the common fouling barnacle, Amphibalanus amphitrite

    KAUST Repository

    Chen, Hsi-Nien

    2014-10-21

    © 2014, © 2014 Taylor & Francis. Amphibalanus amphitrite is a common fouling barnacle distributed globally in tropical and subtropical waters. In the present study, the genetic (mitochondrial cytochrome oxidase subunit I) and morphological differentiation in A. amphitrite from 25 localities around the world were investigated. The results revealed three clades within A. amphitrite with a genetic divergence of ~ 4% among clades, whereas there were no diagnostic morphological differences among clades. Clade 1 is widely distributed in both temperate and tropical waters, whereas Clade 3 is currently restricted to the tropical region. The deep divergence among clades suggests historical isolation within A. amphitrite; thus, the present geographical overlaps are possibly a result of the combined effects of rising sea level and human-mediated dispersals. This study highlights the genetic differentiation that exists in a common, widely distributed fouling organism with great dispersal potential; future antifouling research should take into account the choice of lineages.

  5. The genetic diversity and population structure of common bean ...

    African Journals Online (AJOL)

    SAM

    2014-07-16

    Jul 16, 2014 ... variation and, hence, restricting the amount of adapted genetic diversity ... the phenotypic diversity of common bean in Uganda. The selection ... The place of collection/origin was also consi- dered in ..... Bean Research and Development Programs at NaCRRI and CIAT .... Evolution 92:1101-1104. Kami JA ...

  6. Evidence of Common Genetic Overlap Between Schizophrenia and Cognition.

    Science.gov (United States)

    Hubbard, Leon; Tansey, Katherine E; Rai, Dheeraj; Jones, Peter; Ripke, Stephan; Chambert, Kimberly D; Moran, Jennifer L; McCarroll, Steven A; Linden, David E J; Owen, Michael J; O'Donovan, Michael C; Walters, James T R; Zammit, Stanley

    2016-05-01

    Cognitive impairment is a core feature of schizophrenia but there is limited understanding of the genetic relationship between cognition in the general population and schizophrenia. We examine how common variants associated with schizophreniaen massecontribute to childhood cognitive ability in a population-based sample, and the extent to which common genetic variants associated with childhood cognition explain variation in schizophrenia. Schizophrenia polygenic risk scores were derived from the Psychiatric Genomics Consortium (n= 69 516) and tested for association with IQ, attention, processing speed, working memory, problem solving, and social cognition in over 5000 children aged 8 from the Avon Longitudinal Study of Parents and Children birth cohort. Polygenic scores for these cognitive domains were tested for association with schizophrenia in a large UK schizophrenia sample (n= 11 853). Bivariate genome-wide complex trait analysis (GCTA) estimated the amount of shared genetic factors between schizophrenia and cognitive domains. Schizophrenia polygenic risk score was associated with lower performance IQ (P= .001) and lower full IQ (P= .013). Polygenic score for performance IQ was associated with increased risk for schizophrenia (P= 3.56E-04). Bivariate GCTA revealed moderate genetic correlation between schizophrenia and both performance IQ (rG= -.379,P= 6.62E-05) and full IQ (rG= -.202,P= 5.00E-03), with approximately 14% of the genetic component of schizophrenia shared with that for performance IQ. Our results support the presence of shared common genetic factors between schizophrenia and childhood cognitive ability. We observe a genetic relationship between schizophrenia and performance IQ but not verbal IQ or other cognitive variables, which may have implications for studies utilizing cognitive endophenotypes for psychosis.

  7. Genetic diversity analysis of common beans based on molecular markers.

    Science.gov (United States)

    Gill-Langarica, Homar R; Muruaga-Martínez, José S; Vargas-Vázquez, M L Patricia; Rosales-Serna, Rigoberto; Mayek-Pérez, Netzahualcoyotl

    2011-10-01

    A core collection of the common bean (Phaseolus vulgaris L.), representing genetic diversity in the entire Mexican holding, is kept at the INIFAP (Instituto Nacional de Investigaciones Forestales, Agricolas y Pecuarias, Mexico) Germplasm Bank. After evaluation, the genetic structure of this collection (200 accessions) was compared with that of landraces from the states of Oaxaca, Chiapas and Veracruz (10 genotypes from each), as well as a further 10 cultivars, by means of four amplified fragment length polymorphisms (AFLP) +3/+3 primer combinations and seven simple sequence repeats (SSR) loci, in order to define genetic diversity, variability and mutual relationships. Data underwent cluster (UPGMA) and molecular variance (AMOVA) analyses. AFLP analysis produced 530 bands (88.5% polymorphic) while SSR primers amplified 174 alleles, all polymorphic (8.2 alleles per locus). AFLP indicated that the highest genetic diversity was to be found in ten commercial-seed classes from two major groups of accessions from Central Mexico and Chiapas, which seems to be an important center of diversity in the south. A third group included genotypes from Nueva Granada, Mesoamerica, Jalisco and Durango races. Here, SSR analysis indicated a reduced number of shared haplotypes among accessions, whereas the highest genetic components of AMOVA variation were found within accessions. Genetic diversity observed in the common-bean core collection represents an important sample of the total Phaseolus genetic variability at the main Germplasm Bank of INIFAP. Molecular marker strategies could contribute to a better understanding of the genetic structure of the core collection as well as to its improvement and validation.

  8. Genetic diversity analysis of common beans based on molecular markers

    Directory of Open Access Journals (Sweden)

    Homar R. Gill-Langarica

    2011-01-01

    Full Text Available A core collection of the common bean (Phaseolus vulgaris L., representing genetic diversity in the entire Mexican holding, is kept at the INIFAP (Instituto Nacional de Investigaciones Forestales, Agricolas y Pecuarias, Mexico Germplasm Bank. After evaluation, the genetic structure of this collection (200 accessions was compared with that of landraces from the states of Oaxaca, Chiapas and Veracruz (10 genotypes from each, as well as a further 10 cultivars, by means of four amplified fragment length polymorphisms (AFLP +3/+3 primer combinations and seven simple sequence repeats (SSR loci, in order to define genetic diversity, variability and mutual relationships. Data underwent cluster (UPGMA and molecular variance (AMOVA analyses. AFLP analysis produced 530 bands (88.5% polymorphic while SSR primers amplified 174 alleles, all polymorphic (8.2 alleles per locus. AFLP indicated that the highest genetic diversity was to be found in ten commercial-seed classes from two major groups of accessions from Central Mexico and Chiapas, which seems to be an important center of diversity in the south. A third group included genotypes from Nueva Granada, Mesoamerica, Jalisco and Durango races. Here, SSR analysis indicated a reduced number of shared haplotypes among accessions, whereas the highest genetic components of AMOVA variation were found within accessions. Genetic diversity observed in the common-bean core collection represents an important sample of the total Phaseolus genetic variability at the main Germplasm Bank of INIFAP. Molecular marker strategies could contribute to a better understanding of the genetic structure of the core collection as well as to its improvement and validation.

  9. Genetic diversity analysis of common beans based on molecular markers

    Science.gov (United States)

    Gill-Langarica, Homar R.; Muruaga-Martínez, José S.; Vargas-Vázquez, M.L. Patricia; Rosales-Serna, Rigoberto; Mayek-Pérez, Netzahualcoyotl

    2011-01-01

    A core collection of the common bean (Phaseolus vulgaris L.), representing genetic diversity in the entire Mexican holding, is kept at the INIFAP (Instituto Nacional de Investigaciones Forestales, Agricolas y Pecuarias, Mexico) Germplasm Bank. After evaluation, the genetic structure of this collection (200 accessions) was compared with that of landraces from the states of Oaxaca, Chiapas and Veracruz (10 genotypes from each), as well as a further 10 cultivars, by means of four amplified fragment length polymorphisms (AFLP) +3/+3 primer combinations and seven simple sequence repeats (SSR) loci, in order to define genetic diversity, variability and mutual relationships. Data underwent cluster (UPGMA) and molecular variance (AMOVA) analyses. AFLP analysis produced 530 bands (88.5% polymorphic) while SSR primers amplified 174 alleles, all polymorphic (8.2 alleles per locus). AFLP indicated that the highest genetic diversity was to be found in ten commercial-seed classes from two major groups of accessions from Central Mexico and Chiapas, which seems to be an important center of diversity in the south. A third group included genotypes from Nueva Granada, Mesoamerica, Jalisco and Durango races. Here, SSR analysis indicated a reduced number of shared haplotypes among accessions, whereas the highest genetic components of AMOVA variation were found within accessions. Genetic diversity observed in the common-bean core collection represents an important sample of the total Phaseolus genetic variability at the main Germplasm Bank of INIFAP. Molecular marker strategies could contribute to a better understanding of the genetic structure of the core collection as well as to its improvement and validation. PMID:22215964

  10. Genetic diversity analysis of common beans based on molecular markers

    Directory of Open Access Journals (Sweden)

    Homar R. Gill-Langarica

    Full Text Available A core collection of the common bean (Phaseolus vulgaris L., representing genetic diversity in the entire Mexican holding, is kept at the INIFAP (Instituto Nacional de Investigaciones Forestales, Agricolas y Pecuarias, Mexico Germplasm Bank. After evaluation, the genetic structure of this collection (200 accessions was compared with that of landraces from the states of Oaxaca, Chiapas and Veracruz (10 genotypes from each, as well as a further 10 cultivars, by means of four amplified fragment length polymorphisms (AFLP +3/+3 primer combinations and seven simple sequence repeats (SSR loci, in order to define genetic diversity, variability and mutual relationships. Data underwent cluster (UPGMA and molecular variance (AMOVA analyses. AFLP analysis produced 530 bands (88.5% polymorphic while SSR primers amplified 174 alleles, all polymorphic (8.2 alleles per locus. AFLP indicated that the highest genetic diversity was to be found in ten commercial-seed classes from two major groups of accessions from Central Mexico and Chiapas, which seems to be an important center of diversity in the south. A third group included genotypes from Nueva Granada, Mesoamerica, Jalisco and Durango races. Here, SSR analysis indicated a reduced number of shared haplotypes among accessions, whereas the highest genetic components of AMOVA variation were found within accessions. Genetic diversity observed in the common-bean core collection represents an important sample of the total Phaseolus genetic variability at the main Germplasm Bank of INIFAP. Molecular marker strategies could contribute to a better understanding of the genetic structure of the core collection as well as to its improvement and validation.

  11. Common genetic variants influence human subcortical brain structures

    NARCIS (Netherlands)

    Hibar, Derrek P.; Stein, Jason L.; Renteria, Miguel E.; Arias-Vasquez, Alejandro; Desrivieres, Sylvane; Jahanshad, Neda; Toro, Roberto; Wittfeld, Katharina; Abramovic, Lucija; Andersson, Micael; Aribisala, Benjamin S.; Armstrong, Nicola J.; Bernard, Manon; Bohlken, Marc M.; Boks, Marco P.; Bralten, Janita; Brown, Andrew A.; Chakravarty, M. Mallar; Chen, Qiang; Ching, Christopher R. K.; Cuellar-Partida, Gabriel; den Braber, Anouk; Giddaluru, Sudheer; Goldman, Aaron L.; Grimm, Oliver; Guadalupe, Tulio; Hass, Johanna; Woldehawariat, Girma; Holmes, Avram J.; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H.; Loohuis, Loes M. Olde; Luciano, Michelle; Macare, Christine; Mather, Karen A.; Mattheisen, Manuel; Milaneschi, Yuri; Nho, Kwangsik; Papmeyer, Martina; Ramasamy, Adaikalavan; Risacher, Shannon L.; Roiz-Santianez, Roberto; Rose, Emma J.; Salami, Alireza; Saemann, Philipp G.; Schmaal, Lianne; Schork, Andrew J.; Shin, Jean; Strike, Lachlan T.; Teumer, Alexander; van Donkelaar, Marjolein M. J.; van Eijk, Kristel R.; Walters, Raymond K.; Westlye, Lars T.; Whelan, Christopher D.; Winkler, Anderson M.; Zwiers, Marcel P.; Alhusaini, Saud; Athanasiu, Lavinia; Ehrlich, Stefan; Hakobjan, Marina M. H.; Hartberg, Cecilie B.; Haukvik, Unn K.; Heister, Angelien J. G. A. M.; Hoehn, David; Kasperaviciute, Dalia; Liewald, David C. M.; Lopez, Lorna M.; Makkinje, Remco R. R.; Matarin, Mar; Naber, Marlies A. M.; McKay, D. Reese; Needham, Margaret; Nugent, Allison C.; Puetz, Benno; Royle, Natalie A.; Shen, Li; Sprooten, Emma; Trabzuni, Daniah; van der Marel, Saskia S. L.; van Hulzen, Kimm J. E.; Walton, Esther; Wolf, Christiane; Almasy, Laura; Ames, David; Arepalli, Sampath; Assareh, Amelia A.; Bastin, Mark E.; Brodaty, Henry; Bulayeva, Kazima B.; Carless, Melanie A.; Cichon, Sven; Corvin, Aiden; Curran, Joanne E.; Czisch, Michael; de Zubicaray, Greig I.; Dillman, Allissa; Duggirala, Ravi; Dyer, Thomas D.; Erk, Susanne; Fedko, Iryna O.; Ferrucci, Luigi; Foroud, Tatiana M.; Fox, Peter T.; Fukunaga, Masaki; Gibbs, J. Raphael; Goering, Harald H. H.; Green, Robert C.; Guelfi, Sebastian; Hansell, Narelle K.; Hartman, Catharina A.; Hegenscheid, Katrin; Heinz, Andreas; Hernandez, Dena G.; Heslenfeld, Dirk J.; Hoekstra, Pieter J.; Holsboer, Florian; Homuth, Georg; Hottenga, Jouke-Jan; Ikeda, Masashi; Jack, Clifford R.; Jenkinson, Mark; Johnson, Robert; Kanai, Ryota; Keil, Maria; Kent, Jack W.; Kochunov, Peter; Kwok, John B.; Lawrie, Stephen M.; Liu, Xinmin; Longo, Dan L.; McMahon, Katie L.; Meisenzah, Eva; Melle, Ingrid; Mahnke, Sebastian; Montgomery, Grant W.; Mostert, Jeanette C.; Muehleisen, Thomas W.; Nalls, Michael A.; Nichols, Thomas E.; Nilsson, Lars G.; Noethen, Markus M.; Ohi, Kazutaka; Olvera, Rene L.; Perez-Iglesias, Rocio; Pike, G. Bruce; Potkin, Steven G.; Reinvang, Ivar; Reppermund, Simone; Rietschel, Marcella; Romanczuk-Seiferth, Nina; Rosen, Glenn D.; Rujescu, Dan; Schnell, Knut; Schofield, Peter R.; Smith, Colin; Steen, Vidar M.; Sussmann, Jessika E.; Thalamuthu, Anbupalam; Toga, Arthur W.; Traynor, Bryan J.; Troncoso, Juan; Turner, Jessica A.; Valdes Hernandez, Maria C.; van't Ent, Dennis; van der Brug, Marcel; van der Wee, Nic J. A.; van Tol, Marie-Jose; Veltman, Dick J.; Wassink, Thomas H.; Westman, Eric; Zielke, Ronald H.; Zonderman, Alan B.; Ashbrook, David G.; Hager, Reinmar; Lu, Lu; McMahon, Francis J.; Morris, Derek W.; Williams, Robert W.; Brunner, Han G.; Buckner, Randy L.; Buitelaar, Jan K.; Cahn, Wiepke; Calhoun, Vince D.; Cavalleri, Gianpiero L.; Crespo-Facorro, Benedicto; Dale, Anders M.; Davies, Gareth E.; Delanty, Norman; Depondt, Chantal; Djurovic, Srdjan; Drevets, Wayne C.; Espeseth, Thomas; Gollub, Randy L.; Ho, Beng-Choon; Hoffman, Wolfgang; Hosten, Norbert; Kahn, Rene S.; Le Hellard, Stephanie; Meyer-Lindenberg, Andreas; Mueller-Myhsok, Bertram; Nauck, Matthias; Nyberg, Lars; Pandolfo, Massimo; Penninx, Brenda W. J. H.; Roffman, Joshua L.; Sisodiya, Sanjay M.; Smoller, Jordan W.; van Bokhoven, Hans; van Haren, Neeltje E. M.; Voelzke, Henry; Walter, Henrik; Weiner, Michael W.; Wen, Wei; White, Tonya; Agartz, Ingrid; Andreassen, Ole A.; Blangero, John; Boomsma, Dorret I.; Brouwer, Rachel M.; Cannon, Dara M.; Cookson, Mark R.; de Geus, Eco J. C.; Deary, Ian J.; Donohoe, Gary; Fernandez, Guillen; Fisher, Simon E.; Francks, Clyde; Glahn, David C.; Grabe, Hans J.; Gruber, Oliver; Hardy, John; Hashimoto, Ryota; Pol, Hilleke E. Hulshoff; Joensson, Erik G.; Kloszewska, Iwona; Lovestone, Simon; Mattay, Venkata S.; Mecocci, Patrizia; McDonald, Colm; McIntosh, Andrew M.; Ophoff, Roel A.; Paus, Tomas; Pausova, Zdenka; Ryten, Mina; Sachdev, Perminder S.; Saykin, Andrew J.; Simmons, Andy; Singleton, Andrew; Soininen, Hilkka; Wardlaw, Joanna M.; Weale, Michael E.; Weinberger, Daniel R.; Adams, Hieab H. H.; Launer, Lenore J.; Seiler, Stephan; Schmidt, Reinhold; Chauhan, Ganesh; Satizabal, Claudia L.; Becker, James T.; Yanek, Lisa; van der Lee, Sven J.; Ebling, Maritza; Fischl, Bruce; Longstreth, W. T.; Greve, Douglas; Schmidt, Helena; Nyquist, Paul; Vinke, Louis N.; van Duijn, Cornelia M.; Xue, Luting; Mazoyer, Bernard; Bis, Joshua C.; Gudnason, Vilmundur; Seshadri, Sudha; Ikram, M. Arfan; Martin, Nicholas G.; Wright, Margaret J.; Schumann, Gunter; Franke, Barbara; Thompson, Paul M.; Medland, Sarah E.

    2015-01-01

    The highly complex structure of the human brain is strongly shaped by genetic influences(1). Subcortical brain regions form circuits with cortical areas to coordinate movement(2), learning, memory(3) and motivation(4), and altered circuits can lead to abnormal behaviour and disease(5). To investigat

  12. Common genetic variants influence human subcortical brain structures

    NARCIS (Netherlands)

    D.P. Hibar (Derrek); J.L. Stein; M.E. Rentería (Miguel); A. Arias-Vásquez (Alejandro); S. Desrivières (Sylvane); N. Jahanshad (Neda); R. Toro (Roberto); K. Wittfeld (Katharina); L. Abramovic (Lucija); M. Andersson (Micael); B. Aribisala (Benjamin); N.J. Armstrong (Nicola J.); M. Bernard (Manon); M.M. Bohlken (Marc M.); M.P.M. Boks (Marco); L.B.C. Bralten (Linda); A.A. Brown (Andrew); M.M. Chakravarty (M. Mallar); Q. Chen (Qiang); C.R.K. Ching (Christopher); G. Cuellar-Partida (Gabriel); A. den Braber (Anouk); S. Giddaluru (Sudheer); A.L. Goldman (Aaron L.); O. Grimm (Oliver); T. Guadalupe (Tulio); J. Hass (Johanna); G. Woldehawariat (Girma); A.J. Holmes (Avram); M. Hoogman (Martine); D. Janowitz (Deborah); T. Jia (Tianye); S. Kim (Shinseog); M. Klein (Marieke); B. Kraemer (Bernd); P.H. Lee (Phil H.); L.M. Olde Loohuis (Loes M.); M. Luciano (Michelle); C. MacAre (Christine); R. Mather; M. Mattheisen (Manuel); Y. Milaneschi (Yuri); K. Nho (Kwangsik); M. Papmeyer (Martina); A. Ramasamy (Adaikalavan); S.L. Risacher (Shannon); R. Roiz-Santiañez (Roberto); E.J. Rose (Emma); A. Salami (Alireza); P.G. Sämann (Philipp); L. Schmaal (Lianne); N.J. Schork (Nicholas); J. Shin (Jean); V.M. Strike (Vanessa); A. Teumer (Alexander); M.M.J. Van Donkelaar (Marjolein M. J.); K.R. van Eijk (Kristel); R.K. Walters (Raymond); L.T. Westlye (Lars); C.D. Whelan (Christopher); A.M. Winkler (Anderson); M.P. Zwiers (Marcel); S. Alhusaini (Saud); L. Athanasiu (Lavinia); S.M. Ehrlich (Stefan); M. Hakobjan (Marina); C.B. Hartberg (Cecilie B.); U.K. Haukvik (Unn); A.J.G.A.M. Heister (Angelien J. G. A. M.); D. Hoehn (David); D. Kasperaviciute (Dalia); D.C. Liewald (David C.); L.M. Lopez (Lorna); R.R.R. Makkinje (Remco R. R.); M. Matarin (Mar); M.A.M. Naber (Marlies A. M.); D. Reese McKay; M. Needham (Margaret); A.C. Nugent (Allison); B. Pütz (Benno); N.A. Royle (Natalie); L. Shen (Li); R. Sprooten (Roy); D. Trabzuni (Danyah); S.S.L. Van Der Marel (Saskia S. L.); K.J.E. Van Hulzen (Kimm J. E.); E. Walton (Esther); A. Björnsson (Asgeir); L. Almasy (Laura); D. Ames (David); S. Arepalli (Sampath); A.A. Assareh; M.E. Bastin (Mark); H. Brodaty (Henry); K. Bulayeva (Kazima); M.A. Carless (Melanie); S. Cichon (Sven); A. Corvin (Aiden); J.E. Curran (Joanne); M. Czisch (Michael); G.I. de Zubicaray (Greig); A. Dillman (Allissa); A. Duggirala (Aparna); M.D. Dyer (Matthew); S. Erk; I. Fedko (Iryna); L. Ferrucci (Luigi); T. Foroud (Tatiana); P.T. Fox (Peter); M. Fukunaga (Masaki); J. Raphael Gibbs; H.H.H. Göring (Harald H.); R.C. Green (Robert C.); S. Guelfi (Sebastian); N.K. Hansell (Narelle); C.A. Hartman (Catharina); K. Hegenscheid (Katrin); J. Heinz (Judith); D.G. Hernandez (Dena); D.J. Heslenfeld (Dirk); P.J. Hoekstra (Pieter); F. Holsboer; G. Homuth (Georg); J.J. Hottenga (Jouke Jan); M. Ikeda (Masashi); C.R. Jack Jr. (Clifford); S. Jenkinson (Sarah); R. Johnson (Robert); R. Kanai (Ryota); M. Keil (Maria); J.W. Kent (Jack W.); P. Kochunov (Peter); J.B. Kwok (John B.); S. Lawrie (Stephen); X. Liu (Xinmin); D.L. Longo (Dan L.); K.L. Mcmahon (Katie); E. Meisenzahl (Eva); I. Melle (Ingrid); S. Mohnke (Sebastian); G.W. Montgomery (Grant); J.C. Mostert (Jeanette C.); T.W. Mühleisen (Thomas); M.A. Nalls (Michael); T.E. Nichols (Thomas); L.G. Nilsson; M.M. Nöthen (Markus); K. Ohi (Kazutaka); R.L. Olvera (Rene); R. Perez-Iglesias (Rocio); G. Bruce Pike; S.G. Potkin (Steven); I. Reinvang (Ivar); S. Reppermund; M. Rietschel (M.); N. Seiferth (Nina); G.D. Rosen (Glenn D.); D. Rujescu (Dan); K. Schnell (Kerry); C.J. Schofield (Christopher); C. Smith (Colin); V.M. Steen (Vidar); J. Sussmann (Jessika); A. Thalamuthu (Anbupalam); A.W. Toga (Arthur W.); B. Traynor (Bryan); J.C. Troncoso (Juan); J. Turner (Jessica); M.C. Valdés Hernández (Maria); D. van 't Ent (Dennis); M.P. van der Brug (Marcel); N.J. van der Wee (Nic); M.J.D. van Tol (Marie-José); D.J. Veltman (Dick); A.M.J. Wassink (Annemarie); E. Westman (Eric); R.H. Zielke (Ronald H.); A.B. Zonderman (Alan B.); D.G. Ashbrook (David G.); R. Hager (Reinmar); L. Lu (Lu); F.J. Mcmahon (Francis J); D.W. Morris (Derek W); R.W. Williams (Robert W.); H.G. Brunner; M. Buckner; J.K. Buitelaar (Jan K.); W. Cahn (Wiepke); V.D. Calhoun Vince D. (V.); G. Cavalleri (Gianpiero); B. Crespo-Facorro (Benedicto); A.M. Dale (Anders); G.E. Davies (Gareth); N. Delanty; C. Depondt (Chantal); S. Djurovic (Srdjan); D.A. Drevets (Douglas); T. Espeseth (Thomas); R.L. Gollub (Randy); B.C. Ho (Beng ); W. Hoffmann (Wolfgang)

    2015-01-01

    textabstractThe highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate

  13. Common genetic variants influence human subcortical brain structures

    NARCIS (Netherlands)

    Hibar, Derrek P.; Stein, Jason L.; Renteria, Miguel E.; Arias-Vasquez, Alejandro; Desrivieres, Sylvane; Jahanshad, Neda; Toro, Roberto; Wittfeld, Katharina; Abramovic, Lucija; Andersson, Micael; Aribisala, Benjamin S.; Armstrong, Nicola J.; Bernard, Manon; Bohlken, Marc M.; Boks, Marco P.; Bralten, Janita; Brown, Andrew A.; Chakravarty, M. Mallar; Chen, Qiang; Ching, Christopher R. K.; Cuellar-Partida, Gabriel; den Braber, Anouk; Giddaluru, Sudheer; Goldman, Aaron L.; Grimm, Oliver; Guadalupe, Tulio; Hass, Johanna; Woldehawariat, Girma; Holmes, Avram J.; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H.; Loohuis, Loes M. Olde; Luciano, Michelle; Macare, Christine; Mather, Karen A.; Mattheisen, Manuel; Milaneschi, Yuri; Nho, Kwangsik; Papmeyer, Martina; Ramasamy, Adaikalavan; Risacher, Shannon L.; Roiz-Santianez, Roberto; Rose, Emma J.; Salami, Alireza; Saemann, Philipp G.; Schmaal, Lianne; Schork, Andrew J.; Shin, Jean; Strike, Lachlan T.; Teumer, Alexander; van Donkelaar, Marjolein M. J.; van Eijk, Kristel R.; Walters, Raymond K.; Westlye, Lars T.; Whelan, Christopher D.; Winkler, Anderson M.; Zwiers, Marcel P.; Alhusaini, Saud; Athanasiu, Lavinia; Ehrlich, Stefan; Hakobjan, Marina M. H.; Hartberg, Cecilie B.; Haukvik, Unn K.; Heister, Angelien J. G. A. M.; Hoehn, David; Kasperaviciute, Dalia; Liewald, David C. M.; Lopez, Lorna M.; Makkinje, Remco R. R.; Matarin, Mar; Naber, Marlies A. M.; McKay, D. Reese; Needham, Margaret; Nugent, Allison C.; Puetz, Benno; Royle, Natalie A.; Shen, Li; Sprooten, Emma; Trabzuni, Daniah; van der Marel, Saskia S. L.; van Hulzen, Kimm J. E.; Walton, Esther; Wolf, Christiane; Almasy, Laura; Ames, David; Arepalli, Sampath; Assareh, Amelia A.; Bastin, Mark E.; Brodaty, Henry; Bulayeva, Kazima B.; Carless, Melanie A.; Cichon, Sven; Corvin, Aiden; Curran, Joanne E.; Czisch, Michael; de Zubicaray, Greig I.; Dillman, Allissa; Duggirala, Ravi; Dyer, Thomas D.; Erk, Susanne; Fedko, Iryna O.; Ferrucci, Luigi; Foroud, Tatiana M.; Fox, Peter T.; Fukunaga, Masaki; Gibbs, J. Raphael; Goering, Harald H. H.; Green, Robert C.; Guelfi, Sebastian; Hansell, Narelle K.; Hartman, Catharina A.; Hegenscheid, Katrin; Heinz, Andreas; Hernandez, Dena G.; Heslenfeld, Dirk J.; Hoekstra, Pieter J.; Holsboer, Florian; Homuth, Georg; Hottenga, Jouke-Jan; Ikeda, Masashi; Jack, Clifford R.; Jenkinson, Mark; Johnson, Robert; Kanai, Ryota; Keil, Maria; Kent, Jack W.; Kochunov, Peter; Kwok, John B.; Lawrie, Stephen M.; Liu, Xinmin; Longo, Dan L.; McMahon, Katie L.; Meisenzah, Eva; Melle, Ingrid; Mahnke, Sebastian; Montgomery, Grant W.; Mostert, Jeanette C.; Muehleisen, Thomas W.; Nalls, Michael A.; Nichols, Thomas E.; Nilsson, Lars G.; Noethen, Markus M.; Ohi, Kazutaka; Olvera, Rene L.; Perez-Iglesias, Rocio; Pike, G. Bruce; Potkin, Steven G.; Reinvang, Ivar; Reppermund, Simone; Rietschel, Marcella; Romanczuk-Seiferth, Nina; Rosen, Glenn D.; Rujescu, Dan; Schnell, Knut; Schofield, Peter R.; Smith, Colin; Steen, Vidar M.; Sussmann, Jessika E.; Thalamuthu, Anbupalam; Toga, Arthur W.; Traynor, Bryan J.; Troncoso, Juan; Turner, Jessica A.; Valdes Hernandez, Maria C.; van't Ent, Dennis; van der Brug, Marcel; van der Wee, Nic J. A.; van Tol, Marie-Jose; Veltman, Dick J.; Wassink, Thomas H.; Westman, Eric; Zielke, Ronald H.; Zonderman, Alan B.; Ashbrook, David G.; Hager, Reinmar; Lu, Lu; McMahon, Francis J.; Morris, Derek W.; Williams, Robert W.; Brunner, Han G.; Buckner, Randy L.; Buitelaar, Jan K.; Cahn, Wiepke; Calhoun, Vince D.; Cavalleri, Gianpiero L.; Crespo-Facorro, Benedicto; Dale, Anders M.; Davies, Gareth E.; Delanty, Norman; Depondt, Chantal; Djurovic, Srdjan; Drevets, Wayne C.; Espeseth, Thomas; Gollub, Randy L.; Ho, Beng-Choon; Hoffman, Wolfgang; Hosten, Norbert; Kahn, Rene S.; Le Hellard, Stephanie; Meyer-Lindenberg, Andreas; Mueller-Myhsok, Bertram; Nauck, Matthias; Nyberg, Lars; Pandolfo, Massimo; Penninx, Brenda W. J. H.; Roffman, Joshua L.; Sisodiya, Sanjay M.; Smoller, Jordan W.; van Bokhoven, Hans; van Haren, Neeltje E. M.; Voelzke, Henry; Walter, Henrik; Weiner, Michael W.; Wen, Wei; White, Tonya; Agartz, Ingrid; Andreassen, Ole A.; Blangero, John; Boomsma, Dorret I.; Brouwer, Rachel M.; Cannon, Dara M.; Cookson, Mark R.; de Geus, Eco J. C.; Deary, Ian J.; Donohoe, Gary; Fernandez, Guillen; Fisher, Simon E.; Francks, Clyde; Glahn, David C.; Grabe, Hans J.; Gruber, Oliver; Hardy, John; Hashimoto, Ryota; Pol, Hilleke E. Hulshoff; Joensson, Erik G.; Kloszewska, Iwona; Lovestone, Simon; Mattay, Venkata S.; Mecocci, Patrizia; McDonald, Colm; McIntosh, Andrew M.; Ophoff, Roel A.; Paus, Tomas; Pausova, Zdenka; Ryten, Mina; Sachdev, Perminder S.; Saykin, Andrew J.; Simmons, Andy; Singleton, Andrew; Soininen, Hilkka; Wardlaw, Joanna M.; Weale, Michael E.; Weinberger, Daniel R.; Adams, Hieab H. H.; Launer, Lenore J.; Seiler, Stephan; Schmidt, Reinhold; Chauhan, Ganesh; Satizabal, Claudia L.; Becker, James T.; Yanek, Lisa; van der Lee, Sven J.; Ebling, Maritza; Fischl, Bruce; Longstreth, W. T.; Greve, Douglas; Schmidt, Helena; Nyquist, Paul; Vinke, Louis N.; van Duijn, Cornelia M.; Xue, Luting; Mazoyer, Bernard; Bis, Joshua C.; Gudnason, Vilmundur; Seshadri, Sudha; Ikram, M. Arfan; Martin, Nicholas G.; Wright, Margaret J.; Schumann, Gunter; Franke, Barbara; Thompson, Paul M.; Medland, Sarah E.

    2015-01-01

    The highly complex structure of the human brain is strongly shaped by genetic influences(1). Subcortical brain regions form circuits with cortical areas to coordinate movement(2), learning, memory(3) and motivation(4), and altered circuits can lead to abnormal behaviour and disease(5). To

  14. Common genetic variants influence human subcortical brain structures

    NARCIS (Netherlands)

    D.P. Hibar (Derrek); J.L. Stein; M.E. Rentería (Miguel); A. Arias-Vásquez (Alejandro); S. Desrivières (Sylvane); N. Jahanshad (Neda); R. Toro (Roberto); K. Wittfeld (Katharina); L. Abramovic; M. Andersson (Micael); B. Aribisala (Benjamin); N.J. Armstrong (Nicola J.); M. Bernard (Manon); M.M. Bohlken (Marc M.); M.P.M. Boks (Marco); L.B.C. Bralten (Linda); A.A. Brown (Andrew); M.M. Chakravarty (M. Mallar); Q. Chen (Qiang); C.R.K. Ching (Christopher); G. Cuellar-Partida (Gabriel); A. den Braber (Anouk); S. Giddaluru (Sudheer); A.L. Goldman (Aaron L.); O. Grimm (Oliver); T. Guadalupe (Tulio); J. Hass (Johanna); G. Woldehawariat (Girma); A.J. Holmes (Avram); M. Hoogman (Martine); D. Janowitz (Deborah); T. Jia (Tianye); S. Kim (Shinseog); M. Klein (Marieke); B. Kraemer (Bernd); P.H. Lee (Phil H.); L.M. Olde Loohuis (Loes M.); M. Luciano (Michelle); C. MacAre (Christine); R. Mather; M. Mattheisen (Manuel); Y. Milaneschi (Yuri); K. Nho (Kwangsik); M. Papmeyer (Martina); A. Ramasamy (Adaikalavan); S.L. Risacher (Shannon); R. Roiz-Santiañez (Roberto); E.J. Rose (Emma); A. Salami (Alireza); P.G. Sämann (Philipp); L. Schmaal (Lianne); N.J. Schork (Nicholas); J. Shin (Jean); V.M. Strike (Vanessa); A. Teumer (Alexander); M.M.J. Van Donkelaar (Marjolein M. J.); K.R. van Eijk (Kristel); R.K. Walters (Raymond); L.T. Westlye (Lars); C.D. Whelan (Christopher); A.M. Winkler (Anderson); M.P. Zwiers (Marcel); S. Alhusaini (Saud); L. Athanasiu (Lavinia); S.M. Ehrlich (Stefan); M. Hakobjan (Marina); C.B. Hartberg (Cecilie B.); U.K. Haukvik (Unn); A.J.G.A.M. Heister (Angelien J. G. A. M.); D. Hoehn (David); D. Kasperaviciute (Dalia); D.C. Liewald (David C.); L.M. Lopez (Lorna); R.R.R. Makkinje (Remco R. R.); M. Matarin (Mar); M.A.M. Naber (Marlies A. M.); D. Reese McKay; M. Needham (Margaret); A.C. Nugent (Allison); B. Pütz (Benno); N.A. Royle (Natalie); L. Shen (Li); R. Sprooten (Roy); D. Trabzuni (Danyah); S.S.L. Van Der Marel (Saskia S. L.); K.J.E. Van Hulzen (Kimm J. E.); E. Walton (Esther); A. Björnsson (Asgeir); L. Almasy (Laura); D. Ames (David); S. Arepalli (Sampath); A.A. Assareh; M.E. Bastin (Mark); H. Brodaty (Henry); K. Bulayeva (Kazima); M.A. Carless (Melanie); S. Cichon (Sven); A. Corvin (Aiden); J.E. Curran (Joanne); M. Czisch (Michael); G.I. de Zubicaray (Greig); A. Dillman (Allissa); A. Duggirala (Aparna); M.D. Dyer (Matthew); S. Erk; I. Fedko (Iryna); L. Ferrucci (Luigi); T. Foroud (Tatiana); P.T. Fox (Peter); M. Fukunaga (Masaki); J. Raphael Gibbs; H.H.H. Göring (Harald H.); R.C. Green (Robert C.); S. Guelfi (Sebastian); N.K. Hansell (Narelle); C.A. Hartman (Catharina); K. Hegenscheid (Katrin); J. Heinz (Judith); D.G. Hernandez (Dena); D.J. Heslenfeld (Dirk); P.J. Hoekstra (Pieter); F. Holsboer; G. Homuth (Georg); J.J. Hottenga (Jouke Jan); M. Ikeda (Masashi); C.R. Jack Jr. (Clifford); S. Jenkinson (Sarah); R. Johnson (Robert); R. Kanai (Ryota); M. Keil (Maria); J.W. Kent (Jack W.); P. Kochunov (Peter); J.B. Kwok (John B.); S. Lawrie (Stephen); X. Liu (Xinmin); D.L. Longo (Dan L.); K.L. Mcmahon (Katie); E. Meisenzahl (Eva); I. Melle (Ingrid); S. Mohnke (Sebastian); G.W. Montgomery (Grant); J.C. Mostert (Jeanette C.); T.W. Mühleisen (Thomas); M.A. Nalls (Michael); T.E. Nichols (Thomas); L.G. Nilsson; M.M. Nöthen (Markus); K. Ohi (Kazutaka); R.L. Olvera (Rene); R. Perez-Iglesias (Rocio); G. Bruce Pike; S.G. Potkin (Steven); I. Reinvang (Ivar); S. Reppermund; M. Rietschel (M.); N. Seiferth (Nina); G.D. Rosen (Glenn D.); D. Rujescu (Dan); K. Schnell (Kerry); C.J. Schofield (Christopher); C. Smith (Colin); V.M. Steen (Vidar); J. Sussmann (Jessika); A. Thalamuthu (Anbupalam); A.W. Toga (Arthur W.); B. Traynor (Bryan); J.C. Troncoso (Juan); J. Turner (Jessica); M.C. Valdés Hernández (Maria); D. van 't Ent (Dennis); M.P. van der Brug (Marcel); N.J. van der Wee (Nic); M.J.D. van Tol (Marie-José); D.J. Veltman (Dick); A.M.J. Wassink (Annemarie); E. Westman (Eric); R.H. Zielke (Ronald H.); A.B. Zonderman (Alan B.); D.G. Ashbrook (David G.); R. Hager (Reinmar); L. Lu (Lu); F.J. Mcmahon (Francis J); D.W. Morris (Derek W); R.W. Williams (Robert W.); H.G. Brunner; M. Buckner; J.K. Buitelaar (Jan K.); W. Cahn (Wiepke); V.D. Calhoun Vince D. (V.); G. Cavalleri (Gianpiero); B. Crespo-Facorro (Benedicto); A.M. Dale (Anders); G.E. Davies (Gareth); N. Delanty; C. Depondt (Chantal); S. Djurovic (Srdjan); D.A. Drevets (Douglas); T. Espeseth (Thomas); R.L. Gollub (Randy); B.C. Ho (Beng ); W. Hoffmann (Wolfgang); N. Hosten (Norbert); R. Kahn; S. Le Hellard (Stephanie); A. Meyer-Lindenberg; B. Müller-Myhsok (B.); M. Nauck (Matthias); L. Nyberg (Lars); M. Pandolfo (Massimo); B.W.J.H. Penninx (Brenda); J.L. Roffman (Joshua); S.M. Sisodiya (Sanjay); J.W. Smoller; H. van Bokhoven (Hans); N.E.M. van Haren (Neeltje E.); H. Völzke (Henry); H.J. Walter (Henrik); M.W. Weiner (Michael); W. Wen (Wei); T.J.H. White (Tonya); I. Agartz (Ingrid); O.A. Andreassen (Ole A.); J. Blangero (John); D.I. Boomsma (Dorret); R.M. Brouwer (Rachel); D.M. Cannon (Dara); M.R. Cookson (Mark); E.J.C. de Geus (Eco); I.J. Deary (Ian J.); D.J. Donohoe (Dennis); G. Fernandez (Guillén); S.E. Fisher (Simon); C. Francks (Clyde); D.C. Glahn (David); H.J. Grabe (Hans Jörgen); O. Gruber (Oliver); J. Hardy (John); R. Hashimoto (Ryota); H.E. Hulshoff Pol (Hilleke); E.G. Jönsson (Erik); I. Kloszewska (Iwona); S. Lovestone (Simon); V.S. Mattay (Venkata S.); P. Mecocci (Patrizia); C. McDonald (Colm); A.M. McIntosh (Andrew); R.A. Ophoff (Roel); T. Paus (Tomas); Z. Pausova (Zdenka); M. Ryten (Mina); P.S. Sachdev (Perminder); A.J. Saykin (Andrew); A. Simmons (Andrew); A. Singleton (Andrew); H. Soininen (H.); J.M. Wardlaw (J.); M.E. Weale (Michael); D.R. Weinberger (Daniel); H.H.H. Adams (Hieab); L.J. Launer (Lenore); S. Seiler (Stephan); R. Schmidt (Reinhold); G. Chauhan (Ganesh); C.L. Satizabal (Claudia L.); J.T. Becker (James); L.R. Yanek (Lisa); S. van der Lee (Sven); M. Ebling (Maritza); B. Fischl (Bruce); W.T. Longstreth Jr; D. Greve (Douglas); R. Schmidt (Reinhold); P. Nyquist (Paul); L.N. Vinke (Louis N.); C.M. van Duijn (Cock); L. Xue (Luting); B. Mazoyer (Bernard); J.C. Bis (Joshua); V. Gudnason (Vilmundur); S. Seshadri (Sudha); M.A. Ikram (Arfan); N.G. Martin (Nicholas); M.J. Wright (Margaret); G. Schumann (Gunter); B. Franke (Barbara); P.M. Thompson (Paul); S.E. Medland (Sarah Elizabeth)

    2015-01-01

    textabstractThe highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate h

  15. RARE DISEASES AND GENETIC DISCRIMINATION

    Directory of Open Access Journals (Sweden)

    Mariela Yaneva – Deliverska

    2011-04-01

    Full Text Available Rare diseases are characterised by their low prevalence (less than 1/2,000 and their heterogeneity. They affect both children and adults anywhere in the world. From the medical perspective, rare diseases are characterised by the large number and broad diversity of disorders and symptoms that vary not only from disease to disease, but also within the same disease.Main characteristics of rare diseases include:· Rare diseases are often chronic, progressive, degenerative, and often life-threatening· Rare diseases are disabling: the quality of life of patients is often compromised by the lack or loss of autonomy· High level of pain and suffering for the patient and his/ her family · No existing effective cure· There are between 6000 and 8000 rare diseases· 75% of rare diseases affect children· 30% of rare disease patients die before the age of 5· 80% of rare diseases have identified genetic origins. Other rare diseases are the result of infections (bacterial or viral, allergies and environmental causes, or are degenerative and proliferative.Beyond the diversity of the diseases, rare disease patients and their families are confronted with the same wide range of difficulties arising directly from the rarity of these pathologies. The period between the emergence of the first symptoms and the appropriate diagnosis involves unacceptable and highly risky delays, as well as wrong diagnosis leading to inaccurate treatments. Living with a rare disease has implications in all areas of life, whether school, choice of future work, leisure time with friends, or affective life. It may lead to stigmatisation, isolation, exclusion from social community, discrimination for insurance subscription (health insurance, travel insurance, mortgage, and often reduced professional opportunities.Innovative treatments are often unevenly available in the EU because of delays in price determination and/or reimbursement decision, lack of experience of the treating

  16. Common mechanisms of onset of cancer and neurodegenerative diseases.

    Science.gov (United States)

    Ariga, Hiroyoshi

    2015-01-01

    Onset of cancer and neurodegenerative disease occurs by abnormal cell growth and neuronal cell death, respectively, and the number of patients with both diseases has been increasing in parallel with an increase in mean lifetime, especially in developed countries. Although both diseases are sporadic, about 10% of the diseases are genetically inherited, and analyses of such familial forms of gene products have contributed to an understanding of the molecular mechanisms underlying the onset and pathogenesis of these diseases. I have been working on c-myc, a protooncogene, for a long time and identified various c-Myc-binding proteins that play roles in c-Myc-derived tumorigenesis. Among these proteins, some proteins have been found to be also responsible for the onset of neurodegenerative diseases, including Parkinson's disease, retinitis pigmentosa and cerebellar atrophy. In this review, I summarize our findings indicating the common mechanisms of onset between cancer and neurodegenerative diseases, with a focus on genes such as DJ-1 and Myc-Modulator 1 (MM-1) and signaling pathways that contribute to the onset and pathogenesis of cancer and neurodegenerative diseases.

  17. Coeliac disease and autoimmune disease-genetic overlap and screening

    NARCIS (Netherlands)

    Lundin, Knut E. A.; Wijmenga, Cisca

    Coeliac disease is a treatable, gluten-induced disease that often occurs concurrently with other autoimmune diseases. In genetic studies since 2007, a partial genetic overlap between these diseases has been revealed and further insights into the pathophysiology of coeliac disease and autoimmunity

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

    Directory of Open Access Journals (Sweden)

    Anthony R Torres

    2016-10-01

    Full Text Available 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 variants, rather than common variants, have been found in numerous genome wide genetic studies and many have concluded that the common variant—common disease hypothesis is incorrect. One interpretation is that rare variants are major contributors to genetic diseases and autism involves the interaction of many rare variants, especially in the brain. It is obvious there is much yet to be learned about autism genetics.Evidence has been mounting over the years indicating immune involvement in autism, particularly the HLA genes on chromosome 6 and KIR genes on chromosome 19. These two large multigene complexes have important immune functions and have been shown to interact to eliminate unwanted virally infected and malignant cells. HLA proteins have important functions in antigen presentation in adaptive immunity and specific epitopes on HLA class I proteins act as cognate ligands for KIR receptors in innate immunity. Data suggests that HLA alleles and KIR activating genes/haplotypes are common variants in different autism populations. For example, class I allele (HLA-A2 and HLA-G 14bp-indel frequencies are significantly increased by more than 5% over control populations (Table2. The HLA-DR4 Class II and shared epitope frequencies are significantly above the control populations (Table 2. Three activating KIR genes: 3DS1, 2DS1 and 2DS2 have increased frequencies of 15%, 22% and 14% in autism populations, respectively. There is a 6% increase in total activating KIR

  19. Identification of common genetic variation that modulates alternative splicing.

    Directory of Open Access Journals (Sweden)

    Jeremy Hull

    2007-06-01

    Full Text Available Alternative splicing of genes is an efficient means of generating variation in protein function. Several disease states have been associated with rare genetic variants that affect splicing patterns. Conversely, splicing efficiency of some genes is known to vary between individuals without apparent ill effects. What is not clear is whether commonly observed phenotypic variation in splicing patterns, and hence potential variation in protein function, is to a significant extent determined by naturally occurring DNA sequence variation and in particular by single nucleotide polymorphisms (SNPs. In this study, we surveyed the splicing patterns of 250 exons in 22 individuals who had been previously genotyped by the International HapMap Project. We identified 70 simple cassette exon alternative splicing events in our experimental system; for six of these, we detected consistent differences in splicing pattern between individuals, with a highly significant association between splice phenotype and neighbouring SNPs. Remarkably, for five out of six of these events, the strongest correlation was found with the SNP closest to the intron-exon boundary, although the distance between these SNPs and the intron-exon boundary ranged from 2 bp to greater than 1,000 bp. Two of these SNPs were further investigated using a minigene splicing system, and in each case the SNPs were found to exert cis-acting effects on exon splicing efficiency in vitro. The functional consequences of these SNPs could not be predicted using bioinformatic algorithms. Our findings suggest that phenotypic variation in splicing patterns is determined by the presence of SNPs within flanking introns or exons. Effects on splicing may represent an important mechanism by which SNPs influence gene function.

  20. Pervasive Sharing of Genetic Effects in Autoimmune Disease

    DEFF Research Database (Denmark)

    Cotsapas, Chris; Voight, Benjamin F.; Rossin, Elizabeth

    2011-01-01

    Genome-wide association (GWA) studies have identified numerous, replicable, genetic associations between common single nucleotide polymorphisms (SNPs) and risk of common autoimmune and inflammatory (immune-mediated) diseases, some of which are shared between two diseases. Along with epidemiological...... and clinical evidence, this suggests that some genetic risk factors may be shared across diseases-as is the case with alleles in the Major Histocompatibility Locus. In this work we evaluate the extent of this sharing for 107 immune disease-risk SNPs in seven diseases: celiac disease, Crohn's disease, multiple......-mediated disease risk SNPs are associated to multiple-but not all-immune-mediated diseases (SNP-wise P-CPMA...

  1. Down syndrome and Alzheimer's disease: Common pathways, common goals.

    Science.gov (United States)

    Hartley, Dean; Blumenthal, Thomas; Carrillo, Maria; DiPaolo, Gilbert; Esralew, Lucille; Gardiner, Katheleen; Granholm, Ann-Charlotte; Iqbal, Khalid; Krams, Michael; Lemere, Cynthia; Lott, Ira; Mobley, William; Ness, Seth; Nixon, Ralph; Potter, Huntington; Reeves, Roger; Sabbagh, Marwan; Silverman, Wayne; Tycko, Benjamin; Whitten, Michelle; Wisniewski, Thomas

    2015-06-01

    In the United States, estimates indicate there are between 250,000 and 400,000 individuals with Down syndrome (DS), and nearly all will develop Alzheimer's disease (AD) pathology starting in their 30s. With the current lifespan being 55 to 60 years, approximately 70% will develop dementia, and if their life expectancy continues to increase, the number of individuals developing AD will concomitantly increase. Pathogenic and mechanistic links between DS and Alzheimer's prompted the Alzheimer's Association to partner with the Linda Crnic Institute for Down Syndrome and the Global Down Syndrome Foundation at a workshop of AD and DS experts to discuss similarities and differences, challenges, and future directions for this field. The workshop articulated a set of research priorities: (1) target identification and drug development, (2) clinical and pathological staging, (3) cognitive assessment and clinical trials, and (4) partnerships and collaborations with the ultimate goal to deliver effective disease-modifying treatments. Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  2. Prevalence of common disease-associated variants in Asian Indians

    Directory of Open Access Journals (Sweden)

    Allayee Hooman

    2008-02-01

    Full Text Available Abstract Background Asian Indians display a high prevalence of diseases linked to changes in diet and environment that have arisen as their lifestyle has become more westernized. Using 1200 genome-wide polymorphisms in 432 individuals from 15 Indian language groups, we have recently shown that: (i Indians constitute a distinct population-genetic cluster, and (ii despite the geographic and linguistic diversity of the groups they exhibit a relatively low level of genetic heterogeneity. Results We investigated the prevalence of common polymorphisms that have been associated with diseases, such as atherosclerosis (ALOX5, hypertension (CYP3A5, AGT, GNB3, diabetes (CAPN10, TCF7L2, PTPN22, prostate cancer (DG8S737, rs1447295, Hirschsprung disease (RET, and age-related macular degeneration (CFH, LOC387715. In addition, we examined polymorphisms associated with skin pigmentation (SLC24A5 and with the ability to taste phenylthiocarbamide (TAS2R38. All polymorphisms were studied in a cohort of 576 India-born Asian Indians sampled in the United States. This sample consisted of individuals whose mother tongue is one of 14 of the 22 "official" languages recognized in India as well as individuals whose mother tongue is Parsi, a cultural group that has resided in India for over 1000 years. Analysis of the data revealed that allele frequency differences between the different Indian language groups were small, and interestingly the variant alleles of ALOX5 g.8322G>A and g.50778G>A, and PTPN22 g.36677C>T were present only in a subset of the Indian language groups. Furthermore, a latitudinal cline was identified both for the allele frequencies of the SNPs associated with hypertension (CYP3A5, AGT, GNB3, as well as for those associated with the ability to taste phenylthiocarbamide (TAS2R38. Conclusion Although caution is warranted due to the fact that this US-sampled Indian cohort may not represent a random sample from India, our results will hopefully assist in the

  3. Association studies in common endocrine diseases (review article

    Directory of Open Access Journals (Sweden)

    Akrami SM

    2007-05-01

    Full Text Available Our understanding of the pathogenesis of endocrine disorders increase rapidly by genetic studies at the molecular level. Common endocrine disorders such as diabetes mellitus, obesity, osteoporosis, dyslipidemia and cancer follow the multifactorial model in the genetic aspect. This review tries to clarify the approach in molecular studies of such diseases for clinicians in different specialties. How to evaluate a possible association between a single nucleotide polymorphism and an endocrinopathy or its complication is the main concern of this review. Two approaches for gene mapping will be discussed as well as main challenges regarding each approach. All such genetic studies ideally include some test of the association between genome sequence variation and the phenotype of interest such as the trait itself, the presence of a given complication, or measures of some endocrinopathy-related intermediate trait. Despite different advances in this analysis, there are major concerns regarding the overall performance and robustness of genetic association studies. By using powerful new high-throughput methods, further insights to molecular basis of such endocrine disorders can be expected. Close correlation between geneticists and clinicians can effectively bridge between basic sciences and clinical investigations.

  4. Genetic Correlation between Body Fat Percentage and Cardiorespiratory Fitness Suggests Common Genetic Etiology

    DEFF Research Database (Denmark)

    Schnurr, Theresia Maria; Gjesing, Anette Marianne Prior; Sandholt, Camilla Helene

    2016-01-01

    Objectives: It has long been discussed whether fitness or fatness is a more important determinant of health status. If the same genetic factors that promote body fat percentage (body fat%) are related to cardiorespiratory fitness (CRF), part of the concurrent associations with health outcomes could...... reflect a common genetic origin. In this study we aimed to 1) examine genetic correlations between body fat% and CRF; 2) determine whether CRF can be attributed to a genetic risk score (GRS) based on known body fat% increasing loci; and 3) examine whether the fat mass and obesity associated (FTO) locus...... associates with CRF. Methods: Genetic correlations based on pedigree information were examined in a family based cohort (n = 230 from 55 families). For the genetic association analyses, we examined two Danish population-based cohorts (ntotal = 3206). The body fat% GRS was created by summing the alleles...

  5. Genetic Correlation between Body Fat Percentage and Cardiorespiratory Fitness Suggests Common Genetic Etiology

    DEFF Research Database (Denmark)

    Schnurr, Theresia M; Gjesing, Anette P; Sandholt, Camilla H

    2016-01-01

    OBJECTIVES: It has long been discussed whether fitness or fatness is a more important determinant of health status. If the same genetic factors that promote body fat percentage (body fat%) are related to cardiorespiratory fitness (CRF), part of the concurrent associations with health outcomes could...... reflect a common genetic origin. In this study we aimed to 1) examine genetic correlations between body fat% and CRF; 2) determine whether CRF can be attributed to a genetic risk score (GRS) based on known body fat% increasing loci; and 3) examine whether the fat mass and obesity associated (FTO) locus...... associates with CRF. METHODS: Genetic correlations based on pedigree information were examined in a family based cohort (n = 230 from 55 families). For the genetic association analyses, we examined two Danish population-based cohorts (ntotal = 3206). The body fat% GRS was created by summing the alleles...

  6. Common variants in CASP3 confer susceptibility to Kawasaki disease.

    Science.gov (United States)

    Onouchi, Yoshihiro; Ozaki, Kouichi; Buns, Jane C; Shimizu, Chisato; Hamada, Hiromichi; Honda, Takafumi; Terai, Masaru; Honda, Akihito; Takeuchi, Takashi; Shibuta, Shoichi; Suenaga, Tomohiro; Suzuki, Hiroyuki; Higashi, Kouji; Yasukawa, Kumi; Suzuki, Yoichi; Sasago, Kumiko; Kemmotsu, Yasushi; Takatsuki, Shinichi; Saji, Tsutomu; Yoshikawa, Tetsushi; Nagai, Toshiro; Hamamoto, Kunihiro; Kishi, Fumio; Ouchi, Kazunobu; Sato, Yoshitake; Newburger, Jane W; Baker, Annette L; Shulman, Stanford T; Rowley, Anne H; Yashiro, Mayumi; Nakamura, Yoshikazu; Wakui, Keiko; Fukushima, Yoshimitsu; Fujino, Akihiro; Tsunoda, Tatsuhiko; Kawasaki, Tomisaku; Hata, Akira; Nakamura, Yusuke; Tanaka, Toshihiro

    2010-07-15

    Kawasaki disease (KD; OMIM 611775) is an acute vasculitis syndrome which predominantly affects small- and medium-sized arteries of infants and children. Epidemiological data suggest that host genetics underlie the disease pathogenesis. Here we report that multiple variants in the caspase-3 gene (CASP3) that are in linkage disequilibrium confer susceptibility to KD in both Japanese and US subjects of European ancestry. We found that a G to A substitution of one commonly associated SNP located in the 5' untranslated region of CASP3 (rs72689236; P = 4.2 x 10(-8) in the Japanese and P = 3.7 x 10(-3) in the European Americans) abolished binding of nuclear factor of activated T cells to the DNA sequence surrounding the SNP. Our findings suggest that altered CASP3 expression in immune effecter cells influences susceptibility to KD.

  7. Human genetics of infectious diseases: a unified theory

    Science.gov (United States)

    Casanova, Jean-Laurent; Abel, Laurent

    2007-01-01

    Since the early 1950s, the dominant paradigm in the human genetics of infectious diseases postulates that rare monogenic immunodeficiencies confer vulnerability to multiple infectious diseases (one gene, multiple infections), whereas common infections are associated with the polygenic inheritance of multiple susceptibility genes (one infection, multiple genes). Recent studies, since 1996 in particular, have challenged this view. A newly recognised group of primary immunodeficiencies predisposing the individual to a principal or single type of infection is emerging. In parallel, several common infections have been shown to reflect the inheritance of one major susceptibility gene, at least in some populations. This novel causal relationship (one gene, one infection) blurs the distinction between patient-based Mendelian genetics and population-based complex genetics, and provides a unified conceptual frame for exploring the molecular genetic basis of infectious diseases in humans. PMID:17255931

  8. Distilling pathophysiology from complex disease genetics.

    Science.gov (United States)

    Chakravarti, Aravinda; Clark, Andrew G; Mootha, Vamsi K

    2013-09-26

    Technologies for genome-wide sequence interrogation have dramatically improved our ability to identify loci associated with complex human disease. However, a chasm remains between correlations and causality that stems, in part, from a limiting theoretical framework derived from Mendelian genetics and an incomplete understanding of disease physiology. Here we propose a set of criteria, akin to Koch's postulates for infectious disease, for assigning causality between genetic variants and human disease phenotypes. Copyright © 2013 Elsevier Inc. All rights reserved.

  9. Genetics of Behçet's Disease

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    Tamer İrfan Kaya

    2012-01-01

    Full Text Available Behçet's disease (BD is a systemic inflammatory disorder characterized mainly by recurrent oral and genital ulcers and eye involvement. Although the pathogenesis remains poorly understood, a variety of studies have demonstrated that genetic predisposition is a major factor in disease susceptibility. Peculiar geographical distribution of BD along the ancient Silk Road has been regarded as evidence supporting genetic influence. The observed aggregation of BD in families of patients with BD is also supportive for a genetic component in its etiology. HLA-B51 (B510101 subtype is the most strongly associated genetic marker for BD in countries on the Silk Road. In recent years, several genome-wide association studies and genetic polymorphism studies have also found new genetic associations with BD, which may have a supplementary role in disease susceptibility and/or severity. The author reviewed the HLA and non-HLA genetic association studies.

  10. The genetic background of inflammatory bowel disease.

    Science.gov (United States)

    Yang, H; Rotter, J I

    2000-01-01

    Available evidence indicates that genetic factors are essential in providing the susceptibility to the majority of the various forms of inflammatory bowel disease occurring in man. It is also clear that the genetic susceptibility to these diseases is complex, and that more than one gene may predispose (the concept of multilocus/oligogenic inheritance), and likely in different etiologic combinations (the concept of genetic heterogeneity). Paradigms are now available that should lead to the identification of a number of these predisposing genes. These paradigms include the candidate gene approach, systematic genome wide scans, and mouse human synteny. While genome wide scans are currently limited to multiplex family linkage studies, both candidate genes and mouse human synteny can be approached in either linkage or association paradigms. Eventually whole genome association studies will be available as well. Identification of inflammatory bowel disease predisposing genes should lead to their incorporation in studies of natural history, investigation of environmental risk factors, and especially utilization of genetic markers in clinical trials. This will allow us to identify the best therapy available for the individual patient based on their unique genetic constitution. With advances in molecular technology, the search for genes influencing traits and diseases with a complex genetic background, such as the inflammatory bowel diseases, has become a realistic task. Although exogenous or infectious agents may contribute to the pathogenesis or may trigger the onset of disease, and the immune system almost certainly mediates the tissue damage, it is clear from available data that genetic factors determine the susceptibility of a given individual to inflammatory bowel disease (reviewed below). Thus, genetic studies are essential for the delineation of the basic etiologies of the various forms of inflammatory bowel disease and thus can aid in the development of radically

  11. Common lung conditions: chronic obstructive pulmonary disease.

    Science.gov (United States)

    Delzell, John E

    2013-06-01

    The etiology of chronic obstructive pulmonary disease (COPD) is chronic lung inflammation. In the United States, this inflammation most commonly is caused by smoking. COPD is diagnosed when an at-risk patient presents with respiratory symptoms and has irreversible airway obstruction indicated by a forced expiratory volume in 1 second/forced vital capacity ratio of less than 0.7. Management goals for COPD include smoking cessation, symptom reduction, exacerbation reduction, hospitalization avoidance, and improvement of quality of life. Stable patients with COPD who remain symptomatic despite using short-acting bronchodilators should start inhaled maintenance drugs to reduce symptoms and exacerbations, avoid hospitalizations, and improve quality of life. A long-acting anticholinergic or a long-acting beta2-agonist (LABA) can be used for initial therapy; these drugs have fewer adverse effects than inhaled corticosteroids (ICS). If patients remain symptomatic despite monotherapy, dual therapy with a long-acting anticholinergic and a LABA, or a LABA and an ICS, may be beneficial. Triple therapy (ie, a long-acting anticholinergic, a LABA, and an ICS) also is used, but it is unclear if triple therapy is superior to dual therapy. Roflumilast, an oral selective inhibitor of phosphodiesterase 4, is used to manage moderate to severe COPD. Continuous oxygen therapy is indicated for patients with COPD who have severe hypoxemia (ie, PaO2 less than 55 mm Hg or an oxygen saturation less than 88% on room air). Nonpharmacologic strategies also are useful to improve patient outcomes. Pulmonary rehabilitation improves dyspnea and quality of life. Pulmonary rehabilitation after an acute exacerbation reduces hospitalizations and mortality, and improves quality of life and exercise capacity. Smoking cessation is the most effective management strategy for reducing morbidity and mortality in patients with COPD. Lung volume reduction surgery, bullectomy, and lung transplantation are

  12. Italian Common Bean Landraces: History, Genetic Diversity and Seed Quality

    Directory of Open Access Journals (Sweden)

    Angela R. Piergiovanni

    2010-05-01

    Full Text Available The long tradition of common bean cultivation in Italy has allowed the evolution of many landraces adapted to restricted areas. Nowadays, in response to market demands, old landraces are gradually being replaced by improved cultivars. However, landraces still survive in marginal areas of several Italian regions. Most of them appear severely endangered with risk of extinction due to the advanced age of the farmers and the socio-cultural context where they are cultivated. The present contribution is an overview of the state of the art about the knowledge of Italian common bean germplasm, describing the most important and recent progresses made in its characterization, including genetic diversity and nutritional aspects.

  13. Common Periodontal Diseases of Children and Adolescents

    OpenAIRE

    Hayat Al-Ghutaimel; Hisham Riba; Salem Al-Kahtani; Saad Al-Duhaimi

    2014-01-01

    Background. Since 2000, studies, experiments, and clinical observations revealed high prevalence of periodontal diseases among children and adolescents. Therefore, this paper was designed to provide an update for dental practitioners on epidemiology, microbiology, pathology, prevention, diagnosis, and treatment of periodontal diseases in children and adolescents. Methods. This paper reviews the current literature concerning periodontal diseases in pediatric dentistry. It includes MEDLINE data...

  14. Feline and canine coronaviruses: common genetic and pathobiological features.

    Science.gov (United States)

    Le Poder, Sophie

    2011-01-01

    A new human coronavirus responsible for severe acute respiratory syndrome (SARS) was identified in 2003, which raised concern about coronaviruses as agents of serious infectious disease. Nevertheless, coronaviruses have been known for about 50 years to be major agents of respiratory, enteric, or systemic infections of domestic and companion animals. Feline and canine coronaviruses are widespread among dog and cat populations, sometimes leading to the fatal diseases known as feline infectious peritonitis (FIP) and pantropic canine coronavirus infection in cats and dogs, respectively. In this paper, different aspects of the genetics, host cell tropism, and pathogenesis of the feline and canine coronaviruses (FCoV and CCoV) will be discussed, with a view to illustrating how study of FCoVs and CCoVs can improve our general understanding of the pathobiology of coronaviruses.

  15. Feline and Canine Coronaviruses: Common Genetic and Pathobiological Features

    Directory of Open Access Journals (Sweden)

    Sophie Le Poder

    2011-01-01

    Full Text Available A new human coronavirus responsible for severe acute respiratory syndrome (SARS was identified in 2003, which raised concern about coronaviruses as agents of serious infectious disease. Nevertheless, coronaviruses have been known for about 50 years to be major agents of respiratory, enteric, or systemic infections of domestic and companion animals. Feline and canine coronaviruses are widespread among dog and cat populations, sometimes leading to the fatal diseases known as feline infectious peritonitis (FIP and pantropic canine coronavirus infection in cats and dogs, respectively. In this paper, different aspects of the genetics, host cell tropism, and pathogenesis of the feline and canine coronaviruses (FCoV and CCoV will be discussed, with a view to illustrating how study of FCoVs and CCoVs can improve our general understanding of the pathobiology of coronaviruses.

  16. Systematic analysis, comparison, and integration of disease based human genetic association data and mouse genetic phenotypic information

    Directory of Open Access Journals (Sweden)

    Wang S Alex

    2010-01-01

    Full Text Available Abstract Background The genetic contributions to human common disorders and mouse genetic models of disease are complex and often overlapping. In common human diseases, unlike classical Mendelian disorders, genetic factors generally have small effect sizes, are multifactorial, and are highly pleiotropic. Likewise, mouse genetic models of disease often have pleiotropic and overlapping phenotypes. Moreover, phenotypic descriptions in the literature in both human and mouse are often poorly characterized and difficult to compare directly. Methods In this report, human genetic association results from the literature are summarized with regard to replication, disease phenotype, and gene specific results; and organized in the context of a systematic disease ontology. Similarly summarized mouse genetic disease models are organized within the Mammalian Phenotype ontology. Human and mouse disease and phenotype based gene sets are identified. These disease gene sets are then compared individually and in large groups through dendrogram analysis and hierarchical clustering analysis. Results Human disease and mouse phenotype gene sets are shown to group into disease and phenotypically relevant groups at both a coarse and fine level based on gene sharing. Conclusion This analysis provides a systematic and global perspective on the genetics of common human disease as compared to itself and in the context of mouse genetic models of disease.

  17. Pervasive sharing of genetic effects in autoimmune disease.

    Directory of Open Access Journals (Sweden)

    Chris Cotsapas

    2011-08-01

    Full Text Available Genome-wide association (GWA studies have identified numerous, replicable, genetic associations between common single nucleotide polymorphisms (SNPs and risk of common autoimmune and inflammatory (immune-mediated diseases, some of which are shared between two diseases. Along with epidemiological and clinical evidence, this suggests that some genetic risk factors may be shared across diseases-as is the case with alleles in the Major Histocompatibility Locus. In this work we evaluate the extent of this sharing for 107 immune disease-risk SNPs in seven diseases: celiac disease, Crohn's disease, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes. We have developed a novel statistic for Cross Phenotype Meta-Analysis (CPMA which detects association of a SNP to multiple, but not necessarily all, phenotypes. With it, we find evidence that 47/107 (44% immune-mediated disease risk SNPs are associated to multiple-but not all-immune-mediated diseases (SNP-wise P(CPMA<0.01. We also show that distinct groups of interacting proteins are encoded near SNPs which predispose to the same subsets of diseases; we propose these as the mechanistic basis of shared disease risk. We are thus able to leverage genetic data across diseases to construct biological hypotheses about the underlying mechanism of pathogenesis.

  18. Common Periodontal Diseases of Children and Adolescents

    Directory of Open Access Journals (Sweden)

    Hayat Al-Ghutaimel

    2014-01-01

    “microbiology of periodontal diseases,” “classification of periodontal diseases,” “epidemiology of periodontal diseases,” and “treatment of periodontal diseases.” Articles were evaluated by title and/or abstract and relevance to pediatric dentistry. Sixty-five citations were selected by this method and by the references within the chosen articles. A review of the comprehensive textbooks on pediatric dentistry and periodontology was done. Some recommendations were based on the opinions of experienced researchers and clinicians, when data were inconclusive.

  19. Are there common genetic and environmental factors behind the endophenotypes associated with the metabolic syndrome?

    DEFF Research Database (Denmark)

    Benyamin, B; Sørensen, T I A; Schousboe, K

    2007-01-01

    AIMS/HYPOTHESIS: The cluster of obesity, insulin resistance, dyslipidaemia and hypertension, called the metabolic syndrome, has been suggested as a risk factor for cardiovascular disease and type 2 diabetes. The aim of the present study was to evaluate whether there are common genetic...... and environmental factors influencing this cluster in a general population of twin pairs. MATERIALS AND METHODS: A multivariate genetic analysis was performed on nine endophenotypes associated with the metabolic syndrome from 625 adult twin pairs of the GEMINAKAR study of the Danish Twin Registry. RESULTS: All...

  20. Common DNA sequence variation and psychiatric disease

    NARCIS (Netherlands)

    Ripke, S.

    2014-01-01

    In a genome-wide association study (GWAS), a large number of SNPs are genotyped in a large number of cases (with disease) and controls (without disease) using commercially available high-throughput genotyping platforms. In a GWAS, the genotype data collected in cases and unaffected, population-match

  1. Coeliac disease and autoimmune disease-genetic overlap and screening.

    Science.gov (United States)

    Lundin, Knut E A; Wijmenga, Cisca

    2015-09-01

    Coeliac disease is a treatable, gluten-induced disease that often occurs concurrently with other autoimmune diseases. In genetic studies since 2007, a partial genetic overlap between these diseases has been revealed and further insights into the pathophysiology of coeliac disease and autoimmunity have been gained. However, genetic screening is not sensitive and specific enough to accurately predict disease development. The current method to diagnose individuals with coeliac disease is serological testing for the presence of autoantibodies whilst the patient is on a regular, gluten-containing diet, followed by gastroduodenoscopy with duodenal biopsy. Serological test results can also predict the probability of coeliac disease development, even if asymptomatic. In patients with autoimmune diseases known to occur alongside coeliac disease (particularly type 1 diabetes mellitus or thyroid disorders), disease screening-and subsequent treatment if coeliac disease is detected-could have beneficial effects on progression or potential complications of both diseases, owing to the effectiveness of gluten-free dietary interventions in coeliac disease. However, whether diagnosis of coeliac disease and subsequent dietary treatment can prevent autoimmune diseases is debated. In this Review, the genetic and immunological features of coeliac disease, overlap with other autoimmune diseases and implications for current screening strategies will be discussed.

  2. Angiomyolipoma have common mutations in TSC2 but no other common genetic events.

    Directory of Open Access Journals (Sweden)

    Wei Qin

    Full Text Available Renal angiomyolipoma are part of the PEComa family of neoplasms, and occur both in association with Tuberous Sclerosis Complex (TSC and independent of that disorder. Previous studies on the molecular genetic alterations that occur in angiomyolipoma are very limited. We evaluated 9 angiomyolipoma for which frozen tissue was available from a consecutive surgical series. Seven of 8 samples subjected to RT-PCR-cDNA sequencing showed mutations in TSC2; none showed mutations in TSC1 or RHEB. Six of the seven mutations were deletions. We searched for 983 activating and inactivating mutations in 115 genes, and found none in these tumors. Similarly analysis for genomic regions of loss or gain, assessed by Affymetrix SNP6.0 analysis, showed no abnormalities. Loss of heterozygosity in the TSC2 region was commonly seen, except in patients with low frequency TSC2 mutations. We conclude that sporadic renal angiomyolipoma usually have mutations in TSC2, but not TSC1 or RHEB, and have no other common genomic events, among those we searched for. However, chromosomal translocations and gene fusion events were not assessed here. TSC2 inactivation by mutation is a consistent and likely necessary genetic event in the pathogenesis of most angiomyolipoma.

  3. Applying genetics in inflammatory disease drug discovery

    DEFF Research Database (Denmark)

    Folkersen, Lasse; Biswas, Shameek; Frederiksen, Klaus Stensgaard

    2015-01-01

    Recent groundbreaking work in genetics has identified thousands of small-effect genetic variants throughout the genome that are associated with almost all major diseases. These genome-wide association studies (GWAS) are often proposed as a source of future medical breakthroughs. However......, with several notable exceptions, the journey from a small-effect genetic variant to a functional drug has proven arduous, and few examples of actual contributions to drug discovery exist. Here, we discuss novel approaches of overcoming this hurdle by using instead public genetics resources as a pragmatic guide...... alongside existing drug discovery methods. Our aim is to evaluate human genetic confidence as a rationale for drug target selection....

  4. Genetics of Congenital Heart Disease: Past and Present.

    Science.gov (United States)

    Muntean, Iolanda; Togănel, Rodica; Benedek, Theodora

    2016-11-02

    Congenital heart disease is the most common congenital anomaly, representing an important cause of infant morbidity and mortality. Congenital heart disease represents a group of heart anomalies that include septal defects, valve defects, and outflow tract anomalies. The exact genetic, epigenetic, or environmental basis of congenital heart disease remains poorly understood, although the exact mechanism is likely multifactorial. However, the development of new technologies including copy number variants, single-nucleotide polymorphism, next-generation sequencing are accelerating the detection of genetic causes of heart anomalies. Recent studies suggest a role of small non-coding RNAs, micro RNA, in congenital heart disease. The recently described epigenetic factors have also been found to contribute to cardiac morphogenesis. In this review, we present past and recent genetic discoveries in congenital heart disease.

  5. Common pathophysiological mechanisms of chronic kidney disease: therapeutic perspectives.

    Science.gov (United States)

    López-Novoa, José M; Martínez-Salgado, Carlos; Rodríguez-Peña, Ana B; López-Hernández, Francisco J

    2010-10-01

    It is estimated that over 10% of the adult population in developed countries have some degree of chronic kidney disease (CKD). CKD is a progressive and irreversible deterioration of the renal excretory function that results in implementation of renal replacement therapy in the form of dialysis or renal transplant, which may also lead to death. CKD poses a growing problem to society as the incidence of the disease increases at an annual rate of 8%, and consumes up to 2% of the global health expenditure. CKD is caused by a variety of factors including diabetes, hypertension, infection, reduced blood supply to the kidneys, obstruction of the urinary tract and genetic alterations. The nephropathies associated with some of these conditions have been modeled in animals, this being crucial to understanding their pathophysiological mechanism and assessing prospective treatments at the preclinical level. This article reviews and updates the pathophysiological knowledge acquired primarily from experimental models and human studies of CKD. It also highlights the common mechanism(s) underlying the most relevant chronic nephropathies which lead to the appearance of a progressive, common renal phenotype regardless of aetiology. Based on this knowledge, a therapeutic horizon for the treatment of CKD is described. Present therapy primarily based upon renin-angiotensin inhibition, future diagnostics and therapeutic perspectives based upon anti-inflammatory, anti-fibrotic and hemodynamic approaches, new drugs targeting specific signaling pathways, and advances in gene and cell therapies, are all elaborated.

  6. Current Evidence and Insights about Genetics in Thoracic Aorta Disease

    OpenAIRE

    2013-01-01

    Thoracic aortic aneurysms have been historically considered to be caused by etiologic factors similar to those implied in abdominal aortic aneurysms. However, during the past decade, there has been increasing evidence that almost 20% of thoracic aortic aneurysms may be associated with a genetic disease, often within a syndromic or familial disorder. Moreover, the presence of congenital anomalies, such as bicuspid aortic valve, may have a unique common genetic underlying cause. Finally, also s...

  7. Genetics Home Reference: Kawasaki disease

    Science.gov (United States)

    ... Email Facebook Twitter Home Health Conditions Kawasaki disease Kawasaki disease Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Kawasaki disease is a sudden and time-limited (acute) ...

  8. Genetics Home Reference: Hartnup disease

    Science.gov (United States)

    ... Email Facebook Twitter Home Health Conditions Hartnup disease Hartnup disease Enable Javascript to view the expand/collapse boxes. Download PDF Open All Close All Description Hartnup disease is a condition caused by the body's ...

  9. Genetics Home Reference: Krabbe disease

    Science.gov (United States)

    ... Resources (3 links) MalaCards: krabbe disease Orphanet: Krabbe disease Tulane University Patient Support and Advocacy Resources (3 links) Children Living with Inherited Metabolic Diseases Hunter's Hope Foundation National Organization for Rare Disorders ...

  10. Genetics Home Reference: celiac disease

    Science.gov (United States)

    ... Email Facebook Twitter Home Health Conditions celiac disease celiac disease Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Celiac disease is a condition in which the immune system ...

  11. Genetic Testing for Complex Diseases: a Simulation Study Perspective

    CERN Document Server

    Vinh, Nguyen Xuan

    2011-01-01

    It is widely recognized nowadays that complex diseases are caused by, amongst the others, multiple genetic factors. The recent advent of genome-wide association study (GWA) has triggered a wave of research aimed at discovering genetic factors underlying common complex diseases. While the number of reported susceptible genetic variants is increasing steadily, the application of such findings into diseases prognosis for the general population is still unclear, and there are doubts about whether the size of the contribution by such factors is significant. In this respect, some recent simulation-based studies have shed more light to the prospect of genetic tests. In this report, we discuss several aspects of simulation-based studies: their parameters, their assumptions, and the information they provide.

  12. Genetics of Nonalcoholic Fatty Liver Disease: An Overview

    Institute of Scientific and Technical Information of China (English)

    Jharna Puppala; Siva Prasad Siddapuram; Jyothy Akka; Anjana Munshi

    2013-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the world today.Its incidence in adults and children is rising rapidly due to the ongoing epidemics of obesity and type 2 diabetes.Hence,it has become a global public health issue.Environmental factors have been found to play a major role in the etiology of NAFLD,especially for genetically susceptible populations.Among these,one of the most important factors is junk food,especially the typical "Western-style" diet rich in simple carbohydrates,saturated fat,and highly processed food materials.Genetic predisposition to NAFLD does occur; however,a precise definition of genetic factors responsible for NAFLD is still lacking.Specific variants of different genes have been shown to present a risk for NAFLD.Genetic studies might be helpful in the management of the disease by developing novel treatment strategies based on individual's genotype.

  13. Systems genetics view of endometriosis: a common complex disorder.

    Science.gov (United States)

    Baranov, Vladislav S; Ivaschenko, Tatyana E; Liehr, Thomas; Yarmolinskaya, Maria I

    2015-02-01

    Endometriosis is a condition in which cells derived from the endometrium grow outside the uterus, e.g. in the peritoneum (external genital endometriosis). As these cells are under the influence of female hormones, major symptoms of endometriosis are pain, especially during the cycle, and infertility. Numerous hypotheses for the formation of endometriosis can be found in the literature, but there is growing evidence of serious genetic contributions to endometriosis susceptibility. The involvement of genes, steroid hormone metabolism, immunological reactions, receptor formation, inflammation, proliferation, apoptosis, intercellular adhesion, cell invasion and angiogenesis as well as genes regulating the activity of aforementioned enzymes have been suggested. Some more recently suggested candidate genes picked up in genome-wide association studies are involved in oncogenesis, metaplasia of endometrium cells and pathways of embryonic development of the female reproductive system. However, gene mutations proven to be causative for endometriosis have not been identified so far, even though the abnormal expression of candidate genes for endometriosis could be provoked by different epigenetic modifications including DNA methylation, heterochromatization or introduction of regulatory miRNA. We hypothesize that endometriosis is induced by a combination of abnormal genetic and/or epigenetic mutations: the latter pave the way for pathological changes which become irreversible, and according to the "epigenetic landscape" theory, this proceeds to the typical clinical manifestations. Two stages in the endometriosis pathway are suggested: (1) induction of primary endometrial cells toward endometriosis, and (2) implantation and progression of these cells into endometriosis lesions. The model favors endometriosis as an outgrowth of primary cells different in their origin, canalization of pathological processes, manifestation diversity provoked by unique genetic background and

  14. [The genetics of collagen diseases].

    Science.gov (United States)

    Kaplan, J; Maroteaux, P; Frezal, J

    1986-01-01

    Heritable disorders of collagen include Ehler-Danlos syndromes (11 types are actually known), Larsen syndrome and osteogenesis imperfecta. Their clinical, genetic and biochemical features are reviewed. Marfan syndrome is closely related to heritable disorders of collagen.

  15. Genetically Modified Pig Models for Human Diseases

    Institute of Scientific and Technical Information of China (English)

    Nana Fan; Liangxue Lai

    2013-01-01

    Genetically modified animal models are important for understanding the pathogenesis of human disease and developing therapeutic strategies.Although genetically modified mice have been widely used to model human diseases,some of these mouse models do not replicate important disease symptoms or pathology.Pigs are more similar to humans than mice in anatomy,physiology,and genome.Thus,pigs are considered to be better animal models to mimic some human diseases.This review describes genetically modified pigs that have been used to model various diseases including neurological,cardiovascular,and diabetic disorders.We also discuss the development in gene modification technology that can facilitate the generation of transgenic pig models for human diseases.

  16. Genetics Home Reference: Pelizaeus-Merzbacher disease

    Science.gov (United States)

    ... Garbern JY. Pelizaeus-Merzbacher disease: pathogenic mechanisms and insights into the roles of proteolipid protein 1 in ... healthcare professional . About Genetics Home Reference Site Map Customer Support Selection Criteria for Links USA.gov Copyright ...

  17. Unraveling the genetics of chronic kidney disease using animal models

    NARCIS (Netherlands)

    Korstanje, Ron; DiPetrillo, K.

    2004-01-01

    Identifying genes underlying common forms of kidney disease in humans has proven difficult, expensive, and time consuming. Quantitative trait loci (QTL) for several complex traits are concordant among mice, rats, and humans, suggesting that genetic findings from these animal models are relevant to

  18. Point mutations as a source of de novo genetic disease

    NARCIS (Netherlands)

    Ligt, J. de; Veltman, J.A.; Vissers, L.E.L.M.

    2013-01-01

    Family-based next generation sequencing (NGS) has recently pointed to an important role for de novo germline point mutations in both rare and common genetic disorders associated with reduced fitness. In this review we highlight the impact of the mutational target size on the frequency of diseases ca

  19. Genetics Home Reference: Fabry disease

    Science.gov (United States)

    ... AJ, Germain DP, Goldman M, Grabowski G, Packman S, Wilcox WR. Fabry disease, an under-recognized multisystemic disorder: ... Sims K, Brodie SE, Pastores GM, Strotmann JM, Wilcox WR. Fabry disease: guidelines for the evaluation and ...

  20. Application of R to investigate common gene regulatory network pathway among bipolar disorder and associate diseases

    Directory of Open Access Journals (Sweden)

    Nahida Habib

    2016-12-01

    Full Text Available Depression, Major Depression or mental disorder creates severe diseases. Mental illness such as Unipolar Major Depression, Bipolar Disorder, Dysthymia, Schizophrenia, Cardiovascular Diseases (Hypertension, Coronary Heart Disease, Stroke etc., are known as Major Depression. Several studies have revealed the possibilities about the association among Bipolar Disorder, Schizophrenia, Coronary Heart Diseases and Stroke with each other. The current study aimed to investigate the relationships between genetic variants in the above four diseases and to create a common pathway or PPI network. The associated genes of each disease are collected from different gene database with verification using R. After performing some preprocessing, mining and operations using R on collected genes, seven (7 common associated genes are discovered on selected four diseases (SZ, BD, CHD and Stroke. In each of the iteration, the numbers of collected genes are reduced up to 51%, 36%, 10%, 2% and finally less than 1% respectively. Moreover, common pathway on selected diseases has been investigated in this research.

  1. Diabetic Myonecrosis: Uncommon Complications in Common Diseases

    Directory of Open Access Journals (Sweden)

    Sisira Sran

    2014-01-01

    Full Text Available We report a case of sudden thigh pain from spontaneous quadriceps necrosis, also known as diabetic myonecrosis, in a 28-year-old patient with poorly controlled diabetes mellitus. Diabetic muscle infarction is a rare end-organ complication seen in patients with poor glycemic control and advanced chronic microvascular complications. Proposed mechanisms involve atherosclerotic microvascular occlusion, ischemia-reperfusion related injury, vasculitis with microthrombi formation, and an acquired antiphospholipid syndrome. Diabetic myonecrosis most commonly presents as sudden thigh pain with swelling and should be considered in any patient who has poorly controlled diabetes mellitus.

  2. Understanding rare and common diseases in the context of human evolution.

    Science.gov (United States)

    Quintana-Murci, Lluis

    2016-11-07

    The wealth of available genetic information is allowing the reconstruction of human demographic and adaptive history. Demography and purifying selection affect the purge of rare, deleterious mutations from the human population, whereas positive and balancing selection can increase the frequency of advantageous variants, improving survival and reproduction in specific environmental conditions. In this review, I discuss how theoretical and empirical population genetics studies, using both modern and ancient DNA data, are a powerful tool for obtaining new insight into the genetic basis of severe disorders and complex disease phenotypes, rare and common, focusing particularly on infectious disease risk.

  3. Pathogenesis: common pathways between hidradenitis suppurativa and Crohn disease.

    Science.gov (United States)

    García Martínez, F J; Menchén, L

    2016-09-01

    Both hidradenitis suppurativa and Crohn disease are considered chronic inflammatory diseases due to immune dysregulation. The high prevalence of Crohn disease patients diagnosed with hidradenitis suppurativa suggests the existence of common pathogenic links. The present literature review analyses the similarities and differences in the pathogenesis of the two diseases, in the search for new research and knowledge targets.

  4. Evidence-based psychiatric genetics, AKA the false dichotomy between common and rare variant hypotheses.

    Science.gov (United States)

    Visscher, P M; Goddard, M E; Derks, E M; Wray, N R

    2012-05-01

    In this article, we review some of the data that contribute to our understanding of the genetic architecture of psychiatric disorders. These include results from evolutionary modelling (hence no data), the observed recurrence risk to relatives and data from molecular markers. We briefly discuss the common-disease common-variant hypothesis, the success (or otherwise) of genome-wide association studies, the evidence for polygenic variance and the likely success of exome and whole-genome sequencing studies. We conclude that the perceived dichotomy between 'common' and 'rare' variants is not only false, but unhelpful in making progress towards increasing our understanding of the genetic basis of psychiatric disorders. Strong evidence has been accumulated that is consistent with the contribution of many genes to risk of disease, across a wide range of allele frequencies and with a substantial proportion of genetic variation in the population in linkage disequilibrium with single-nucleotide polymorphisms (SNPs) on commercial genotyping arrays. At the same time, most causal variants that segregate in the population are likely to be rare and in total these variants also explain a significant proportion of genetic variation. It is the combination of allele frequency, effect size and functional characteristics that will determine the success of new experimental paradigms such as whole exome/genome sequencing to detect such loci. Empirical results suggest that roughly half the genetic variance is tagged by SNPs on commercial genome-wide chips, but that individual causal variants have a small effect size, on average. We conclude that larger experimental sample sizes are essential to further our understanding of the biology underlying psychiatric disorders.

  5. Genetic and Epigenetic Determinants in Autoinflammatory Diseases

    Science.gov (United States)

    Álvarez-Errico, Damiana; Vento-Tormo, Roser; Ballestar, Esteban

    2017-01-01

    The concept of autoinflammation has evolved over the past 20 years, beginning with the discovery that mutations in the Mediterranean Fever (MEFV) gene were causative of Familial Mediterranean Fever. Currently, autoinflammatory diseases comprise a wide range of disorders with the common features of recurrent fever attacks, prevalence of hyperreactive innate immune cells, and signs of inflammation that can be systemic or organ specific in the absence of pathogenic infection of autoimmunity. Innate immune cells from the myeloid compartment are the main effectors of uncontrolled inflammation that is caused in great extent by the overproduction of inflammatory cytokines such as IL-1β and IL-18. Defects in several signaling pathways that control innate immune defense, particularly the hyperreactivity of one or more inflammasomes, are at the core of pathologic autoinflammatory phenotypes. Although many of the autoinflammatory syndromes are known to be monogenic, some of them are genetically complex and are impacted by environmental factors. Recently, epigenetic dysregulation has surfaced as an additional contributor to pathogenesis. In the present review, we discuss data that are currently available to describe the contribution of epigenetic mechanisms in autoinflammatory diseases.

  6. Phenotypic commonalities in familial and sporadic Parkinson disease.

    Science.gov (United States)

    Baba, Yasuhiko; Markopoulou, Katerina; Putzke, John D; Whaley, Nathaniel R; Farrer, Matthew J; Wszolek, Zbigniew K; Uitti, Ryan J

    2006-04-01

    Parkinson disease (PD) is a clinically well-documented neurodegenerative disorder. However, the mechanism or mechanisms of its phenotypic expressions are still unknown. To compare phenotypes by examining demographic and clinical features of patients with familial PD and sporadic PD and with or without a family history of PD. Historical review of patients with sporadic PD in clinic-based samples and individual patients diagnosed with PD from families whose linkage to mutations or loci has been identified. Movement disorder clinic in a referral center. A total of 1277 patients with sporadic PD and 40 patients with familial PD. Clinical features, including distribution by sex, initial motor symptom, location of initial motor symptom, and frequency of asymmetric motor symptoms. Despite different etiologic backgrounds, both familial and sporadic PD exhibited several interesting commonalities, including a higher incidence in men, tremor as the initial motor symptom (predominantly involving the upper extremities), and asymmetric parkinsonism during disease course. The increased incidence of parkinsonism in men with familial PD suggests that the sex disparity is more likely the result of a protective effect against development of PD in women than of an increased risk in men that is associated with environmental factors. Phenotypic similarity among familial and sporadic PD indicates that a similar topographic distribution of the nigrostriatal lesion exists in patients with either form of PD regardless of apparent genetic influence.

  7. Convergence of circuit dysfunction in ASD: a common bridge between diverse genetic and environmental risk factors and common clinical electrophysiology

    Science.gov (United States)

    Port, Russell G.; Gandal, Michael J.; Roberts, Timothy P. L.; Siegel, Steven J.; Carlson, Gregory C.

    2014-01-01

    Most recent estimates indicate that 1 in 68 children are affected by an autism spectrum disorder (ASD). Though decades of research have uncovered much about these disorders, the pathological mechanism remains unknown. Hampering efforts is the seeming inability to integrate findings over the micro to macro scales of study, from changes in molecular, synaptic and cellular function to large-scale brain dysfunction impacting sensory, communicative, motor and cognitive activity. In this review, we describe how studies focusing on neuronal circuit function provide unique context for identifying common neurobiological disease mechanisms of ASD. We discuss how recent EEG and MEG studies in subjects with ASD have repeatedly shown alterations in ensemble population recordings (both in simple evoked related potential latencies and specific frequency subcomponents). Because these disease-associated electrophysiological abnormalities have been recapitulated in rodent models, studying circuit differences in these models may provide access to abnormal circuit function found in ASD. We then identify emerging in vivo and ex vivo techniques, focusing on how these assays can characterize circuit level dysfunction and determine if these abnormalities underlie abnormal clinical electrophysiology. Such circuit level study in animal models may help us understand how diverse genetic and environmental risks can produce a common set of EEG, MEG and anatomical abnormalities found in ASD. PMID:25538564

  8. Convergence of circuit dysfunction in ASD: a common bridge between diverse genetic and environmental risk factors and common clinical electrophysiology.

    Science.gov (United States)

    Port, Russell G; Gandal, Michael J; Roberts, Timothy P L; Siegel, Steven J; Carlson, Gregory C

    2014-01-01

    Most recent estimates indicate that 1 in 68 children are affected by an autism spectrum disorder (ASD). Though decades of research have uncovered much about these disorders, the pathological mechanism remains unknown. Hampering efforts is the seeming inability to integrate findings over the micro to macro scales of study, from changes in molecular, synaptic and cellular function to large-scale brain dysfunction impacting sensory, communicative, motor and cognitive activity. In this review, we describe how studies focusing on neuronal circuit function provide unique context for identifying common neurobiological disease mechanisms of ASD. We discuss how recent EEG and MEG studies in subjects with ASD have repeatedly shown alterations in ensemble population recordings (both in simple evoked related potential latencies and specific frequency subcomponents). Because these disease-associated electrophysiological abnormalities have been recapitulated in rodent models, studying circuit differences in these models may provide access to abnormal circuit function found in ASD. We then identify emerging in vivo and ex vivo techniques, focusing on how these assays can characterize circuit level dysfunction and determine if these abnormalities underlie abnormal clinical electrophysiology. Such circuit level study in animal models may help us understand how diverse genetic and environmental risks can produce a common set of EEG, MEG and anatomical abnormalities found in ASD.

  9. Convergence of Circuit Dysfunction in ASD: A common bridge between diverse genetic and environmental risk factors and common clinical neurophysiology.

    Directory of Open Access Journals (Sweden)

    Russell G Port

    2014-12-01

    Full Text Available Most recent estimates indicate that 1 in 68 children are affected by an autism spectrum disorder (ASD. Though decades of research have uncovered much about these disorders, the pathological mechanism remains unknown. Hampering efforts is the seeming inability to integrate findings over the micro to macro scales of study, from changes in molecular, synaptic and cellular function to large-scale brain dysfunction impacting sensory, communicative, motor and cognitive activity. In this review, we describe how studies focusing on neuronal circuit function provide unique context for identifying common neurobiological disease mechanisms of ASD. We discuss how recent EEG and MEG studies in subjects with ASD have repeatedly shown alterations in ensemble population recordings (both in simple evoked related potential latencies and specific frequency subcomponents. Because these disease-associated electrophysiological abnormalities have been recapitulated in rodent models, studying circuit differences in these models may provide access to abnormal circuit function found in ASD. We then identify emerging in-vivo and ex-vivo techniques, focusing on how these assays can characterize circuit level dysfunction and determine if these abnormalities underlie abnormal clinical electrophysiology. Such circuit level study in animal models may help us understand how diverse genetic and environmental risks can produce a common set of EEG, MEG and anatomical abnormalities found in ASD.

  10. Genetics Home Reference: Wilson disease

    Science.gov (United States)

    ... body. Mutations in the ATP7B gene prevent the transport protein from functioning properly. With a shortage of functional ... GeneReview: Wilson Disease MedlinePlus Encyclopedia: Wilson's disease National Human Genome Research Institute General Information from MedlinePlus (5 ...

  11. Phenotype-Based Genetic Association Studies (PGAS—Towards Understanding the Contribution of Common Genetic Variants to Schizophrenia Subphenotypes

    Directory of Open Access Journals (Sweden)

    Hannelore Ehrenreich

    2014-02-01

    Full Text Available Neuropsychiatric diseases ranging from schizophrenia to affective disorders and autism are heritable, highly complex and heterogeneous conditions, diagnosed purely clinically, with no supporting biomarkers or neuroimaging criteria. Relying on these “umbrella diagnoses”, genetic analyses, including genome-wide association studies (GWAS, were undertaken but failed to provide insight into the biological basis of these disorders. “Risk genotypes” of unknown significance with low odds ratios of mostly <1.2 were extracted and confirmed by including ever increasing numbers of individuals in large multicenter efforts. Facing these results, we have to hypothesize that thousands of genetic constellations in highly variable combinations with environmental co-factors can cause the individual disorder in the sense of a final common pathway. This would explain why the prevalence of mental diseases is so high and why mutations, including copy number variations, with a higher effect size than SNPs, constitute only a small part of variance. Elucidating the contribution of normal genetic variation to (disease phenotypes, and so re-defining disease entities, will be extremely labor-intense but crucial. We have termed this approach PGAS (“phenotype-based genetic association studies”. Ultimate goal is the definition of biological subgroups of mental diseases. For that purpose, the GRAS (Göttingen Research Association for Schizophrenia data collection was initiated in 2005. With >3000 phenotypical data points per patient, it comprises the world-wide largest currently available schizophrenia database (N > 1200, combining genome-wide SNP coverage and deep phenotyping under highly standardized conditions. First PGAS results on normal genetic variants, relevant for e.g., cognition or catatonia, demonstrated proof-of-concept. Presently, an autistic subphenotype of schizophrenia is being defined where an unfortunate accumulation of normal genotypes, so

  12. Parkinson's disease: piecing together a genetic jigsaw.

    NARCIS (Netherlands)

    M.C.J. Dekker (Marieke); V. Bonifati (Vincenzo); C.M. van Duijn (Cock)

    2003-01-01

    textabstractThe role of genetics in the pathogenesis of Parkinson's disease has been subject to debate for decades. In recent years, the discovery of five genes and several more loci has provided important insight into its molecular aetiology. Some Parkinson's disease genes possibly cause

  13. A genetic perspective on coeliac disease

    NARCIS (Netherlands)

    Trynka, Gosia; Wijmenga, Cisca; van Heel, David A.

    2010-01-01

    Coeliac disease is an inflammatory disorder of the small intestine with an autoimmune component and strong heritability. Genetic studies have confirmed strong association to HLA and identified 39 nonHLA risk genes, mostly immune-related. Over 50% of the disease-associated single nucleotide

  14. Introduction to Protein Structure through Genetic Diseases

    Science.gov (United States)

    Schneider, Tanya L.; Linton, Brian R.

    2008-01-01

    An illuminating way to learn about protein function is to explore high-resolution protein structures. Analysis of the proteins involved in genetic diseases has been used to introduce students to protein structure and the role that individual mutations can play in the onset of disease. Known mutations can be correlated to changes in protein…

  15. Introduction to Protein Structure through Genetic Diseases

    Science.gov (United States)

    Schneider, Tanya L.; Linton, Brian R.

    2008-01-01

    An illuminating way to learn about protein function is to explore high-resolution protein structures. Analysis of the proteins involved in genetic diseases has been used to introduce students to protein structure and the role that individual mutations can play in the onset of disease. Known mutations can be correlated to changes in protein…

  16. Parkinson's disease: piecing together a genetic jigsaw.

    NARCIS (Netherlands)

    M.C.J. Dekker (Marieke); V. Bonifati (Vincenzo); C.M. van Duijn (Cock)

    2003-01-01

    textabstractThe role of genetics in the pathogenesis of Parkinson's disease has been subject to debate for decades. In recent years, the discovery of five genes and several more loci has provided important insight into its molecular aetiology. Some Parkinson's disease genes possibly cause Parkinson'

  17. Genetic Testing in Huntington’s Disease

    OpenAIRE

    J Gordon Millichap

    1997-01-01

    The historical and clinical profiles of Huntington’s disease (HD) presenting in 44 juveniles who were tested for CAG repeat expansions in the gene for HD were defined in a study reported by the US Huntington Disease Genetic Testing Group from the Hennepin County Medical Center, Minneapolis, MN.

  18. Review article : inflammatory bowel disease and genetics

    NARCIS (Netherlands)

    Weersma, R. K.; Van Dullemen, H. M.; Van der Steege, G.; Nolte, I. M.; Kleibeuker, J. H.; Dijkstra, G.

    2007-01-01

    Introduction Inflammatory bowel disease (IBD) comprising ulcerative colitis (UC) and Crohn's disease (CD) is multigenic disorder. Tremendous progress has been achieved in unravelling the genetic background of IBD. It has led to the discovery of mutations in NOD2 associated with ileal CD and numerous

  19. Current evidence and insights about genetics in thoracic aorta disease.

    Science.gov (United States)

    Bisleri, Gianluigi; Bagozzi, Lorenzo; Muneretto, Claudio

    2013-01-01

    Thoracic aortic aneurysms have been historically considered to be caused by etiologic factors similar to those implied in abdominal aortic aneurysms. However, during the past decade, there has been increasing evidence that almost 20% of thoracic aortic aneurysms may be associated with a genetic disease, often within a syndromic or familial disorder. Moreover, the presence of congenital anomalies, such as bicuspid aortic valve, may have a unique common genetic underlying cause. Finally, also sporadic forms have been found to be potentially associated with genetic disorders, as highlighted by the analysis of rare variants and expression of specific microRNAs. We therefore sought to perform a comprehensive review of the role of genetic causes in the development of thoracic aortic aneurysms, by analyzing in detail the current evidence of genetic alterations in syndromes such as Marfan, Loeys-Dietz, and Ehler-Danlos, familial or sporadic forms, or forms associated with bicuspid aortic valve.

  20. Current Evidence and Insights about Genetics in Thoracic Aorta Disease

    Directory of Open Access Journals (Sweden)

    Gianluigi Bisleri

    2013-01-01

    Full Text Available Thoracic aortic aneurysms have been historically considered to be caused by etiologic factors similar to those implied in abdominal aortic aneurysms. However, during the past decade, there has been increasing evidence that almost 20% of thoracic aortic aneurysms may be associated with a genetic disease, often within a syndromic or familial disorder. Moreover, the presence of congenital anomalies, such as bicuspid aortic valve, may have a unique common genetic underlying cause. Finally, also sporadic forms have been found to be potentially associated with genetic disorders, as highlighted by the analysis of rare variants and expression of specific microRNAs. We therefore sought to perform a comprehensive review of the role of genetic causes in the development of thoracic aortic aneurysms, by analyzing in detail the current evidence of genetic alterations in syndromes such as Marfan, Loeys-Dietz, and Ehler-Danlos, familial or sporadic forms, or forms associated with bicuspid aortic valve.

  1. Genetics in Parkinson disease: Mendelian versus non-Mendelian inheritance.

    Science.gov (United States)

    Hernandez, Dena G; Reed, Xylena; Singleton, Andrew B

    2016-10-01

    Parkinson's disease is a common, progressive neurodegenerative disorder, affecting 3% of those older than 75 years of age. Clinically, Parkinson's disease (PD) is associated with resting tremor, postural instability, rigidity, bradykinesia, and a good response to levodopa therapy. Over the last 15 years, numerous studies have confirmed that genetic factors contribute to the complex pathogenesis of PD. Highly penetrant mutations producing rare, monogenic forms of the disease have been discovered in singular genes such as SNCA, Parkin, DJ-1, PINK 1, LRRK2, and VPS35. Unique variants with incomplete penetrance in LRRK2 and GBA have been shown to be strong risk factors for PD in certain populations. Additionally, over 20 common variants with small effect sizes are now recognized to modulate the risk for PD. Investigating Mendelian forms of PD has provided precious insight into the pathophysiology that underlies the more common idiopathic form of disease; however, no treatment methodologies have developed. Furthermore, for identified common risk alleles, the functional basis underlying risk principally remains unknown. The challenge over the next decade will be to strengthen the findings delivered through genetic discovery by assessing the direct, biological consequences of risk variants in tandem with additional high-content, integrated datasets. This review discusses monogenic risk factors and mechanisms of Mendelian inheritance of Parkinson disease. Highly penetrant mutations in SNCA, Parkin, DJ-1, PINK 1, LRRK2 and VPS35 produce rare, monogenic forms of the disease, while unique variants within LRRK2 and GBA show incomplete penetrance and are strong risk factors for PD. Additionally, over 20 common variants with small effect sizes modulate disease risk. The challenge over the next decade is to strengthen genetic findings by assessing direct, biological consequences of risk variants in tandem with high-content, integrated datasets. This article is part of a special

  2. Common Diseases and Some Demographic Characteristics among Saudi Women

    Science.gov (United States)

    Al-Haramlah, Ahmed Abdulrahman; Al-Bakr, Fawziah; Merza, Haniah

    2015-01-01

    This study aimed to detect the common diseases among Saudi women and their relationship with the level of physical activity and some variables. This study was applied to 1233 Saudi woman in different regions of the Kingdom, and adopted to explore the common diseases: obesity, hypertension, diabetes, cholesterol and asthma. The study results showed…

  3. Genetics Home Reference: Caffey disease

    Science.gov (United States)

    ... do not experience its signs or symptoms; this phenomenon is called incomplete penetrance. In some cases, an ... O, Phadke SR. COL1A1 mutation in an Indian child with Caffey disease. Indian J Pediatr. 2011 Jul; ...

  4. Genetics Home Reference: Schindler disease

    Science.gov (United States)

    ... spectrum disorders are characterized by impaired communication and socialization skills. Related Information What does it mean if ... deficiency Patient Support and Advocacy Resources (3 links) Children Living with Inherited Metabolic Diseases (CLIMB) ISMRD: The ...

  5. Genetics Home Reference: Tangier disease

    Science.gov (United States)

    ... characterized by significantly reduced levels of high-density lipoprotein ( HDL ) in the blood. HDL transports cholesterol and ... This Condition A-alphalipoprotein Neuropathy alpha High Density Lipoprotein Deficiency Disease Analphalipoproteinemia Cholesterol thesaurismosis Familial High Density ...

  6. Huntington’s Disease Genetics

    OpenAIRE

    Richard H Myers

    2004-01-01

    Summary:Huntington’s disease (HD) is a dominantly transmitted neurodegenerative disorder with wide variation in onset age but with an average age at onset of 40 years. Children of HD gene carriers have a 50% chance of inheriting the disease. The characteristic symptoms of HD are involuntary choreiform movements, cognitive impairment, mood disorders, and behavioral changes which are chronic and progressive over the course of the illness. HD is a “trinucleotide repeat” disorder, which is caused...

  7. Kin-Aggregations Explain Chaotic Genetic Patchiness, a Commonly Observed Genetic Pattern, in a Marine Fish.

    Science.gov (United States)

    Selwyn, Jason D; Hogan, J Derek; Downey-Wall, Alan M; Gurski, Lauren M; Portnoy, David S; Heath, Daniel D

    2016-01-01

    The phenomenon of chaotic genetic patchiness is a pattern commonly seen in marine organisms, particularly those with demersal adults and pelagic larvae. This pattern is usually associated with sweepstakes recruitment and variable reproductive success. Here we investigate the biological underpinnings of this pattern in a species of marine goby Coryphopterus personatus. We find that populations of this species show tell-tale signs of chaotic genetic patchiness including: small, but significant, differences in genetic structure over short distances; a non-equilibrium or "chaotic" pattern of differentiation among locations in space; and within locus, within population deviations from the expectations of Hardy-Weinberg equilibrium (HWE). We show that despite having a pelagic larval stage, and a wide distribution across Caribbean coral reefs, this species forms groups of highly related individuals at small spatial scales (<10 metres). These spatially clustered family groups cause the observed deviations from HWE and local population differentiation, a finding that is rarely demonstrated, but could be more common than previously thought.

  8. Disease-Concordant Twins Empower Genetic Association Studies.

    Science.gov (United States)

    Tan, Qihua; Li, Weilong; Vandin, Fabio

    2017-01-01

    Genome-wide association studies with moderate sample sizes are underpowered, especially when testing SNP alleles with low allele counts, a situation that may lead to high frequency of false-positive results and lack of replication in independent studies. Related individuals, such as twin pairs concordant for a disease, should confer increased power in genetic association analysis because of their genetic relatedness. We conducted a computer simulation study to explore the power advantage of the disease-concordant twin design, which uses singletons from disease-concordant twin pairs as cases and ordinary healthy samples as controls. We examined the power gain of the twin-based design for various scenarios (i.e., cases from monozygotic and dizygotic twin pairs concordant for a disease) and compared the power with the ordinary case-control design with cases collected from the unrelated patient population. Simulation was done by assigning various allele frequencies and allelic relative risks for different mode of genetic inheritance. In general, for achieving a power estimate of 80%, the sample sizes needed for dizygotic and monozygotic twin cases were one half and one fourth of the sample size of an ordinary case-control design, with variations depending on genetic mode. Importantly, the enriched power for dizygotic twins also applies to disease-concordant sibling pairs, which largely extends the application of the concordant twin design. Overall, our simulation revealed a high value of disease-concordant twins in genetic association studies and encourages the use of genetically related individuals for highly efficiently identifying both common and rare genetic variants underlying human complex diseases without increasing laboratory cost. © 2016 John Wiley & Sons Ltd/University College London.

  9. Inflammatory bowel disease: Genetic and epidemiologic considerations

    Institute of Scientific and Technical Information of China (English)

    Judy H Cho

    2008-01-01

    Genome-wide association studies have firmly established that many genomic loci contribute to inflammatory bowel disease, especially in Crohn's disease. These studies have newly-established the importance of the interleukin 23 and autophagy pathways in disease pathogenesis. Future challenges include: (1) the establishment of precisely causal alleles, (2) definition of altered functional outcomes of associated and causal alleles and (3) integration of genetic findings with environmental factors.

  10. Genetic mechanisms and age-related macular degeneration: common variants, rare variants, copy number variations, epigenetics, and mitochondrial genetics

    Directory of Open Access Journals (Sweden)

    Liu Melissa M

    2012-08-01

    Full Text Available Abstract Age-related macular degeneration (AMD is a complex and multifaceted disease involving contributions from both genetic and environmental influences. Previous work exploring the genetic contributions of AMD has implicated numerous genomic regions and a variety of candidate genes as modulators of AMD susceptibility. Nevertheless, much of this work has revolved around single-nucleotide polymorphisms (SNPs, and it is apparent that a significant portion of the heritability of AMD cannot be explained through these mechanisms. In this review, we consider the role of common variants, rare variants, copy number variations, epigenetics, microRNAs, and mitochondrial genetics in AMD. Copy number variations in regulators of complement activation genes (CFHR1 and CFHR3 and glutathione S transferase genes (GSTM1 and GSTT1 have been associated with AMD, and several additional loci have been identified as regions of potential interest but require further evaluation. MicroRNA dysregulation has been linked to the retinal pigment epithelium degeneration in geographic atrophy, ocular neovascularization, and oxidative stress, all of which are hallmarks in the pathogenesis of AMD. Certain mitochondrial DNA haplogroups and SNPs in mitochondrially encoded NADH dehydrogenase genes have also been associated with AMD. The role of these additional mechanisms remains only partly understood, but the importance of their further investigation is clear to elucidate more completely the genetic basis of AMD.

  11. Genetic Architecture of Atherosclerosis in Mice: A Systems Genetics Analysis of Common Inbred Strains.

    Directory of Open Access Journals (Sweden)

    Brian J Bennett

    2015-12-01

    Full Text Available Common forms of atherosclerosis involve multiple genetic and environmental factors. While human genome-wide association studies have identified numerous loci contributing to coronary artery disease and its risk factors, these studies are unable to control environmental factors or examine detailed molecular traits in relevant tissues. We now report a study of natural variations contributing to atherosclerosis and related traits in over 100 inbred strains of mice from the Hybrid Mouse Diversity Panel (HMDP. The mice were made hyperlipidemic by transgenic expression of human apolipoprotein E-Leiden (APOE-Leiden and human cholesteryl ester transfer protein (CETP. The mice were examined for lesion size and morphology as well as plasma lipid, insulin and glucose levels, and blood cell profiles. A subset of mice was studied for plasma levels of metabolites and cytokines. We also measured global transcript levels in aorta and liver. Finally, the uptake of acetylated LDL by macrophages from HMDP mice was quantitatively examined. Loci contributing to the traits were mapped using association analysis, and relationships among traits were examined using correlation and statistical modeling. A number of conclusions emerged. First, relationships among atherosclerosis and the risk factors in mice resemble those found in humans. Second, a number of trait-loci were identified, including some overlapping with previous human and mouse studies. Third, gene expression data enabled enrichment analysis of pathways contributing to atherosclerosis and prioritization of candidate genes at associated loci in both mice and humans. Fourth, the data provided a number of mechanistic inferences; for example, we detected no association between macrophage uptake of acetylated LDL and atherosclerosis. Fifth, broad sense heritability for atherosclerosis was much larger than narrow sense heritability, indicating an important role for gene-by-gene interactions. Sixth, stepwise linear

  12. Higher usual alcohol consumption was associated with a lower 41-y mortality risk from coronary artery disease in men independent of genetic and common environmental factors: the prospective NHLBI Twin Study.

    Science.gov (United States)

    Dai, Jun; Mukamal, Kenneth J; Krasnow, Ruth E; Swan, Gary E; Reed, Terry

    2015-07-01

    Evidence that alcohol consumption is inversely associated with long-term coronary artery disease (CAD) mortality independent of genetic and early life environmental factors is lacking. We evaluated whether alcohol consumption was prospectively associated with CAD mortality risk independent of familial factors. In total, 843 male twins (396 pairs and 51 unpaired twins) aged 42-55 y (mean: 48 y) without baseline CAD reported beer, wine, and spirits consumption at baseline (1969-1973) and were followed up to 2010 in the prospective National Heart, Lung, and Blood Institute Twin Study. Data on usual alcohol consumption over the past year were collected. Outcome was time to event, where the primary event was death from CAD and secondary events were death from cardiovascular disease and all causes. HRs were estimated by using frailty survival models, both overall and within-pair. There were 129 CAD deaths and 219 cardiovascular deaths during 41 y of follow-up. In the whole cohort, after adjustment for caloric intake and cardiovascular disease risk factors, overall HRs per 10-g increment in alcohol intake were 0.94 (95% CI: 0.89, 0.98) for CAD and 0.97 (95% CI: 0.93, 1.00) for cardiovascular mortality. The within-pair adjusted HRs for a twin with 10-g higher daily alcohol consumption than his co-twin were 0.90 (95% CI: 0.84, 0.97) for CAD and 0.95 (95% CI: 0.90, 1.00) for cardiovascular disease mortality in the cohort pooled by zygosity, which remained similar among monozygotic twins. All 3 beverage types tended to be associated with lower CAD mortality risk within-pair to a similar degree. Alcohol consumption was not associated with total mortality risk overall or within-pair. Higher usual alcohol consumption is associated with lower CAD mortality risk, independent of germline and early life environment and adulthood experience shared among twins, supporting a possible causal role of alcohol consumption in lowering CAD death risk. This trial was registered at

  13. Currently Clinical Views on Genetics of Wilson's Disease

    Institute of Scientific and Technical Information of China (English)

    Chen Chen; Bo Shen; Jia-Jia Xiao; Rong Wu; Sarah Jane Duff Canning; Xiao-Ping Wang

    2015-01-01

    Objective:The objective of this study was to review the research on clinical genetics of Wilson's disease (WD).Data Sources:We searched documents from PubMed and Wanfang databases both in English and Chinese up to 2014 using the keywords WD in combination with genetic,ATP7B gene,gene mutation,genotype,phenotype.Study Selection:Publications about the ATP7B gene and protein function associated with clinical features were selected.Results:Wilson's disease,also named hepatolenticular degeneration,is an autosomal recessive genetic disorder characterized by abnormal copper metabolism caused by mutations to the copper-transporting gene A TP7B.Decreased biliary copper excretion and reduced incorporation of copper into apoceruloplasmin caused by defunctionalization of ATP7B protein lead to accumulation of copper in many tissues and organs,including liver,brain,and cornea,finally resulting in liver disease and extrapyramidal symptoms.It is the most common genetic neurological disorder in the onset of adolescents,second to muscular dystrophy in China.Early diagnosis and medical therapy are of great significance for improving the prognosis of WD patients.However,diagnosis of this disease is usually difficult because of its complicated phenotypes.In the last 10 years,an increasing number of clinical studies have used molecular genetics techniques.Improved diagnosis and prediction of the progression of this disease at the molecular level will aid in the development of more individualized and effective interventions,which is a key to transition from molecular genetic research to the clinical study.Conclusions:Clinical genetics studies are necessary to understand the mechanism underlying WD at the molecular level from the genotype to the phenotype.Clinical genetics research benefits newly emerging medical treatments including stem cell transplantation and gene therapy for WD patients.

  14. Genetics of Parkinson disease and essential tremor.

    Science.gov (United States)

    Wider, Christian; Ross, Owen A; Wszolek, Zbigniew K

    2010-08-01

    Elucidating the genetic background of Parkinson disease and essential tremor is crucial to understand the pathogenesis and improve diagnostic and therapeutic strategies. A number of approaches have been applied including familial and association studies, and studies of gene expression profiles to identify genes involved in susceptibility to Parkinson disease. These studies have nominated a number of candidate Parkinson disease genes and novel loci including Omi/HtrA2, GIGYF2, FGF20, PDXK, EIF4G1 and PARK16. A recent notable finding has been the confirmation for the role of heterozygous mutations in glucocerebrosidase (GBA) as risk factors for Parkinson disease. Finally, association studies have nominated genetic variation in the leucine-rich repeat and Ig containing 1 gene (LINGO1) as a risk for both Parkinson disease and essential tremor, providing the first genetic evidence of a link between the two conditions. Although undoubtedly genes remain to be identified, considerable progress has been achieved in the understanding of the genetic basis of Parkinson disease. This same effort is now required for essential tremor. The use of next-generation high-throughput sequencing and genotyping technologies will help pave the way for future insight leading to advances in diagnosis, prevention and cure.

  15. Genetics Home Reference: prion disease

    Science.gov (United States)

    ... protein called prion protein (PrP). Although the precise function of this protein is unknown, researchers have proposed roles in several ... promote its transformation into PrP Sc . The abnormal protein builds up in the brain, forming ... have no family history of the disease and no identified mutation in ...

  16. Genetics Home Reference: multiminicore disease

    Science.gov (United States)

    ... This Page Ferreiro A, Estournet B, Chateau D, Romero NB, Laroche C, Odent S, Toutain A, Cabello A, Fontan D, dos Santos HG, Haenggeli CA, Bertini E, Urtizberea JA, Guicheney P, Fardeau M. Multi-minicore disease--searching for ... Straub V, Villanova M, Leroy JP, Romero NB, Martin JJ, Muntoni F, Voit T, Estournet ...

  17. Common Genetic Components of Obesity Traits and Serum Leptin

    DEFF Research Database (Denmark)

    Hasselbalch, Ann L; Benyamin, Beben; Visscher, Peter M

    2008-01-01

    , waist and hip, and skin-fold thickness, body composition assessment by bioimpedance (fat mass and fat-free mass), and measurement of serum leptin level. Bivariate variance component analyses estimated the additive genetic correlations between these measurements. The genetic correlations between...

  18. [Complex diseases: the importance of genetics].

    Science.gov (United States)

    Libioulle, C; Bours, V

    2012-01-01

    Complex diseases usually harbour hereditary factors linked with multiple susceptibility genes. The additive effects of genetic and environmental factors are responsible for the pathology. The impact of heredity has been demonstrated through family studies, but also, and mostly, through the study of adopted people and twins. Recently, genome wide association studies (GWAS) allowed the identification of many susceptibility genes for most complex diseases. However, a large part of the heritability is still missing, probably because of insufficient exploration of rare genetic variants and/or epigenetic factors. The ultimate goal of these genetic studies is the definition of an individual risk leading to specific preventive measures (model "predict and prevent"), but this purpose remains very remote for the majority of complex diseases.

  19. Chronic obstructive pulmonary disease and genetics

    DEFF Research Database (Denmark)

    Ingebrigtsen, T.; Thomsen, S.F.; Vestbo, J.

    2008-01-01

    smokers develop COPD. This indicates a genetic contribution to the individual disease susceptibility. Although many genes have been examined, the puzzle of COPD genetics seems still largely unsolved. It is therefore important to measure phenotypes and to perform genome-wide scans of COPD patients in order......Chronic obstructive pulmonary disease (COPD) is characterised by airflow limitation and is associated with an inflammatory response of the lungs primarily caused by cigarette smoking. Cigarette smoking is by far the most important environmental risk factor for COPD, but less than half of all heavy...

  20. Chronic obstructive pulmonary disease and genetics

    DEFF Research Database (Denmark)

    Ingebrigtsen, T.; Thomsen, S.F.; Vestbo, J.

    2008-01-01

    Chronic obstructive pulmonary disease (COPD) is characterised by airflow limitation and is associated with an inflammatory response of the lungs primarily caused by cigarette smoking. Cigarette smoking is by far the most important environmental risk factor for COPD, but less than half of all heavy...... smokers develop COPD. This indicates a genetic contribution to the individual disease susceptibility. Although many genes have been examined, the puzzle of COPD genetics seems still largely unsolved. It is therefore important to measure phenotypes and to perform genome-wide scans of COPD patients in order...

  1. Genetic research in coronary heart disease.

    Science.gov (United States)

    Motulsky, A G

    1984-01-01

    Coronary heart disease research along genetic lines is difficult. Studies in molecular genetics of apolipoprotein and receptor variability appear most promising in the near future. However, unexpected discoveries and methodology may turn up that may completely change the field. Exclusive concentration on lipid research therefore should be avoided. It is likely that most advances will come from carefully designed studies that ask specific questions. Such research design is appropriate not only for laboratory studies but also for clinical and epidemiological investigations. The collaboration of clinicians, biochemists, geneticists, epidemiologists, and statisticians is likely to lead to better understanding of coronary heart disease.

  2. Genetic Correlation between Body Fat Percentage and Cardiorespiratory Fitness Suggests Common Genetic Etiology

    DEFF Research Database (Denmark)

    Schnurr, Theresia M; Gjesing, Anette P; Sandholt, Camilla H

    2016-01-01

    reflect a common genetic origin. In this study we aimed to 1) examine genetic correlations between body fat% and CRF; 2) determine whether CRF can be attributed to a genetic risk score (GRS) based on known body fat% increasing loci; and 3) examine whether the fat mass and obesity associated (FTO) locus...... of twelve independent risk variants known to associate with body fat%. We assessed CRF as maximal oxygen uptake expressed in millilitres of oxygen uptake per kg of body mass (VO2 max), per kg fat-free mass (VO2 maxFFM ), or per kg fat mass (VO2 maxFM ). All analyses were adjusted for age and sex, and when...... was associated with a 0.42 mL/kg/min unit decrease in VO2 max per allele (p = 0.0092, age and sex adjusted). Both associations were abolished after additional adjustment for body fat %. The fat% increasing GRS and FTO risk allele were associated with decreased VO2 maxFM but not with VO2 maxFFM . Conclusions Our...

  3. Baboons as a model to study genetics and epigenetics of human disease.

    Science.gov (United States)

    Cox, Laura A; Comuzzie, Anthony G; Havill, Lorena M; Karere, Genesio M; Spradling, Kimberly D; Mahaney, Michael C; Nathanielsz, Peter W; Nicolella, Daniel P; Shade, Robert E; Voruganti, Saroja; VandeBerg, John L

    2013-01-01

    A major challenge for understanding susceptibility to common human diseases is determining genetic and environmental factors that influence mechanisms underlying variation in disease-related traits. The most common diseases afflicting the US population are complex diseases that develop as a result of defects in multiple genetically controlled systems in response to environmental challenges. Unraveling the etiology of these diseases is exceedingly difficult because of the many genetic and environmental factors involved. Studies of complex disease genetics in humans are challenging because it is not possible to control pedigree structure and often not practical to control environmental conditions over an extended period of time. Furthermore, access to tissues relevant to many diseases from healthy individuals is quite limited. The baboon is a well-established research model for the study of a wide array of common complex diseases, including dyslipidemia, hypertension, obesity, and osteoporosis. It is possible to acquire tissues from healthy, genetically characterized baboons that have been exposed to defined environmental stimuli. In this review, we describe the genetic and physiologic similarity of baboons with humans, the ability and usefulness of controlling environment and breeding, and current genetic and genomic resources. We discuss studies on genetics of heart disease, obesity, diabetes, metabolic syndrome, hypertension, osteoporosis, osteoarthritis, and intrauterine growth restriction using the baboon as a model for human disease. We also summarize new studies and resources under development, providing examples of potential translational studies for targeted interventions and therapies for human disease.

  4. Genetics Home Reference: glycogen storage disease type 0

    Science.gov (United States)

    ... links) Genetic Testing Registry: Glycogen storage disease 0, muscle Genetic Testing Registry: Hypoglycemia with deficiency of glycogen synthetase in ... Sheet (PDF) Disease InfoSearch: Glycogen storage disease 0, ... Manual Consumer Version: Disorders of Carbohydrate Metabolism Orphanet: Glycogen ...

  5. Breast cancer predisposition and brain hemispheric laterality specification likely share a common genetic cause.

    Science.gov (United States)

    Klar, Amar J S

    2011-01-01

    The majority of breast cancer cases seen in women remain unexplained by simple Mendelian genetics. It is generally hypothesized that such non-familial, so-called sporadic cases, result from exposure of the affected individuals to a cancer-causing environment and/or from stochastic cell biological errors. Clearly, adverse environment exposure can cause disease, but is that necessarily the cause of most sporadic cases? Curiously, female breast cancer patients who were selected to prefer right-hand-use reportedly exhibited a higher incidence of reversed-brain hemispheric laterality when compared to that of the public at large. Notably, such a higher level of hemispheric reversal is also found in healthy, left-handed or ambidextrous persons. Based on the association between these disparate traits, a new hypothesis for the etiology of sporadic breast cancer cases is advanced here; breast cancer predisposition and brain laterality development likely share a common genetic cause.

  6. Novel genetic markers in inflammatory bowel disease

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Genetic factors play a significant role in determining inflammatory bowel disease (IBD) susceptibility. Epidemiologic data support genetic contribution to the pathogenesis of IBD, which include familial aggregation, twin studies, racial and ethnic differences in disease prevalence. Linkage studies have identified several susceptibility genes contained in different genomic regions named IBD1 to IBD9. Nucleotide oligomerization domain (NOD2) and human leukocyte antigen (HLA) genes are the most extensively studied genetic regions (IBD1 and IBD3 respectively) in IBD. Mutations of the NOD2 gene are associated with Crohn's disease (CD) and several HLA genes are associated with ulcerative colitis (UC) and CD. Toll like receptors (TLRs) have an important role in the innate immune response against infections by mediating recognition of pathogen-associated microbial patterns. Studying single-nucleotide polymorphisms (SNPs) in molecules involved in bacterial recognition seems to be essential to define genetic backgrounds at risk of IBD. Recently, numerous new genes have been identified to be involved in the genetic susceptibility to IBD: NOD1/Caspase-activation recruitment domains 4 (CARD4), Chemokine ligand 20 (CCL20), IL-11, and IL-18 among others. The characterization of these novel genes potentially will lead to the identification of therapeutic agents and clinical assessment of phenotype and prognosis in patients with IBD.

  7. Genetic testing in congenital heart disease:A clinical approach

    Institute of Scientific and Technical Information of China (English)

    Marie A Chaix; Gregor Andelfinger; Paul Khairy

    2016-01-01

    Congenital heart disease(CHD) is the most common type of birth defect. Traditionally, a polygenic model defined by the interaction of multiple genes and environmental factors was hypothesized to account for different forms of CHD. It is now understood that the contribution of genetics to CHD extends beyond a single unified paradigm. For example, monogenic models and chromosomal abnormalities have been associated with various syndromic and non-syndromic forms of CHD. In such instances, genetic investigation and testing may potentially play an important role in clinical care. A family tree with a detailed phenotypic description serves as the initial screening tool to identify potentially inherited defects and to guide further genetic investigation. The selection of a genetic test is contingent upon the particular diagnostic hypothesis generated by clinical examination. Genetic investigation in CHD may carry the potential to improve prognosis by yielding valuable information with regards to personalized medical care, confidence in the clinical diagnosis, and/or targeted patient followup. Moreover, genetic assessment may serve as a tool to predict recurrence risk, define the pattern of inheritance within a family, and evaluate the need for further family screening. In some circumstances, prenatal or preimplantation genetic screening could identify fetuses or embryos at high risk for CHD. Although genetics may appear to constitute a highly specialized sector of cardiology, basic knowledge regarding inheritance patterns, recurrence risks, and available screening and diagnostic tools, including their strengths and limitations, could assist the treating physician in providing sound counsel.

  8. Human Genetic Variation and Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Sun Ju Chung

    2010-05-01

    Full Text Available Parkinson’s disease (PD is a chronic neurodegenerative disorder with multifactorial etiology. In the past decade, the genetic causes of monogenic forms of familial PD have been defined. However, the etiology and pathogenesis of the majority of sporadic PD cases that occur in outbred populations have yet to be clarified. The recent development of resources such as the International HapMap Project and technological advances in high-throughput genotyping have provided new basis for genetic association studies of common complex diseases, including PD. A new generation of genome-wide association studies will soon offer a potentially powerful approach for mapping causal genes and will likely change treatment and alter our perception of the genetic determinants of PD. However, the execution and analysis of such studies will require great care.

  9. Can Protein in Common Skin Bacteria Offer Disease Protection?

    Science.gov (United States)

    ... https://medlineplus.gov/news/fullstory_162192.html Can Protein in Common Skin Bacteria Offer Disease Protection? RoxP ... Swedish researchers report that Propionibacterium acnes secretes a protein called RoxP that protects against bacteria that are ...

  10. Common Occupational Health Problems In Disease Control In Nigeria

    African Journals Online (AJOL)

    Common Occupational Health Problems In Disease Control In Nigeria. ... laboratories, hazardous gases like ethylene oxide and nitrous oxides; physical agents like ... When duely exposed, health workers are at high risk of health problems like ...

  11. The modular nature of genetic diseases.

    NARCIS (Netherlands)

    Oti, M.O.; Brunner, H.G.

    2007-01-01

    Evidence from many sources suggests that similar phenotypes are begotten by functionally related genes. This is most obvious in the case of genetically heterogeneous diseases such as Fanconi anemia, Bardet-Biedl or Usher syndrome, where the various genes work together in a single biological module.

  12. Genetics Home Reference: Paget disease of bone

    Science.gov (United States)

    ... Clin Pathol. 2010 Mar;63(3):199-203. doi: 10.1136/jcp.2009.064428. Epub 2009 Oct 26. Review. Citation on PubMed Ralston SH, Albagha OM. Genetics of Paget's disease of bone. Curr Osteoporos Rep. 2014 Sep;12(3):263-71. doi: 10.1007/s11914-014-0219-y. Review. Citation ...

  13. Genetic risk factors for autoimmune diseases

    NARCIS (Netherlands)

    Feltkamp, T.E.W.; Aarden, L.A.; Lucas, C.J.; Verweij, C.L.; Vries, R.R.P. de

    1999-01-01

    In most autoimmune diseases multigenic factors play a significant role in pathogenesis. Progress in identifying these genetic factors, many of which are located outside the major histocompatibility complex, was the subject of a recent meeting. Chemicals/CAS: Interleukin-10, 130068-27-8; Transforming

  14. Genetic diseases with rheumatic manifestations in children.

    Science.gov (United States)

    Prahalad, S; Colbert, R A

    1998-09-01

    Many nonrheumatic diseases of childhood present with musculoskeletal abnormalities. A significant proportion of these disorders have a genetic basis, many involving defects in structural proteins of the connective tissue. Chief among these are collagen mutations resulting in spondyloepiphyseal dysplasias and Ehlers-Danlos syndrome, as well as fibrillin defects associated with Marfan's syndrome. A variety of other chromosomal anomalies are associated with musculoskeletal abnormalities, and may result from as yet unidentified connective tissue defects. In addition, metabolic diseases may result in findings of hyper- or hypomobility, or carpal tunnel syndrome. Helpful clinical clues to identify nonrheumatologic musculoskeletal disease, as well as recent advances in our understanding of the genetic basis of several of these disorders, are reviewed here.

  15. Mixing omics: combining genetics and metabolomics to study rheumatic diseases.

    Science.gov (United States)

    Menni, Cristina; Zierer, Jonas; Valdes, Ana M; Spector, Tim D

    2017-03-01

    Metabolomics is an exciting field in systems biology that provides a direct readout of the biochemical activities taking place within an individual at a particular point in time. Metabolite levels are influenced by many factors, including disease status, environment, medications, diet and, importantly, genetics. Thanks to their dynamic nature, metabolites are useful for diagnosis and prognosis, as well as for predicting and monitoring the efficacy of treatments. At the same time, the strong links between an individual's metabolic and genetic profiles enable the investigation of pathways that underlie changes in metabolite levels. Thus, for the field of metabolomics to yield its full potential, researchers need to take into account the genetic factors underlying the production of metabolites, and the potential role of these metabolites in disease processes. In this Review, the methodological aspects related to metabolomic profiling and any potential links between metabolomics and the genetics of some of the most common rheumatic diseases are described. Links between metabolomics, genetics and emerging fields such as the gut microbiome and proteomics are also discussed.

  16. Global distribution of consanguinity and their impact on complex diseases: Genetic disorders from an endogamous population

    Directory of Open Access Journals (Sweden)

    Abdulbari Bener

    2017-10-01

    Conclusion: The present study revealed a higher incidence of certain diseases in consanguineous population with a high significant increase in the prevalence of common adult diseases such as diabetes mellitus, cancer, blood disorders, mental disorders, heart diseases, asthma, gastro-intestinal disorders, hypertension, hearing deficit, G6PD and common eye diseases. This confirms the role of genetic factors across the full spectrum of disease and not only for Mendelian disorders.

  17. Complement genetics, deficiencies, and disease associations.

    Science.gov (United States)

    Mayilyan, Karine R

    2012-07-01

    The complement system is a key component of innate immunity. More than 45 genes encoding the proteins of complement components or their isotypes and subunits, receptors, and regulators have been discovered. These genes are distributed throughout different chromosomes, with 19 genes comprising three significant complement gene clusters in the human genome. Genetic deficiency of any early component of the classical pathway (C1q, C1r/s, C2, C4, and C3) is associated with autoimmune diseases due to the failure of clearance of immune complexes (IC) and apoptotic materials, and the impairment of normal humoral response. Deficiencies of mannan-binding lectin (MBL) and the early components of the alternative (factor D, properdin) and terminal pathways (from C3 onward components: C5, C6, C7, C8, C9) increase susceptibility to infections and their recurrence. While the association of MBL deficiency with a number of autoimmune and infectious disorders has been well established, the effects of the deficiency of other lectin pathway components (ficolins, MASPs) have been less extensively investigated due to our incomplete knowledge of the genetic background of such deficiencies and the functional activity of those components. For complement regulators and receptors, the consequences of their genetic deficiency vary depending on their specific involvement in the regulatory or signalling steps within the complement cascade and beyond. This article reviews current knowledge and concepts about the genetic load of complement component deficiencies and their association with diseases. An integrative presentation of genetic data with the latest updates provides a background to further investigations of the disease association investigations of the complement system from the perspective of systems biology and systems genetics.

  18. A genetic future for coronary heart disease?

    Science.gov (United States)

    Weiner, Kate; Martin, Paul

    2008-04-01

    This paper is concerned with changing conceptions of genetic disease. It is based on an analysis of biomedical literature and focuses on the treatment of coronary heart disease (CHD) in four published commentary papers. The aim of this analysis is to explore the ways in which CHD is constructed as genetic and the place of genetic discourses in the wider set of ideas that circulate about the disease. This analysis is then used to consider some of the claims of the geneticisation thesis (Lippman 1991, 1992). The analysis suggests that a genetic vision for understanding and managing CHD has emerged, which has many of the hallmarks of the geneticisation imagined by Lippman. However, a number of alternative and competing models of CHD are also supported within the biomedical discourse. These are related to the different disciplines with a stake in the field of CHD, and their struggles for authority. In conclusion, it is suggested that the geneticisation thesis, as a universal claim, is at odds with the diffuse and distributed nature of biomedical knowledge and practice. Rather than analysing geneticisation in a literal way, it may be more fruitful to see the thesis, itself, as a form of boundary work (Gieryn 1983).

  19. Genetics Home Reference: glycogen storage disease type I

    Science.gov (United States)

    ... Wolfsdorf JI, Watson MS; American College of Medical Genetics and Genomics. Diagnosis and management of glycogen storage disease type ... practice guideline of the American College of Medical Genetics and Genomics. Genet Med. 2014 Nov;16(11):e1. Citation ...

  20. Machado-Joseph disease in Brazil: from the first descriptions to the emergence as the most common spinocerebellar ataxia

    Directory of Open Access Journals (Sweden)

    José Luiz Pedroso

    2012-08-01

    Full Text Available Machado-Joseph disease is an autosomal dominant inherited disorder of Azorean ancestry firstly described in 1972. Since then, several Brazilian researchers have studied clinical and genetic issues related to the disease. Nowadays, Machado-Joseph disease is considered the most common spinocerebellar ataxia worldwide. Machado-Joseph disease still has no specific therapy to arrest progression, but the unclear pathophysiological mechanism, features related to genetic characteristics, phenotype variability, apparently global involvement of the nervous system in the disease and the therapeutic challenges continue to attract investigators in the field of spinocerebellar ataxias. Brazilian researchers have distinguished themselves in the ongoing investigation seeking new knowledge about Machado-Joseph disease.

  1. Large animal models of rare genetic disorders: sheep as phenotypically relevant models of human genetic disease.

    Science.gov (United States)

    Pinnapureddy, Ashish R; Stayner, Cherie; McEwan, John; Baddeley, Olivia; Forman, John; Eccles, Michael R

    2015-09-02

    Animals that accurately model human disease are invaluable in medical research, allowing a critical understanding of disease mechanisms, and the opportunity to evaluate the effect of therapeutic compounds in pre-clinical studies. Many types of animal models are used world-wide, with the most common being small laboratory animals, such as mice. However, rodents often do not faithfully replicate human disease, despite their predominant use in research. This discordancy is due in part to physiological differences, such as body size and longevity. In contrast, large animal models, including sheep, provide an alternative to mice for biomedical research due to their greater physiological parallels with humans. Completion of the full genome sequences of many species, and the advent of Next Generation Sequencing (NGS) technologies, means it is now feasible to screen large populations of domesticated animals for genetic variants that resemble human genetic diseases, and generate models that more accurately model rare human pathologies. In this review, we discuss the notion of using sheep as large animal models, and their advantages in modelling human genetic disease. We exemplify several existing naturally occurring ovine variants in genes that are orthologous to human disease genes, such as the Cln6 sheep model for Batten disease. These, and other sheep models, have contributed significantly to our understanding of the relevant human disease process, in addition to providing opportunities to trial new therapies in animals with similar body and organ size to humans. Therefore sheep are a significant species with respect to the modelling of rare genetic human disease, which we summarize in this review.

  2. New Genetic Insights from Autoimmune Thyroid Disease

    Directory of Open Access Journals (Sweden)

    Terry F. Davies

    2012-01-01

    Full Text Available The autoimmune thyroid diseases (AITDs (Graves’ disease and Hashimoto’s thyroiditis are complex genetic diseases which most likely have more than 20 genes contributing to the clinical phenotypes. To date, the genes known to be contributing fall into two categories: immune regulatory genes (including HLA, CTLA4, PTPN22, CD40, CD25, and FCRL3 and thyroid-specific genes (TG and TSHR. However, none of these genes contribute more than a 4-fold increase in risk of developing one of these diseases, and none of the polymorphisms discovered is essential for disease development. Hence, it appears that a variety of different gene interactions can combine to cause the same clinical disease pattern, but the contributing genes may differ from patient to patient and from population to population. Furthermore, this possible mechanism leaves open the powerful influence of the environment and epigenetic modifications of gene expression. For the clinician, this means that genetic profiling of such patients is unlikely to be fruitful in the near future.

  3. [Molecular genetic investigations in muscular diseases].

    Science.gov (United States)

    Burgunder, J M

    2003-08-01

    The last couple of years have witnessed a rapid development in discoveries of the genetic background in myopathies. It is therefore timely to review the impact they have on clinical work. The recognition of a myopathy remains a clinical activity, and biopsy retains a major role. Molecular genetic investigation can be contemplated early in cases with certain typical clinical presentation. In others, the correct indication to such an investigation can only be made based on findings at biopsy. The information of precise mutation can be used for genetic counselling of the family. Knowledge of genes, whose mutations are sufficient to cause certain myopathies, have provided a great amount of knowledge about pathophysiological mechanisms involved. Some are arguably rare diseases, however, this knowledge also helps understand more frequent myopathies, as it has been the case in neurodegenerative disorders.

  4. Feline and Canine Coronaviruses: Common Genetic and Pathobiological Features

    OpenAIRE

    Sophie Le Poder

    2011-01-01

    A new human coronavirus responsible for severe acute respiratory syndrome (SARS) was identified in 2003, which raised concern about coronaviruses as agents of serious infectious disease. Nevertheless, coronaviruses have been known for about 50 years to be major agents of respiratory, enteric, or systemic infections of domestic and companion animals. Feline and canine coronaviruses are widespread among dog and cat populations, sometimes leading to the fatal diseases known as feline infectious ...

  5. Childhood Obesity & Dental Disease: Common Causes, Common Solutions. Oral Health & Obesity Policy Brief

    Science.gov (United States)

    Children Now, 2011

    2011-01-01

    Too many California children suffer from high rates of preventable chronic conditions associated with childhood obesity and dental disease. The state is experiencing a crisis in both areas. Fortunately, common factors that contribute to both conditions--including the rates of breastfeeding, access to healthy food and the consumption of…

  6. OVERVIEWS OF THE TREATMENT AND CONTROL OF COMMON FISH DISEASES

    Directory of Open Access Journals (Sweden)

    Madhuri Sharma

    2012-07-01

    Full Text Available Similar to other animals, fish can also suffer from different diseases. All fish carry pathogens and parasites. Disease is a prime agent affecting fish mortality, especially when fish are young. Pathogens which can cause fish diseases comprise: viral infections, bacterial infections, fungal infections, protozoan infections, water mould infection, etc. Fish are also exposed from different environmental pollutants, including drugs and chemicals. The most common fish diseases, particularly in freshwater aquaria, include columnaris, gill disease, ick (ich, dropsy, tail and fin-rot, fungal infections, white spot disease, pop-eye, cloudy eye, swim bladder disease, lice and nematode worms infestation, water quality induced diseases, constipation, anorexia, chilodonella, ergasilus, tuberculosis, glugea, henneguya, hexamita, hole-in-the-head disease, injuries, leeches in aquaria, lymphocystis, marine velvet, and neon-tetra disease, etc. Antibiotics are frequently used to control fish diseases caused by bacteria, but there is an increasing risk of developing antibiotic resistant strains of bacteria. The non-specific immune functions such as bacteriolytic activity and leukocyte function of fish have been improved by some herbs. Plants have been used as traditional medicine since time immemorial to control bacterial, viral, fungal and other diseases.

  7. Genetics in Ophthalmology III – Posterior Segment Diseases

    Directory of Open Access Journals (Sweden)

    Canan Aslı Utine

    2012-10-01

    Full Text Available Genetic diseases are congenital or acquired hereditary diseases that result from structural/functional disorders of the human genome. Today, the genetic factors that play a role in many diseases are being highlighted with the rapid progress in the field of genetics science. It becomes increasingly important that physicians from all disciplines have knowledge about the basic principles of genetics, patterns of inheritance, etc., so that they can follow the new developments. In genetic eye diseases, ophthalmologists should know the basic clinical and recently rapidly developing genetic characteristics of these diseases in order to properly approach the diagnosis and treatment and to provide genetic counseling. In this paper, posterior segment eye diseases of genetic origin are reviewed, and retinoblastoma, mitochondrial diseases, retinal dysplasia, retinitis pigmentosa, choroideremia, gyrate atrophy, Alström disease, ocular albinism, optic nerve hypoplasia, anophthalmia/microphthalmia and Leber’s congenital amaurosis are covered. (Turk J Ophthalmol 2012; 42: 386-92

  8. Inflammation: The Common Pathway of Stress-Related Diseases

    Science.gov (United States)

    Liu, Yun-Zi; Wang, Yun-Xia; Jiang, Chun-Lei

    2017-01-01

    While modernization has dramatically increased lifespan, it has also witnessed that the nature of stress has changed dramatically. Chronic stress result failures of homeostasis thus lead to various diseases such as atherosclerosis, non-alcoholic fatty liver disease (NAFLD) and depression. However, while 75%–90% of human diseases is related to the activation of stress system, the common pathways between stress exposure and pathophysiological processes underlying disease is still debatable. Chronic inflammation is an essential component of chronic diseases. Additionally, accumulating evidence suggested that excessive inflammation plays critical roles in the pathophysiology of the stress-related diseases, yet the basis for this connection is not fully understood. Here we discuss the role of inflammation in stress-induced diseases and suggest a common pathway for stress-related diseases that is based on chronic mild inflammation. This framework highlights the fundamental impact of inflammation mechanisms and provides a new perspective on the prevention and treatment of stress-related diseases. PMID:28676747

  9. Genetic Markers of Cardiovascular Disease in Rheumatoid Arthritis

    Directory of Open Access Journals (Sweden)

    Luis Rodríguez-Rodríguez

    2012-01-01

    Full Text Available Cardiovascular (CV disease is the most common cause of premature mortality in patients with rheumatoid arthritis (RA. It is the result of an accelerated atherosclerotic process. Both RA and atherosclerosis are complex polygenic diseases. Besides traditional CV risk factors and chronic inflammation, a number of studies have confirmed the role of genetic factors in the development of the atherogenesis observed in RA. In this regard, besides a strong association between the HLA-DRB1*04 shared epitope alleles and both endothelial dysfunction, an early step in the atherosclerotic process, and clinically evident CV disease, other polymorphisms belonging to genes implicated in inflammatory and metabolic pathways, located inside and outside the HLA region, such as the 308 variant (G>A, rs1800629 of the TNFA locus, the rs1801131 polymorphism (A>C; position + 1298 of the MTHFR locus, or a deletion of 32 base pairs on the CCR5 gene, seem to be associated with the risk of CV disease in patients with RA. Despite considerable effort to decipher the genetic basis of CV disease in RA, further studies are required to better establish the genetic influence in the increased risk of CV events observed in patients with RA.

  10. Infectious diseases: Surveillance, genetic modification and simulation

    Science.gov (United States)

    Koh, H. L.; Teh, S.Y.; De Angelis, D. L.; Jiang, J.

    2011-01-01

    Infectious diseases such as influenza and dengue have the potential of becoming a worldwide pandemic that may exert immense pressures on existing medical infrastructures. Careful surveillance of these diseases, supported by consistent model simulations, provides a means for tracking the disease evolution. The integrated surveillance and simulation program is essential in devising effective early warning systems and in implementing efficient emergency preparedness and control measures. This paper presents a summary of simulation analysis on influenza A (H1N1) 2009 in Malaysia. This simulation analysis provides insightful lessons regarding how disease surveillance and simulation should be performed in the future. This paper briefly discusses the controversy over the experimental field release of genetically modified (GM) Aedes aegypti mosquito in Malaysia. Model simulations indicate that the proposed release of GM mosquitoes is neither a viable nor a sustainable control strategy. ?? 2011 WIT Press.

  11. Genetic and environmental influences in Dupuytren's disease

    DEFF Research Database (Denmark)

    Larsen, Søren; Krogsgaard, D G; Larsen, Lisbeth Aagaard;

    2015-01-01

    We aimed to assess the relative contribution of genes and environment in the aetiology of Dupuytren's disease by studying Danish twins born between 1870 and 2000. Twins with a diagnosis (n = 365) and the subgroup who also had an operation (n = 259) after 1977 were identified through linkage...... is involved. The number of concordant male twin pairs with Dupuytren's disease was 17 and 7 (monozygotic and dizygotic pairs, respectively), compared with 60 and 174 discordant monozygotic and dizygotic pairs, yielding probandwise concordance rates of 0.37 (95% confidence interval (CI): 0.26 to 0.50) and 0.......07 (95% CI: 0.04 to 0.14), respectively. The heritability of Dupuytren's disease was approximately 80%. We conclude that genetic factors play a major role in the development of Dupuytren's disease....

  12. Animal Models of Parkinson's Disease: Vertebrate Genetics

    Science.gov (United States)

    Lee, Yunjong; Dawson, Valina L.; Dawson, Ted M.

    2012-01-01

    Parkinson's disease (PD) is a complex genetic disorder that is associated with environmental risk factors and aging. Vertebrate genetic models, especially mice, have aided the study of autosomal-dominant and autosomal-recessive PD. Mice are capable of showing a broad range of phenotypes and, coupled with their conserved genetic and anatomical structures, provide unparalleled molecular and pathological tools to model human disease. These models used in combination with aging and PD-associated toxins have expanded our understanding of PD pathogenesis. Attempts to refine PD animal models using conditional approaches have yielded in vivo nigrostriatal degeneration that is instructive in ordering pathogenic signaling and in developing therapeutic strategies to cure or halt the disease. Here, we provide an overview of the generation and characterization of transgenic and knockout mice used to study PD followed by a review of the molecular insights that have been gleaned from current PD mouse models. Finally, potential approaches to refine and improve current models are discussed. PMID:22960626

  13. [Childhood genetic renal diseases in southern Israel].

    Science.gov (United States)

    Landau, Daniel; Shalev, Hanna

    2010-03-01

    Genetic kidney diseases (GKDs) are an important and well-known entity in pediatric nephrology. Advances in genetic and molecular approaches in the last 15 years have enabled elucidation of the underlying molecular defects in many of these disorders. Herein, the authors summarize the progress that has been made over this period in disclosing the molecular basis of several novel GKDs which were characterized in this area and include Bartter syndrome type IV, type II Bartter syndrome and transient neonatal hyperkalemia, cystinuria and mental retardation, familial hypomagnesemia with secondary hypocalcemia, infantile nephronophthisis and familial hemolytic uremic syndrome with factor H deficiency. Retrospective analysis of the authors' data reveals that GKDs are over-represented among the pediatric population in southern Israel. GKD are seen 4 times more often than end-stage renal disease (ESRD) and comprise 38% of all cases of ESRD in our area. This high rate of GKD is mainly due to the high frequency of consanguineous marriages that prevails in this area. Understanding of the genetic and molecular background of these diseases is a result of a fruitful collaboration between the pediatric nephrologists and scientists, and has a direct implication on the diagnosis and treatment of the affected families.

  14. Common Variants in Mendelian Kidney Disease Genes and Their Association with Renal Function

    Science.gov (United States)

    Fuchsberger, Christian; Köttgen, Anna; O’Seaghdha, Conall M.; Pattaro, Cristian; de Andrade, Mariza; Chasman, Daniel I.; Teumer, Alexander; Endlich, Karlhans; Olden, Matthias; Chen, Ming-Huei; Tin, Adrienne; Kim, Young J.; Taliun, Daniel; Li, Man; Feitosa, Mary; Gorski, Mathias; Yang, Qiong; Hundertmark, Claudia; Foster, Meredith C.; Glazer, Nicole; Isaacs, Aaron; Rao, Madhumathi; Smith, Albert V.; O’Connell, Jeffrey R.; Struchalin, Maksim; Tanaka, Toshiko; Li, Guo; Hwang, Shih-Jen; Atkinson, Elizabeth J.; Lohman, Kurt; Cornelis, Marilyn C.; Johansson, Åsa; Tönjes, Anke; Dehghan, Abbas; Couraki, Vincent; Holliday, Elizabeth G.; Sorice, Rossella; Kutalik, Zoltan; Lehtimäki, Terho; Esko, Tõnu; Deshmukh, Harshal; Ulivi, Sheila; Chu, Audrey Y.; Murgia, Federico; Trompet, Stella; Imboden, Medea; Kollerits, Barbara; Pistis, Giorgio; Harris, Tamara B.; Launer, Lenore J.; Aspelund, Thor; Eiriksdottir, Gudny; Mitchell, Braxton D.; Boerwinkle, Eric; Schmidt, Helena; Hofer, Edith; Hu, Frank; Demirkan, Ayse; Oostra, Ben A.; Turner, Stephen T.; Ding, Jingzhong; Andrews, Jeanette S.; Freedman, Barry I.; Giulianini, Franco; Koenig, Wolfgang; Illig, Thomas; Döring, Angela; Wichmann, H.-Erich; Zgaga, Lina; Zemunik, Tatijana; Boban, Mladen; Minelli, Cosetta; Wheeler, Heather E.; Igl, Wilmar; Zaboli, Ghazal; Wild, Sarah H.; Wright, Alan F.; Campbell, Harry; Ellinghaus, David; Nöthlings, Ute; Jacobs, Gunnar; Biffar, Reiner; Ernst, Florian; Homuth, Georg; Kroemer, Heyo K.; Nauck, Matthias; Stracke, Sylvia; Völker, Uwe; Völzke, Henry; Kovacs, Peter; Stumvoll, Michael; Mägi, Reedik; Hofman, Albert; Uitterlinden, Andre G.; Rivadeneira, Fernando; Aulchenko, Yurii S.; Polasek, Ozren; Hastie, Nick; Vitart, Veronique; Helmer, Catherine; Wang, Jie Jin; Stengel, Bénédicte; Ruggiero, Daniela; Bergmann, Sven; Kähönen, Mika; Viikari, Jorma; Nikopensius, Tiit; Province, Michael; Colhoun, Helen; Doney, Alex; Robino, Antonietta; Krämer, Bernhard K.; Portas, Laura; Ford, Ian; Buckley, Brendan M.; Adam, Martin; Thun, Gian-Andri; Paulweber, Bernhard; Haun, Margot; Sala, Cinzia; Mitchell, Paul; Ciullo, Marina; Vollenweider, Peter; Raitakari, Olli; Metspalu, Andres; Palmer, Colin; Gasparini, Paolo; Pirastu, Mario; Jukema, J. Wouter; Probst-Hensch, Nicole M.; Kronenberg, Florian; Toniolo, Daniela; Gudnason, Vilmundur; Shuldiner, Alan R.; Coresh, Josef; Schmidt, Reinhold; Ferrucci, Luigi; van Duijn, Cornelia M.; Borecki, Ingrid; Kardia, Sharon L.R.; Liu, Yongmei; Curhan, Gary C.; Rudan, Igor; Gyllensten, Ulf; Wilson, James F.; Franke, Andre; Pramstaller, Peter P.; Rettig, Rainer; Prokopenko, Inga; Witteman, Jacqueline; Hayward, Caroline; Ridker, Paul M.; Bochud, Murielle; Heid, Iris M.; Siscovick, David S.; Fox, Caroline S.; Kao, W. Linda; Böger, Carsten A.

    2013-01-01

    Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research. PMID:24029420

  15. Human DNA methylomes of neurodegenerative diseases show common epigenomic patterns

    Science.gov (United States)

    Sanchez-Mut, J V; Heyn, H; Vidal, E; Moran, S; Sayols, S; Delgado-Morales, R; Schultz, M D; Ansoleaga, B; Garcia-Esparcia, P; Pons-Espinal, M; de Lagran, M M; Dopazo, J; Rabano, A; Avila, J; Dierssen, M; Lott, I; Ferrer, I; Ecker, J R; Esteller, M

    2016-01-01

    Different neurodegenerative disorders often show similar lesions, such as the presence of amyloid plaques, TAU-neurotangles and synuclein inclusions. The genetically inherited forms are rare, so we wondered whether shared epigenetic aberrations, such as those affecting DNA methylation, might also exist. The studied samples were gray matter samples from the prefrontal cortex of control and neurodegenerative disease-associated cases. We performed the DNA methylation analyses of Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease and Alzheimer-like neurodegenerative profile associated with Down's syndrome samples. The DNA methylation landscapes obtained show that neurodegenerative diseases share similar aberrant CpG methylation shifts targeting a defined gene set. Our findings suggest that neurodegenerative disorders might have similar pathogenetic mechanisms that subsequently evolve into different clinical entities. The identified aberrant DNA methylation changes can be used as biomarkers of the disorders and as potential new targets for the development of new therapies. PMID:26784972

  16. Genetic control of the angular leaf spot reaction in common bean leaves and pods

    Directory of Open Access Journals (Sweden)

    Jerônimo Constantino Borel

    2011-12-01

    Full Text Available Information about genetic control of plant reaction to pathogens is essential in plant breeding programs focusing resistance. This study aimed to obtain information about genetic control of the angular leaf spot reaction in leaves and pods from common bean (Phaseolus vulgaris L. line ESAL 686. This line was crossed with cultivars Jalo EEP 558 (resistant, Cornell 49-242 (resistant and Carioca MG (susceptible. Generations F1, F2 and backcrosses (BC11 and BC21 were obtained. In the dry season (2009, parents and respective populations were evaluated for angular leaf spot reaction under field conditions. Disease severity was evaluated on leaves and pods using diagrammatic scales. Severity scores were obtained and mean and variance genetic components were estimated for both. Segregation of F2 generation was analyzed for some crosses. Different genes control angular leaf spot reaction in leaves and pods. Mean and variance components showed predominance of additive effects. Heritability was high, however, was greater on pods than on leaves which indicated that leaf reaction is more influenced by the environment.

  17. [Development of expert diagnostic system for common respiratory diseases].

    Science.gov (United States)

    Xu, Wei-hua; Chen, You-ling; Yan, Zheng

    2014-03-01

    To develop an internet-based expert diagnostic system for common respiratory diseases. SaaS system was used to build architecture; pattern of forward reasoning was applied for inference engine design; ASP.NET with C# from the tool pack of Microsoft Visual Studio 2005 was used for website-interview medical expert system.The database of the system was constructed with Microsoft SQL Server 2005. The developed expert system contained large data memory and high efficient function of data interview and data analysis for diagnosis of various diseases.The users were able to perform this system to obtain diagnosis for common respiratory diseases via internet. The developed expert system may be used for internet-based diagnosis of various respiratory diseases,particularly in telemedicine setting.

  18. Genetic variants associated with Crohn's disease

    OpenAIRE

    Michail S; Bultron G; DePaolo RW

    2013-01-01

    Sonia Michail,1 Gilberto Bultron,1 R William DePaolo2 1The University of Southern California, Children's Hospital of Los Angeles, Los Angeles, CA, USA; 2Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Abstract: Crohn's disease is an immune-related disorder characterized by inflammation of the gastrointestinal mucosa, which can occur in any area throughout the digestive tract. This life-long disease commonly presen...

  19. Common themes in changing vector-borne disease scenarios.

    Science.gov (United States)

    Molyneux, David H

    2003-01-01

    The impact of climate change on disease patterns is controversial. However, global burden of disease studies suggest that infectious diseases will contribute a proportionately smaller burden of disease over the next 2 decades as non-communicable diseases emerge as public health problems. However, infectious diseases contribute proportionately more in the poorest quintile of the population. Notwithstanding the different views of the impact of global warming on vector-borne infections this paper reviews the conditions which drive the changing epidemiology of these infections and suggests that such change is linked by common themes including interactions of generalist vectors and reservoir hosts at interfaces with humans, reduced biodiversity associated with anthropogenic environmental changes, increases in Plasmodium falciparum: P. vivax ratios and well-described land use changes such as hydrological, urbanization, agricultural, mining and forest-associated impacts (extractive activities, road building, deforestation and migration) which are seen on a global scale.

  20. Genetic determinants of obesity and related vascular diseases.

    Science.gov (United States)

    Winter, Yaroslav; Sankowski, Roman; Back, Tobias

    2013-01-01

    Obesity is one of the major risk factors of vascular diseases, and its prevalence is increasing worldwide. In the past decade, progress has been made in the understanding of genetic determinants of obesity and obesity-associated diseases. Genome-wide association studies identified a number of genetic variants associated with obesity. In addition to common variants, FTO and MC4R, new loci, such as TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2, and NEGR1 have been detected. In the past years, abdominal obesity has been shown to be a more important vascular risk factor than the body mass index. In the context of vascular risk assessment, identification of genetic polymorphisms associated with accumulation of visceral fat is of special importance. Some polymorphisms associated with abdominal obesity, such as variants of gene encoding microsomal triglyceride transfer protein, have been already discovered. In this chapter, we provide a review of genetic determinants of obesity and discuss their role in obesity-related vascular diseases.

  1. A new conceptual framework for investigating complex genetic disease

    Science.gov (United States)

    Hussain, Shobbir

    2015-01-01

    Some common diseases are known to have an inherited component, however, their population- and familial-incidence patterns do not conform to any known monogenic Mendelian pattern of inheritance and instead they are currently much better explained if an underlying polygenic architecture is posited. Studies that have attempted to identify the causative genetic factors have been designed on this polygenic framework, but so far the yield has been largely unsatisfactory. Based on accumulating recent observations concerning the roles of somatic mosaicism in disease, in this article a second framework which posits a single gene-two hit model which can be modulated by a mutator/anti-mutator genetic background is suggested. I discuss whether such a model can be considered a viable alternative based on current knowledge, its advantages over the current polygenic framework, and describe practical routes via which the new framework can be investigated. PMID:26583033

  2. Understanding genetic information as a commons: From bioprospecting to personalized medicine

    Directory of Open Access Journals (Sweden)

    Nicola Lucchi

    2013-08-01

    Full Text Available The aim of the paper is to discuss how the concept of commons can be enlarged to include genetic resources – both naturally occurring and as essential resources in research laboratories – that are increasingly considered as part of market frameworks. Looking beyond the enclosure of traditional public goods (such as land or water, the paper emphasizes the debate around the progressive commodification of genetic resources and associated genetic information operated by means of intellectual property rights or other forms of management of knowledge. The discourse around commons is used to evaluate alternative tools and strategies to the issue of private appropriation of human genetic resources and natural compounds.

  3. Effects of Common Equine Endocrine Diseases on Reproduction.

    Science.gov (United States)

    Burns, Teresa A

    2016-12-01

    Endocrine diseases, such as equine metabolic syndrome and pituitary pars intermedia dysfunction, are common in domesticated horse populations, and the frequency with which these diseases are encountered and managed by equine veterinary practitioners is expected to increase as the population ages. As clinicians learn more about the effects of these diseases on equine reproductive physiology and efficiency (including effects on reproductive seasonality, ovulation efficiency, implantation, early pregnancy loss, duration of pregnancy, and lactation), strategies and guidelines for improving fertility in affected animals continue to evolve. It is hoped that further research will establish these recommendations more firmly.

  4. THERAPEUTIC IMPLICATIONS OF GENETIC RISK VARIANTS FOR CORONARY ARTERY DISEASE

    Directory of Open Access Journals (Sweden)

    Rajiv Kumar Srivastava

    2017-02-01

    Full Text Available BACKGROUND This review covers therapeutic implication of genetic risk variant responsible for coronary artery disease by utilising the highdensity single-nucleotide microarrays to screen the entire human genome. The sequence of the human genome provides the blueprint for life. Approximately, 99.5% of the human genome Deoxyribonucleic Acid (DNA sequence is identical among humans with 0.5% of the genome sequence (15 million bps accounting for all individual differences. MATERIALS AND METHODS The new technology of the computerised chip array of millions of Single-Nucleotide Polymorphisms (SNPs as Deoxyribonucleic Acid (DNA markers makes it possible to study and detect genetic predisposition to common polygenic disorders such as Coronary Artery Disease (CAD. The sample sizes required for these studies are massive and large; worldwide consortiums such as Coronary Artery Disease Genome-wide Replication and Meta-Analysis (CARDIoGRAM study have been formed to accommodate this requirement. After the identification of 9p21 progress to detect genetic predisposition has been remarkable. RESULTS There are currently a total of 50 genetic risk variants predisposing to CAD of genome-wide significance with confirmation in independent populations. Rare variants (Minor Allele Frequency, MAF <5% will require direct sequencing to detect genetic predisposition. CONCLUSION We can develop new biomarkers for detecting early CAD as well as unique targets for novel therapy. The challenge for the future will be to identify the molecular mechanisms mediating the risk of those genetic risk variants that act through nonconventional risk factors. The ultimate objective for the future is the sequencing and functional analysis of the causative polymorphisms for its therapeutic implications.

  5. Understanding Celiac Disease From Genetics to the Future Diagnostic Strategies

    Directory of Open Access Journals (Sweden)

    Carolina Salazar

    2017-07-01

    Full Text Available Celiac disease (CD is an autoimmune disorder characterized by the permanent inflammation of the small bowel, triggered by the ingestion of gluten. It is associated with a number of symptoms, the most common being gastrointestinal. The prevalence of this illness worldwide is 1%. One of the main problems of CD is its difficulty to be diagnosed due to the various presentations of the disease. Besides, in many cases, CD is asymptomatic. Celiac disease is a multifactorial disease, HLA-DQ2 and HLA-DQ8 haplotypes are predisposition factors. Nowadays, molecular markers are being studied as diagnostic tools. In this review, we explore CD from its basic concept, manifestations, types, current and future methods of diagnosis, and associated disorders. Before addressing the therapeutic approaches, we also provide a brief overview of CD genetics and treatment.

  6. Genetic Testing for Huntington's Disease in Parkinsonism.

    Science.gov (United States)

    Rahman, M S; Nagai, Y; Popiel, H A; Fujikake, N; Okamoto, Y; Ahmed, M U; Islam, M A; Islam, M T; Ahmed, S; Rahman, K M; Uddin, M J; Dey, S K; Ahmed, Q; Hossain, M A; Jahan, N; Toda, T

    2010-10-01

    The study was conducted to find out Huntington's disease (HD) by genetic analysis from those presenting with parkinsonism in the Neurology department of Mymensingh Medical College & Hospital. A sample of about 5ml blood was collected by veni puncture in EDTA tube with informed consent from 9 patients & 7 healthy individuals after approval of the institutional ethics committee for genetic study. The neurological disorder along with a complete history and physical findings were recorded in a prescribed questionnaire by the neurologists of Mymensingh Medical College & Hospital. Extraction of genomic DNA from the venous blood using FlexiGene DNA kit (Qiagen, Japan) was performed in Faculty of Veterinary Science, Bangladesh Agricultural University, Mymensingh, Bangladesh. The extracted DNA was stored and accumulated and then these DNA were sent to Division of Clinical Genetics, Department of Medical Genetics, Osaka University Medical School, Suita, Osaka 565 0871, Japan for PCR and further analysis. PCR amplification of the CAG repeat in the 1T15 gene was performed with primers HD1 and HD3. HD PCR products revealed the DNA product of about 110bp (no. of CAG repeats=21) to 150bp (no. of CAG repeats=34) in both healthy individual and suspected PD patient DNA.

  7. Disease transmission by cannibalism: rare event or common occurrence?

    Science.gov (United States)

    Rudolf, Volker H W; Antonovics, Janis

    2007-05-07

    Cannibalism has been documented as a possible disease transmission route in several species, including humans. However, the dynamics resulting from this type of disease transmission are not well understood. Using a theoretical model, we explore how cannibalism (i.e. killing and consumption of dead conspecifics) and intraspecific necrophagy (i.e. consumption of dead conspecifics) affect host-pathogen dynamics. We show that group cannibalism, i.e. shared consumption of victims, is a necessary condition for disease spread by cannibalism in the absence of alternative transmission modes. Thus, endemic diseases transmitted predominantly by cannibalism are likely to be rare, except in social organisms that share conspecific prey. These results are consistent with a review of the literature showing that diseases transmitted by cannibalism are infrequent in animals, even though both cannibalism and trophic transmission are very common.

  8. Population genetics of invasive common carp Cyprinus carpio L. in coastal drainages in eastern Australia.

    Science.gov (United States)

    Haynes, G D; Gilligan, D M; Grewe, P; Moran, C; Nicholas, F W

    2010-10-01

    The common carp Cyprinus carpio introduced in two drainages in eastern Australia are largely descended from European common carp, and in a third drainage they descend largely from East Asian common carp. The partial genetic differentiation among the species in those drainages is consistent with their origins.

  9. Rare and low-frequency variants in human common diseases and other complex traits.

    Science.gov (United States)

    Lettre, Guillaume

    2014-11-01

    In humans, most of the genetic variation is rare and often population-specific. Whereas the role of rare genetic variants in familial monogenic diseases is firmly established, we are only now starting to explore the contribution of this class of genetic variation to human common diseases and other complex traits. Such large-scale experiments are possible due to the development of next-generation DNA sequencing. Early findings suggested that rare and low-frequency coding variation might have a large effect on human phenotypes (eg, PCSK9 missense variants on low-density lipoprotein-cholesterol and coronary heart diseases). This observation sparked excitement in prognostic and diagnostic medicine, as well as in genetics-driven strategies to develop new drugs. In this review, I describe results and present initial conclusions regarding some of the recent rare and low-frequency variant discoveries. We can already assume that most phenotype-associated rare and low-frequency variants have modest-to-weak phenotypical effect. Thus, we will need large cohorts to identify them, as for common variants in genome-wide association studies. As we expand the list of associated rare and low-frequency variants, we can also better recognise the current limitations: we need to develop better statistical methods to optimally test association with rare variants, including non-coding variation, and to account for potential confounders such as population stratification.

  10. Common and rare genetic risk factors for glaucoma.

    Science.gov (United States)

    Wang, Ryan; Wiggs, Janey L

    2014-09-18

    The characterization of genes responsible for glaucoma is the critical first step toward the development of gene-based diagnostic and screening tests, which could identify individuals at risk for disease before irreversible optic nerve damage occurs. Early-onset forms of glaucoma affecting children and young adults are typically inherited as Mendelian autosomal dominant or recessive traits whereas glaucoma affecting older adults has complex inheritance. In this report, we present a comprehensive overview of the genes and genomic regions contributing to inherited glaucoma.

  11. Large genetic animal models of Huntington's Disease.

    Science.gov (United States)

    Morton, A Jennifer; Howland, David S

    2013-01-01

    The dominant nature of the Huntington's disease gene mutation has allowed genetic models to be developed in multiple species, with the mutation causing an abnormal neurological phenotype in all animals in which it is expressed. Many different rodent models have been generated. The most widely used of these, the transgenic R6/2 mouse, carries the mutation in a fragment of the human huntingtin gene and has a rapidly progressive and fatal neurological phenotype with many relevant pathological changes. Nevertheless, their rapid decline has been frequently questioned in the context of a disease that takes years to manifest in humans, and strenuous efforts have been made to make rodent models that are genetically more 'relevant' to the human condition, including full length huntingtin gene transgenic and knock-in mice. While there is no doubt that we have learned, and continue to learn much from rodent models, their usefulness is limited by two species constraints. First, the brains of rodents differ significantly from humans in both their small size and their neuroanatomical organization. Second, rodents have much shorter lifespans than humans. Here, we review new approaches taken to these challenges in the development of models of Huntington's disease in large brained, long-lived animals. We discuss the need for such models, and how they might be used to fill specific niches in preclinical Huntington's disease research, particularly in testing gene-based therapeutics. We discuss the advantages and disadvantages of animals in which the prodromal period of disease extends over a long time span. We suggest that there is considerable 'value added' for large animal models in preclinical Huntington's disease research.

  12. Mammographic Breast Density and Common Genetic Variants in Breast Cancer Risk Prediction.

    Directory of Open Access Journals (Sweden)

    Charmaine Pei Ling Lee

    Full Text Available Known prediction models for breast cancer can potentially by improved by the addition of mammographic density and common genetic variants identified in genome-wide associations studies known to be associated with risk of the disease. We evaluated the benefit of including mammographic density and the cumulative effect of genetic variants in breast cancer risk prediction among women in a Singapore population.We estimated the risk of breast cancer using a prospective cohort of 24,161 women aged 50 to 64 from Singapore with available mammograms and known risk factors for breast cancer who were recruited between 1994 and 1997. We measured mammographic density using the medio-lateral oblique views of both breasts. Each woman's genotype for 75 SNPs was simulated based on the genotype frequency obtained from the Breast Cancer Association Consortium data and the cumulative effect was summarized by a genetic risk score (GRS. Any improvement in the performance of our proposed prediction model versus one containing only variables from the Gail model was assessed by changes in receiver-operating characteristic and predictive values.During 17 years of follow-up, 680 breast cancer cases were diagnosed. The multivariate-adjusted hazard ratios (95% confidence intervals were 1.60 (1.22-2.10, 2.20 (1.65-2.92, 2.33 (1.71-3.20, 2.12 (1.43-3.14, and 3.27 (2.24-4.76 for the corresponding mammographic density categories: 11-20cm2, 21-30cm2, 31-40cm2, 41-50cm2, 51-60cm2, and 1.10 (1.03-1.16 for GRS. At the predicted absolute 10-year risk thresholds of 2.5% and 3.0%, a model with mammographic density and GRS could correctly identify 0.9% and 0.5% more women who would develop the disease compared to a model using only the Gail variables, respectively.Mammographic density and common genetic variants can improve the discriminatory power of an established breast cancer risk prediction model among females in Singapore.

  13. Genetics in Ophthalmology II–Anterior Segment Diseases

    Directory of Open Access Journals (Sweden)

    Canan Aslı Utine

    2012-10-01

    Full Text Available Genetic diseases are congenital or acquired hereditary diseases that result from structural/functional disorders of the human genome. Today, the genetic factors that play a role in many diseases are being highlighted with the rapid progress in the field of genetics science. It becomes increasingly important that physicians from all disciplines have knowledge about the basic principles of genetics, patterns of inheritance, etc., so that they can follow the new developments. In genetic eye diseases, ophthalmologists should know the basic clinical and recently rapidly developing genetic characteristics of these diseases in order to properly approach the diagnosis and treatment and to provide genetic counseling. In this paper, anterior segment eye diseases of genetic origin are reviewed, and aniridia, anterior segment dysgenesis, glaucoma, corneal dystrophies, cataract, ectopia lentis, myopia, and other refractive errors are covered. (Turk J Ophthalmol 2012; 42: 378-85

  14. Clinical implications of shared genetics and pathogenesis in autoimmune diseases.

    Science.gov (United States)

    Zhernakova, Alexandra; Withoff, Sebo; Wijmenga, Cisca

    2013-11-01

    Many endocrine diseases, including type 1 diabetes mellitus, Graves disease, Addison disease and Hashimoto disease, originate as an autoimmune reaction that affects disease-specific target organs. These autoimmune diseases are characterized by the development of specific autoantibodies and by the presence of autoreactive T cells. They are caused by a complex genetic predisposition that is attributable to multiple genetic variants, each with a moderate-to-low effect size. Most of the genetic variants associated with a particular autoimmune endocrine disease are shared between other systemic and organ-specific autoimmune and inflammatory diseases, such as rheumatoid arthritis, coeliac disease, systemic lupus erythematosus and psoriasis. Here, we review the shared and specific genetic background of autoimmune diseases, summarize their treatment options and discuss how identifying the genetic and environmental factors that predispose patients to an autoimmune disease can help in the diagnosis and monitoring of patients, as well as the design of new treatments.

  15. Genetics of Crohn disease, an archetypal inflammatory barrier disease.

    Science.gov (United States)

    Schreiber, Stefan; Rosenstiel, Philip; Albrecht, Mario; Hampe, Jochen; Krawczak, Michael

    2005-05-01

    Chronic inflammatory disorders such as Crohn disease, atopic eczema, asthma and psoriasis are triggered by hitherto unknown environmental factors that function on the background of some polygenic susceptibility. Recent technological advances have allowed us to unravel the genetic aetiology of these and other complex diseases. Using Crohn disease as an example, we show how the discovery of susceptibility genes furthers our understanding of the underlying disease mechanisms and how it will, ultimately, give rise to new therapeutic developments. The long-term goal of such endeavours is to develop targeted prophylactic strategies. These will probably target the molecular interaction on the mucosal surface between the products of the genome and the microbial metagenome of a patient.

  16. Database tools in genetic diseases research.

    Science.gov (United States)

    Bianco, Anna Monica; Marcuzzi, Annalisa; Zanin, Valentina; Girardelli, Martina; Vuch, Josef; Crovella, Sergio

    2013-02-01

    The knowledge of the human genome is in continuous progression: a large number of databases have been developed to make meaningful connections among worldwide scientific discoveries. This paper reviews bioinformatics resources and database tools specialized in disseminating information regarding genetic disorders. The databases described are useful for managing sample sequences, gene expression and post-transcriptional regulation. In relation to data sets available from genome-wide association studies, we describe databases that could be the starting point for developing studies in the field of complex diseases, particularly those in which the causal genes are difficult to identify.

  17. Development and application of genetically uniform strains of common carp (Cyprinus carpio L.)

    NARCIS (Netherlands)

    Bongers, A.B.J.

    1997-01-01

    In this thesis, the development of genetically uniform strains of common carp, Cyprinus carpio L. is described. As in research on mammals, the use of genetically uniform fish could increase the quality (replicability, reproducability and repeatability) of experiments. Inbreeding was done by gynogene

  18. Functional complementation studies identify candidate genes and common genetic variants associated with ovarian cancer survival

    DEFF Research Database (Denmark)

    Quaye, Lydia; Dafou, Dimitra; Ramus, Susan J;

    2009-01-01

    Common germline genetic variation and/or somatic alterations in tumours may be associated with survival in women diagnosed with ovarian cancer. The successful identification of genetic associations relies on a suitable strategy for identifying and testing candidate genes. We used microcell-mediat...

  19. Glioblastomas with Oligodendroglial Component – Common Origin of the Different Histological Parts and Genetic Subclassification

    Directory of Open Access Journals (Sweden)

    Barbara Klink

    2010-01-01

    Full Text Available Background: Glioblastomas are the most common and most malignant brain tumors in adults. A small subgroup of glioblastomas contains areas with histological features of oligodendroglial differentiation (GBMO. Our objective was to genetically characterize the oligodendroglial and the astrocytic parts of GBMOs and correlate morphologic and genetic features with clinical data.

  20. Genetic variants associated with celiac disease and the risk for coronary artery disease.

    Science.gov (United States)

    Jansen, Henning; Willenborg, Christina; Schlesinger, Sabrina; Ferrario, Paola G; König, Inke R; Erdmann, Jeanette; Samani, Nilesh J; Lieb, Wolfgang; Schunkert, Heribert

    2015-10-01

    Epidemiological evidence suggests that patients with celiac disease are at increased risk for coronary artery disease (CAD). Genetic-epidemiological analyses identified many single nucleotide polymorphisms (SNPs) associated with celiac disease. If there is a causal relation between celiac disease and CAD, one might expect that risk alleles primarily associated with celiac disease also increase the risk of CAD. In this study we identified from literature 41 SNPs that have been previously described to be genome-wide associated with celiac disease (p DIsease Genome-wide Replication and Meta-analysis (CARDIoGRAM) dataset, a meta-analysis comprising genome-wide SNP association data from 22,233 CAD cases and 64,762 controls. 24 out of 41 (58.5 %) risk alleles for celiac disease displayed a positive association with CAD (CAD-OR range 1.001-1.081). The remaining risk alleles for celiac disease (n = 16) revealed CAD-ORs of ≤1.0 (range 0.951-1.0). The proportion of CAD associated alleles was greater but did not differ significantly from the proportion of 50 % expected by chance (p = 0.069). One SNP (rs653178 at the SH2B3/ATXN2 locus) displayed study-wise statistically significant association with CAD with directionality consistent effects on celiac disease and CAD. However, the effect of this locus is most likely driven by pleiotropic effects on multiple other diseases. In conclusion, this genetically based approach provided no convincing evidence that SNPs associated with celiac disease contribute to the risk of CAD. Hence, common non-genetic factors may play a more important role explaining the coincidence of these two complex disease conditions.

  1. Clinical, genetic, and brain sonographic features related to Parkinson's disease in Gaucher disease.

    Science.gov (United States)

    Böttcher, Tobias; Rolfs, Arndt; Meyer, Bianca; Grossmann, Annette; Berg, Daniela; Kropp, Peter; Benecke, Reiner; Walter, Uwe

    2013-10-01

    Homozygous or compound heterozygous mutations in the glucocerebrosidase gene cause Gaucher disease. Moreover, heterozygous glucocerebrosidase gene mutations represent the most common genetic risk factor for Parkinson's disease (PD) known so far. Substantia nigra (SN) hyperechogenicity, a sonographic feature thought to reflect iron accumulation, has been described in both PD and Gaucher disease patients. Here we studied how clinical, genetic, and brain sonographic findings relate to the occurrence of PD in Gaucher disease. Sixteen Gaucher disease patients, 12 PD patients, and 32 control subjects were enrolled. The glucocerebrosidase genotypes were identified by DNA sequencing. All subjects underwent transcranial ultrasound, and eight Gaucher disease patients additionally MRI for comparison with SN ultrasound findings. SN hyperechogenicity and reduced echogenicity of brainstem raphe were more frequent in Gaucher disease patients (62, 37 %) than in controls (12, 12 %; p Gaucher disease patients was unrelated to type or severity of glucocerebrosidase gene mutation, but correlated with iron-sensitive MRI-T2 hypointensity of SN pars compacta, and with age at start of enzyme replacement therapy. While none of the five Gaucher disease patients with signs of PD (definite PD, n = 4; early PD, n = 1) had severe glucocerebrosidase gene mutations known to cause neuronopathic Gaucher disease, all carried a N370S allele, previously reported to predict non-neuronopathic Gaucher disease. Hyposmia, higher non-motor symptoms score (constipation, depression, executive dysfunction), and SN hyperechogenicity were characteristic features of Gaucher disease-related PD. We conclude that the combined clinical, genetic, and transcranial sonographic assessment may improve the PD risk evaluation in Gaucher disease.

  2. Common genetic polymorphisms of microRNA biogenesis pathway genes and breast cancer survival

    Directory of Open Access Journals (Sweden)

    Sung Hyuna

    2012-05-01

    Full Text Available Abstract Background Although the role of microRNA’s (miRNA’s biogenesis pathway genes in cancer development and progression has been well established, the association between genetic variants of this pathway genes and breast cancer survival is still unknown. Methods We used genotype data available from a previously conducted case–control study to investigate association between common genetic variations in miRNA biogenesis pathway genes and breast cancer survival. We investigated the possible associations between 41 germ-line single-nucleotide polymorphisms (SNPs and both disease free survival (DFS and overall survival (OS among 488 breast cancer patients. During the median follow-up of 6.24 years, 90 cases developed disease progression and 48 cases died. Results Seven SNPs were significantly associated with breast cancer survival. Two SNPs in AGO2 (rs11786030 and rs2292779 and DICER1 rs1057035 were associated with both DFS and OS. Two SNPs in HIWI (rs4759659 and rs11060845 and DGCR8 rs9606250 were associated with DFS, while DROSHA rs874332 and GEMIN4 rs4968104 were associated with only OS. The most significant association was observed in variant allele of AGO2 rs11786030 with 2.62-fold increased risk of disease progression (95% confidence interval (CI, 1.41-4.88 and in minor allele homozygote of AGO2 rs2292779 with 2.94-fold increased risk of death (95% CI, 1.52-5.69. We also found cumulative effects of SNPs on DFS and OS. Compared to the subjects carrying 0 to 2 high-risk genotypes, those carrying 3 or 4–6 high-risk genotypes had an increased risk of disease progression with a hazard ratio of 2.16 (95% CI, 1.18- 3.93 and 4.47 (95% CI, 2.45- 8.14, respectively (P for trend, 6.11E-07. Conclusions Our results suggest that genetic variants in miRNA biogenesis pathway genes may be associated with breast cancer survival. Further studies in larger sample size and functional characterizations are warranted to validate these results.

  3. Endophenotype Network Models: Common Core of Complex Diseases

    Science.gov (United States)

    Ghiassian, Susan Dina; Menche, Jörg; Chasman, Daniel I.; Giulianini, Franco; Wang, Ruisheng; Ricchiuto, Piero; Aikawa, Masanori; Iwata, Hiroshi; Müller, Christian; Zeller, Tania; Sharma, Amitabh; Wild, Philipp; Lackner, Karl; Singh, Sasha; Ridker, Paul M.; Blankenberg, Stefan; Barabási, Albert-László; Loscalzo, Joseph

    2016-06-01

    Historically, human diseases have been differentiated and categorized based on the organ system in which they primarily manifest. Recently, an alternative view is emerging that emphasizes that different diseases often have common underlying mechanisms and shared intermediate pathophenotypes, or endo(pheno)types. Within this framework, a specific disease’s expression is a consequence of the interplay between the relevant endophenotypes and their local, organ-based environment. Important examples of such endophenotypes are inflammation, fibrosis, and thrombosis and their essential roles in many developing diseases. In this study, we construct endophenotype network models and explore their relation to different diseases in general and to cardiovascular diseases in particular. We identify the local neighborhoods (module) within the interconnected map of molecular components, i.e., the subnetworks of the human interactome that represent the inflammasome, thrombosome, and fibrosome. We find that these neighborhoods are highly overlapping and significantly enriched with disease-associated genes. In particular they are also enriched with differentially expressed genes linked to cardiovascular disease (risk). Finally, using proteomic data, we explore how macrophage activation contributes to our understanding of inflammatory processes and responses. The results of our analysis show that inflammatory responses initiate from within the cross-talk of the three identified endophenotypic modules.

  4. Periodontal disease associated to systemic genetic disorders.

    Science.gov (United States)

    Nualart Grollmus, Zacy Carola; Morales Chávez, Mariana Carolina; Silvestre Donat, Francisco Javier

    2007-05-01

    A number of systemic disorders increase patient susceptibility to periodontal disease, which moreover evolves more rapidly and more aggressively. The underlying factors are mainly related to alterations in immune, endocrine and connective tissue status. These alterations are associated with different pathologies and syndromes that generate periodontal disease either as a primary manifestation or by aggravating a pre-existing condition attributable to local factors. This is where the role of bacterial plaque is subject to debate. In the presence of qualitative or quantitative cellular immune alterations, periodontal disease may manifest early on a severe localized or generalized basis--in some cases related to the presence of plaque and/or specific bacteria (severe congenital neutropenia or infantile genetic agranulocytosis, Chediak-Higiashi syndrome, Down syndrome and Papillon-Lefévre syndrome). In the presence of humoral immune alterations, periodontal damage may result indirectly as a consequence of alterations in other systems. In connective tissue disorders, bacterial plaque and alterations of the periodontal tissues increase patient susceptibility to gingival inflammation and alveolar resorption (Marfan syndrome and Ehler-Danlos syndrome). The management of periodontal disease focuses on the control of infection and bacterial plaque by means of mechanical and chemical methods. Periodontal surgery and even extraction of the most seriously affected teeth have also been suggested. There are variable degrees of consensus regarding the background systemic disorder, as in the case of Chediak-Higiashi syndrome, where antibiotic treatment proves ineffective; in severe congenital neutropenia or infantile genetic agranulocytosis, where antibiotic prophylaxis is suggested; and in Papillon-Lefévre syndrome, where an established treatment protocol is available.

  5. Iron Deficiency Anemia: A Common and Curable Disease

    Science.gov (United States)

    Miller, Jeffery L.

    2013-01-01

    Iron deficiency anemia arises when the balance of iron intake, iron stores, and the body's loss of iron are insufficient to fully support production of erythrocytes. Iron deficiency anemia rarely causes death, but the impact on human health is significant. In the developed world, this disease is easily identified and treated, but frequently overlooked by physicians. In contrast, it is a health problem that affects major portions of the population in underdeveloped countries. Overall, the prevention and successful treatment for iron deficiency anemia remains woefully insufficient worldwide, especially among underprivileged women and children. Here, clinical and laboratory features of the disease are discussed, and then focus is placed on relevant economic, environmental, infectious, and genetic factors that converge among global populations. PMID:23613366

  6. Shared genetic origins of allergy and autoimmune diseases

    DEFF Research Database (Denmark)

    Waage, J. E.; Kreiner-Møller, E.; Standl, M.

    2015-01-01

    Parallel increases in allergy and autoimmune disease prevalence in recent time suggest shared, but yet unknown, etiologies. Here, we investigated shared genetic loci and molecular pathways to identify possible shared disease mechanisms between allergy and autoimmune diseases....

  7. Impact of recent genetic findings in Parkinson's disease.

    Science.gov (United States)

    Klein, Christine; Lohmann-Hedrich, Katja

    2007-08-01

    Parkinson's disease is the second most common age-related neurodegenerative disorder and is characterized clinically by classical parkinsonism and pathologically by selective loss of dopaminergic neurons in the substantia nigra and Lewy bodies. Although for most classical parkinsonism the etiology is unknown, a clear genetic component has been determined in a minority. Mutations in five causative genes combined [alpha-Synuclein (SNCA), Parkin, PTEN-induced kinase 1 (PINK1), DJ-1, Leucine-rich repeat kinase 2 (LRRK2)] account for 2-3% of all cases with classical parkinsonism, often clinically indistinguishable from idiopathic Parkinson's disease. The functional role of PINK1 and LRRK2 as kinases has been clearly established. Further, mutations in the ATP13A2 gene have been linked to Kufor-Rakeb syndrome (PARK9), a form of atypical parkinsonism. ATP13A2 encodes a lysosomal ATPase and shows elevated expression levels in the brains of sporadic patients, suggesting a potential role in the more common idiopathic Parkinson's disease. Finally, first promising pilot studies have been performed to identify differentially expressed genes and proteins as biomarkers for parkinsonism. The identification of single genes and their functional characterization has enhanced our understanding of the pathogenesis of parkinsonism, has led to improvement of diagnostic tools for genetic parkinsonism, and allows for the purposeful consideration of novel therapeutic targets.

  8. APOL1 kidney risk alleles: population genetics and disease associations.

    Science.gov (United States)

    Limou, Sophie; Nelson, George W; Kopp, Jeffrey B; Winkler, Cheryl A

    2014-09-01

    APOL1 kidney disease is a unique case in the field of the genetics of common disease: 2 variants (termed G1 and G2) with high population frequency have been repeatedly associated with nondiabetic CKDs, with very strong effect size (odds ratios 3-29) in populations of sub-Saharan African descent. This review provides an update on the spectrum of APOL1 kidney disease and on the worldwide distribution of these kidney risk variants. We also summarize the proper way to run a recessive analysis on joint and independent effects of APOL1 G1 and G2 kidney risk variants. Copyright © 2014 National Kidney Foundation, Inc. All rights reserved.

  9. Genetic diagnosis and prognosis of Alzheimer's disease: challenges and opportunities.

    Science.gov (United States)

    Reitz, Christiane

    2015-03-01

    Alzheimer's disease (AD), the most common form of dementia in western societies, is a pathologically and clinically heterogeneous disease with a strong genetic component. The recent advances in high-throughput genome technologies allowing for the rapid analysis of millions of polymorphisms in thousands of subjects has significantly advanced our understanding of the genomic underpinnings of AD susceptibility. During the last 5 years, genome-wide association and whole-exome- and whole-genome sequencing studies have mapped more than 20 disease-associated loci, providing insights into the molecular pathways involved in AD pathogenesis and hinting at potential novel therapeutic targets. This review article summarizes the challenges and opportunities of when using genomic information for the diagnosis and prognosis of AD.

  10. Breast cancer. Part 1: Awareness and common benign diseases.

    Science.gov (United States)

    Harmer, Victoria

    Breast cancer is the most common cancer for women in the United Kingdom and topic on which there is much information. This article discusses the principles behind breast awareness and breast health, detailing common benign breast diseases that cause disproportionate anxiety. The NHS Breast Screening Programme is celebrating 20 years of screening this year, and in all randomized controlled trials of women aged 50 and over, mortality from breast cancer is reduced in those offered screening compared with unscreened controls (although the reduction is not statistically significant in all trials). Once a breast cancer is diagnosed, the different characteristics and stage of the disease can be identified through histopathology and scans. These factors will be discussed later in this article, including illustrating if a cancer is hormone sensitive or HER-2 positive, for example. These factors enable clinicians to recommend a treatment pathway suitable for each individual.

  11. Detection of Common Dental Diseases by Dental Hygiene-Therapists

    OpenAIRE

    Macey, Richard John

    2016-01-01

    Thesis submitted to the University of Manchester by Richard Macey for the Degree of Doctor of Philosophy entitled “Detection of Common Dental Diseases by Dental Hygiene-Therapists”, February 2016.Many adult patients that attend NHS dental practices on a regular basis are asymptomatic and do not need any further treatment other than a routine dental examination (“check-up”). As the oral health of the adult population is predicted to improve further, using the General Dental Practitioner to und...

  12. The most common genetic syndromes and associated anomalies in Latvian patients with cleft lip with or without palate.

    Science.gov (United States)

    Lace, Baiba; Barkane, Biruta; Akota, Ilze

    2006-01-01

    1 over 700 newborns every year is born with cleft lip with/or without palate, in 30% of cases there is a certain genetic mechanism underlying development of disease: chromosomal anomalies, monogenic diseases, exposure to teratogens or in utero disruptive mechanisms. The objective of our study is to describe the most common genetic syndromes and associated anomalies in patients with CL/CP in Latvia. Study material was medical records obtained from Riga Cleft Lip and Palate Centre Registry in a time period of 1980 till 2005. There was analyzed information about patients with identified genetic syndromes and associated anomalies. In a time period from 1980 till 2005, the following genetic syndromes were identified: Van der Woude, Fetal alcohol syndrome, Holzgreve syndrome, Marfan syndrome, Myotonic dystrophy, Klippel-Feil syndrome, Patau syndrome, Potter sequence and Pierre Robin sequence. 16% of CL/CP patients have recognized genetic syndromes or associated anomalies, including profound, severe and moderate mental retardation. Number is lower than expected, but still correlates with date presented in other populations. Long term follow-up of multidisciplinary specialists which includes cardiologists, clinical-geneticists and paediatricians, is needed for CL/CP patients with associated anomalies in order to identify timely side diseases and complications. Grant: Baltic-Taiwan joint research project "Identification of genes involved in craniofacial morphogenesis and susceptibility to orofacial clefting in a human genome scan 2004-2006".

  13. G protein-coupled receptor mutations and human genetic disease.

    Science.gov (United States)

    Thompson, Miles D; Hendy, Geoffrey N; Percy, Maire E; Bichet, Daniel G; Cole, David E C

    2014-01-01

    Genetic variations in G protein-coupled receptor genes (GPCRs) disrupt GPCR function in a wide variety of human genetic diseases. In vitro strategies and animal models have been used to identify the molecular pathologies underlying naturally occurring GPCR mutations. Inactive, overactive, or constitutively active receptors have been identified that result in pathology. These receptor variants may alter ligand binding, G protein coupling, receptor desensitization and receptor recycling. Receptor systems discussed include rhodopsin, thyrotropin, parathyroid hormone, melanocortin, follicle-stimulating hormone (FSH), luteinizing hormone, gonadotropin-releasing hormone (GNRHR), adrenocorticotropic hormone, vasopressin, endothelin-β, purinergic, and the G protein associated with asthma (GPRA or neuropeptide S receptor 1 (NPSR1)). The role of activating and inactivating calcium-sensing receptor (CaSR) mutations is discussed in detail with respect to familial hypocalciuric hypercalcemia (FHH) and autosomal dominant hypocalemia (ADH). The CASR mutations have been associated with epilepsy. Diseases caused by the genetic disruption of GPCR functions are discussed in the context of their potential to be selectively targeted by drugs that rescue altered receptors. Examples of drugs developed as a result of targeting GPCRs mutated in disease include: calcimimetics and calcilytics, therapeutics targeting melanocortin receptors in obesity, interventions that alter GNRHR loss from the cell surface in idiopathic hypogonadotropic hypogonadism and novel drugs that might rescue the P2RY12 receptor congenital bleeding phenotype. De-orphanization projects have identified novel disease-associated receptors, such as NPSR1 and GPR35. The identification of variants in these receptors provides genetic reagents useful in drug screens. Discussion of the variety of GPCRs that are disrupted in monogenic Mendelian disorders provides the basis for examining the significance of common

  14. The most common otorhinolaryngologic manifestations of granulomatous diseases

    Directory of Open Access Journals (Sweden)

    Heshiki, Rosana Emiko

    2008-09-01

    Full Text Available Introduction: Granulomatous diseases result from immunopathologic processes in which there is a failure in the fagocitosis of intracellular organisms. They can cause oral, nasal and pharyngeal mucosa ulcers, vocal cords lesions, otorrhoea and oropharyngeal vegetant lesions. Objective: Describing the most frequent otorhinolaryngologic manifestations in common granulomatous diseases: hanseniasis, paracoccidioidomycosis, leishmaniasis. Method: A retrospective study has been carried out from records of patients diagnosed with the abovementioned diseases between January 1, 2005 and October 31, 2007 in an infectology ambulatory of a tertiary hospital. Results: 142 patients were evaluated; 93 with leishmaniasis, 39 with paracoccidioidomycosis and 10 with hanseniasis. In 93 cases of leishmaniasis, 16 (17.2% had mucosal affection, and the most common signs were septum perforation and nasal mucosal ulcers, both with 8 cases. In paracoccidioidomycosis, oropharyngeal ulcer was the most frequent, with 15 cases (38,4%. Conclusion: Head and neck signs and symptoms are common in patients with leishmaniasis and paracoccidioidomycosis. Nasal manifestations prevail in leishmaniasis and oropharyngeal ones in paracoccidioidomycosis.

  15. Common genetic variation and the control of HIV-1 in humans

    DEFF Research Database (Denmark)

    Fellay, J.; Ge, D.; Shianna, K.V.

    2009-01-01

    To extend the understanding of host genetic determinants of HIV-1 control, we performed a genome-wide association study in a cohort of 2,554 infected Caucasian subjects. The study was powered to detect common genetic variants explaining down to 1.3% of the variability in viral load at set point. ...... genetic variation in HIV-1 control in Caucasians Udgivelsesdato: 2009/12......To extend the understanding of host genetic determinants of HIV-1 control, we performed a genome-wide association study in a cohort of 2,554 infected Caucasian subjects. The study was powered to detect common genetic variants explaining down to 1.3% of the variability in viral load at set point. We...

  16. Genetic determinants of telomere length and risk of common cancers: a Mendelian randomization study.

    Science.gov (United States)

    Zhang, Chenan; Doherty, Jennifer A; Burgess, Stephen; Hung, Rayjean J; Lindström, Sara; Kraft, Peter; Gong, Jian; Amos, Christopher I; Sellers, Thomas A; Monteiro, Alvaro N A; Chenevix-Trench, Georgia; Bickeböller, Heike; Risch, Angela; Brennan, Paul; Mckay, James D; Houlston, Richard S; Landi, Maria Teresa; Timofeeva, Maria N; Wang, Yufei; Heinrich, Joachim; Kote-Jarai, Zsofia; Eeles, Rosalind A; Muir, Ken; Wiklund, Fredrik; Grönberg, Henrik; Berndt, Sonja I; Chanock, Stephen J; Schumacher, Fredrick; Haiman, Christopher A; Henderson, Brian E; Amin Al Olama, Ali; Andrulis, Irene L; Hopper, John L; Chang-Claude, Jenny; John, Esther M; Malone, Kathleen E; Gammon, Marilie D; Ursin, Giske; Whittemore, Alice S; Hunter, David J; Gruber, Stephen B; Knight, Julia A; Hou, Lifang; Le Marchand, Loic; Newcomb, Polly A; Hudson, Thomas J; Chan, Andrew T; Li, Li; Woods, Michael O; Ahsan, Habibul; Pierce, Brandon L

    2015-09-15

    Epidemiological studies have reported inconsistent associations between telomere length (TL) and risk for various cancers. These inconsistencies are likely attributable, in part, to biases that arise due to post-diagnostic and post-treatment TL measurement. To avoid such biases, we used a Mendelian randomization approach and estimated associations between nine TL-associated SNPs and risk for five common cancer types (breast, lung, colorectal, ovarian and prostate cancer, including subtypes) using data on 51 725 cases and 62 035 controls. We then used an inverse-variance weighted average of the SNP-specific associations to estimate the association between a genetic score representing long TL and cancer risk. The long TL genetic score was significantly associated with increased risk of lung adenocarcinoma (P = 6.3 × 10(-15)), even after exclusion of a SNP residing in a known lung cancer susceptibility region (TERT-CLPTM1L) P = 6.6 × 10(-6)). Under Mendelian randomization assumptions, the association estimate [odds ratio (OR) = 2.78] is interpreted as the OR for lung adenocarcinoma corresponding to a 1000 bp increase in TL. The weighted TL SNP score was not associated with other cancer types or subtypes. Our finding that genetic determinants of long TL increase lung adenocarcinoma risk avoids issues with reverse causality and residual confounding that arise in observational studies of TL and disease risk. Under Mendelian randomization assumptions, our finding suggests that longer TL increases lung adenocarcinoma risk. However, caution regarding this causal interpretation is warranted in light of the potential issue of pleiotropy, and a more general interpretation is that SNPs influencing telomere biology are also implicated in lung adenocarcinoma risk.

  17. Governing the management and use of pooled microbial genetic resources: Lessons from the global crop commons

    Directory of Open Access Journals (Sweden)

    Michael Halewood

    2010-01-01

    Full Text Available The paper highlights lessons learned over the last thirty years establishing a governance structure for the global crop commons that are of relevance to current champions of the microbial commons. It argues that the political, legal and biophysical situation in which microbial genetic resources (and their users are located today are similar to the situation of plant genetic resources in the mid-1990s, before the International Treaty on Plant Genetic Resources was negotiated. Consequently, the paper suggests that it may be useful to look to the model of global network of ex situ plant genetic resources collections as a precedent to follow – even if only loosely – in developing an intergovernmentally endorsed legal substructure and governance framework for the microbial commons.

  18. Genetics Home Reference: neonatal onset multisystem inflammatory disease

    Science.gov (United States)

    ... a site of injury or disease to fight microbial invaders and facilitate tissue repair. When this has ... What are the different ways in which a genetic condition can be inherited? More about Inheriting Genetic ...

  19. Genetic Diseases and Genetic Determinism Models in French Secondary School Biology Textbooks

    Science.gov (United States)

    Castera, Jeremy; Bruguiere, Catherine; Clement, Pierre

    2008-01-01

    The presentation of genetic diseases in French secondary school biology textbooks is analysed to determine the major conceptions taught in the field of human genetics. References to genetic diseases, and the processes by which they are explained (monogeny, polygeny, chromosomal anomaly and environmental influence) are studied in recent French…

  20. Genetic Diseases and Genetic Determinism Models in French Secondary School Biology Textbooks

    Science.gov (United States)

    Castera, Jeremy; Bruguiere, Catherine; Clement, Pierre

    2008-01-01

    The presentation of genetic diseases in French secondary school biology textbooks is analysed to determine the major conceptions taught in the field of human genetics. References to genetic diseases, and the processes by which they are explained (monogeny, polygeny, chromosomal anomaly and environmental influence) are studied in recent French…

  1. Fine-Mapping of Common Genetic Variants Associated with Colorectal Tumor Risk Identified Potential Functional Variants.

    Directory of Open Access Journals (Sweden)

    Mengmeng Du

    Full Text Available Genome-wide association studies (GWAS have identified many common single nucleotide polymorphisms (SNPs associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs. We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33. We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s.

  2. Fine-Mapping of Common Genetic Variants Associated with Colorectal Tumor Risk Identified Potential Functional Variants

    Science.gov (United States)

    Gala, Manish; Abecasis, Goncalo; Bezieau, Stephane; Brenner, Hermann; Butterbach, Katja; Caan, Bette J.; Carlson, Christopher S.; Casey, Graham; Chang-Claude, Jenny; Conti, David V.; Curtis, Keith R.; Duggan, David; Gallinger, Steven; Haile, Robert W.; Harrison, Tabitha A.; Hayes, Richard B.; Hoffmeister, Michael; Hopper, John L.; Hudson, Thomas J.; Jenkins, Mark A.; Küry, Sébastien; Le Marchand, Loic; Leal, Suzanne M.; Newcomb, Polly A.; Nickerson, Deborah A.; Potter, John D.; Schoen, Robert E.; Schumacher, Fredrick R.; Seminara, Daniela; Slattery, Martha L.; Hsu, Li; Chan, Andrew T.; White, Emily; Berndt, Sonja I.; Peters, Ulrike

    2016-01-01

    Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs). We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33). We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s). PMID:27379672

  3. PRELIMINARY ANALYSIS OF COMMON LOON GENETIC STRUCTURE IN NORTH AMERICA BASED ON FIVE MICROSATELLITE LOCI

    Science.gov (United States)

    This study seeks to determine fine-scale genetic structure of Common Loon breeding populations in order to link wintering birds with their breeding regions. Common Loons are large piscivorous birds that breed in lakes of northern North America and Iceland. Loons are highly phil...

  4. Common TLR1 genetic variation is not associated with death from melioidosis, a common cause of sepsis in rural Thailand.

    Directory of Open Access Journals (Sweden)

    Narisara Chantratita

    Full Text Available Melioidosis, infection caused by the Gram-negative bacterium Burkholderia pseudomallei, is a common cause of sepsis in northeast Thailand. In white North Americans, common functional genetic variation in TLR1 is associated with organ failure and death from sepsis. We hypothesized that TLR1 variants would be associated with outcomes in Thais with melioidosis. We collated the global frequencies of three TLR1 variants that are common in white North American populations: rs5743551 (-7202A/G, rs4833095 (742A/G, and rs5743618 (1804G/T. We noted a reversal of the minor allele from white North American subjects to Asian populations that was particularly pronounced for rs5743618. In the Utah residents of European ancestry, the frequency of the rs5743618 T allele was 17% whereas in Vietnamese subjects the frequency was >99%. We conducted a genetic association study in 427 patients with melioidosis to determine the association of TLR1 variation with organ failure or death. We genotyped rs5743551 and rs4833095. The variants were in high linkage disequilibrium but neither variant was associated with organ failure or in-hospital death. In 300 healthy Thai individuals we further tested the association of TLR1 variation with ex vivo blood responses to Pam3CSK4, a TLR1 agonist. Neither variant was robustly associated with blood cytokine responses induced by Pam3CSK4. We identified additional common variation in TLR1 by searching public databases and the published literature and screened three additional TLR1 variants for associations with Pam3CSK4-induced responses but found none. We conclude that the genetic architecture of TLR1 variation differs substantially in southeast Asians compared to other populations and common variation in TLR1 in Thais is not associated with outcome from melioidosis or with altered blood responses to Pam3CSK4. Our findings highlight the need for additional studies of TLR1 and other innate immune genetic modulators of the inflammatory

  5. Von Hippel-Lindau Disease: Genetics and Role of Genetic Counseling in a Multiple Neoplasia Syndrome.

    Science.gov (United States)

    Nielsen, Sarah M; Rhodes, Lindsay; Blanco, Ignacio; Chung, Wendy K; Eng, Charis; Maher, Eamonn R; Richard, Stéphane; Giles, Rachel H

    2016-06-20

    Von Hippel-Lindau disease (VHL) is one of the most common inherited neoplasia syndromes and is characterized by highly vascular tumors of the eyes, brain, and spine, as well as benign and malignant tumors and/or cysts of the kidneys, adrenal medullae and sympathetic paraganglia, endolymphatic sac, epididymis, and broad ligament. Since the discovery of the VHL gene in 1993, more than 900 families with VHL have been identified and examined. Genetic testing for VHL is widely available and will detect a disease-causing mutation in rate 95% to 100% of individuals who have a clinical diagnosis of VHL, making it the standard of care for diagnosis of VHL. Furthermore, genetic testing for VHL is indicated in some individuals with seemingly sporadic VHL-related tumor types, as ≤ 10% of pheochromocytoma or early-onset renal cell carcinoma and ≤ 40% of CNS hemangioblastoma harbor germline VHL mutations without a family history or additional features of VHL disease. The majority of VHL mutations are private, but there are also well-characterized founder mutations. VHL is a complex, multiorgan disease that spans the breadth of oncology subspecialties, and, as such, providers in these subspecialties should be aware of when to consider a diagnosis of VHL, when to refer a patient to a genetics specialist for consideration of gene testing, and, perhaps most importantly, how to communicate this sensitive information in an age-appropriate manner to at-risk families. This review will provide state-of-the-art information regarding the genetics of VHL and will serve as a key reference for nongenetics professionals who encounter patients with VHL.

  6. Intraspecific morphological and genetic variation of common species predicts ranges of threatened ones

    Science.gov (United States)

    Fuller, Trevon L.; Thomassen, Henri A.; Peralvo, Manuel; Buermann, Wolfgang; Milá, Borja; Kieswetter, Charles M.; Jarrín-V, Pablo; Devitt, Susan E. Cameron; Mason, Eliza; Schweizer, Rena M.; Schlunegger, Jasmin; Chan, Janice; Wang, Ophelia; Schneider, Christopher J.; Pollinger, John P.; Saatchi, Sassan; Graham, Catherine H.; Wayne, Robert K.; Smith, Thomas B.

    2013-01-01

    Predicting where threatened species occur is useful for making informed conservation decisions. However, because they are usually rare, surveying threatened species is often expensive and time intensive. Here, we show how regions where common species exhibit high genetic and morphological divergence among populations can be used to predict the occurrence of species of conservation concern. Intraspecific variation of common species of birds, bats and frogs from Ecuador were found to be a significantly better predictor for the occurrence of threatened species than suites of environmental variables or the occurrence of amphibians and birds. Fully 93 per cent of the threatened species analysed had their range adequately represented by the geographical distribution of the morphological and genetic variation found in seven common species. Both higher numbers of threatened species and greater genetic and morphological variation of common species occurred along elevation gradients. Higher levels of intraspecific divergence may be the result of disruptive selection and/or introgression along gradients. We suggest that collecting data on genetic and morphological variation in common species can be a cost effective tool for conservation planning, and that future biodiversity inventories include surveying genetic and morphological data of common species whenever feasible. PMID:23595273

  7. Hepatic lipase, genetically elevated high-density lipoprotein, and risk of ischemic cardiovascular disease

    DEFF Research Database (Denmark)

    Johannsen, Trine Holm; Kamstrup, Pia R; Andersen, Rolf V

    2008-01-01

    CONTEXT: Hepatic lipase influences metabolism of high-density lipoprotein (HDL), a risk factor for ischemic cardiovascular disease (ICD: ischemic heart disease and ischemic cerebrovascular disease). OBJECTIVE: We tested the hypothesis that genetic variation in the hepatic lipase genetic variants V.......91 (95% CI 0.89-0.94), respectively; this calculation assumes that genetically elevated HDL levels confer decreased risk similar to common HDL elevations. In contrast, when all cases and controls were combined, the observed odds ratios for ICD for these three genetic variants vs. noncarriers were 1.19 (0.......76-1.88), 1.04 (0.96-1.13), and 1.08 (0.89-1.30), respectively. Hazard/odds ratios for ICD in carriers vs. noncarriers of the four remaining hepatic lipase genetic variants did not differ consistently from 1.0. CONCLUSION: Hepatic lipase genetic variants with elevated levels of HDL cholesterol did...

  8. Recent mitochondrial DNA mutations increase the risk of developing common late-onset human diseases.

    Directory of Open Access Journals (Sweden)

    Gavin Hudson

    2014-05-01

    Full Text Available Mitochondrial DNA (mtDNA is highly polymorphic at the population level, and specific mtDNA variants affect mitochondrial function. With emerging evidence that mitochondrial mechanisms are central to common human diseases, it is plausible that mtDNA variants contribute to the "missing heritability" of several complex traits. Given the central role of mtDNA genes in oxidative phosphorylation, the same genetic variants would be expected to alter the risk of developing several different disorders, but this has not been shown to date. Here we studied 38,638 individuals with 11 major diseases, and 17,483 healthy controls. Imputing missing variants from 7,729 complete mitochondrial genomes, we captured 40.41% of European mtDNA variation. We show that mtDNA variants modifying the risk of developing one disease also modify the risk of developing other diseases, thus providing independent replication of a disease association in different case and control cohorts. High-risk alleles were more common than protective alleles, indicating that mtDNA is not at equilibrium in the human population, and that recent mutations interact with nuclear loci to modify the risk of developing multiple common diseases.

  9. Genetic studies in chronic kidney disease: interpretation and clinical applicability.

    Science.gov (United States)

    Witasp, Anna; Nordfors, Louise; Carrero, Juan Jesus; Luttropp, Karin; Lindholm, Bengt; Schalling, Martin; Stenvinkel, Peter

    2012-01-01

    The tools of modern molecular biology are evolving rapidly, resulting in vastly more efficient approaches to illuminating human genetic variations and their effects on common multifactorial disorders such as chronic kidney disease (CKD). Indeed, candidate gene association studies and genome-wide association studies (GWASs) have generated novel genetic variants in previously unrecognized biological pathways, highlighting disease mechanisms with a potential role in CKD etiology, morbidity and mortality. Nephrologists now need to find ways to make use of these advancements and meet the increasingly stringent requirements for valid study design, data handling and interpretation of genetic studies. Adding to our prior article in this journal, which introduced the basics of genotype-phenotype association studies in CKD, this second article focuses on how to ascertain robust and reproducible findings by applying adequate methodological and statistical approaches to genotype-phenotype studies in CKD populations. Moreover, this review will briefly discuss genotype-based risk prediction, pharmacotherapy, drug target identification and individualized treatment solutions, specifically highlighting potentially important findings in CKD patients. This increased knowledge will hopefully facilitate the exciting transition from conventional clinical medicine to gene-based medicine. However, before this can be accomplished, unsolved issues regarding the complex human genetic architecture as well technical and clinically oriented obstacles will have to be overcome. Additionally, new policies and standardized risk evaluations for genetic testing in the clinical setting will have to be established to guarantee that CKD patients are provided with high-quality genotype-guided counseling that will help to improve their poor outcomes.

  10. Landscape genetics and the spatial distribution of chronic wasting disease.

    Science.gov (United States)

    Blanchong, Julie A; Samuel, Michael D; Scribner, Kim T; Weckworth, Byron V; Langenberg, Julia A; Filcek, Kristine B

    2008-02-23

    Predicting the spread of wildlife disease is critical for identifying populations at risk, targeting surveillance and designing proactive management programmes. We used a landscape genetics approach to identify landscape features that influenced gene flow and the distribution of chronic wasting disease (CWD) in Wisconsin white-tailed deer. CWD prevalence was negatively correlated with genetic differentiation of study area deer from deer in the area of disease origin (core-area). Genetic differentiation was greatest, and CWD prevalence lowest, in areas separated from the core-area by the Wisconsin River, indicating that this river reduced deer gene flow and probably disease spread. Features of the landscape that influence host dispersal and spatial patterns of disease can be identified based on host spatial genetic structure. Landscape genetics may be used to predict high-risk populations based on their genetic connection to infected populations and to target disease surveillance, control and preventative activities.

  11. Landscape genetics and the spatial distribution of chronic wasting disease

    Science.gov (United States)

    Blanchong, Julie A.; Samuel, M.D.; Scribner, K.T.; Weckworth, B.V.; Langenberg, J.A.; Filcek, K.B.

    2008-01-01

    Predicting the spread of wildlife disease is critical for identifying populations at risk, targeting surveillance and designing proactive management programmes. We used a landscape genetics approach to identify landscape features that influenced gene flow and the distribution of chronic wasting disease (CWD) in Wisconsin white-tailed deer. CWD prevalence was negatively correlated with genetic differentiation of study area deer from deer in the area of disease origin (core-area). Genetic differentiation was greatest, and CWD prevalence lowest, in areas separated from the core-area by the Wisconsin River, indicating that this river reduced deer gene flow and probably disease spread. Features of the landscape that influence host dispersal and spatial patterns of disease can be identified based on host spatial genetic structure. Landscape genetics may be used to predict high-risk populations based on their genetic connection to infected populations and to target disease surveillance, control and preventative activities. ?? 2007 The Royal Society.

  12. Genetics and cardiovascular disease: the impact of molecular diagnosis.

    Science.gov (United States)

    Vengoechea, Jaime; McKelvey, Kent D

    2013-04-01

    Information technology is exponentially reducing the cost of genetic testing while multiple clinical applications emerge. Genetic diagnosis increasingly impacts prevention, diagnosis and treatment of disease. In cardiovascular medicine, the establishment of a specific genetic diagnosis may affect management of cardiomyopathy, arrhythmia, connective tissue and metabolic disease. Econometric studies have determined that genetic testing is cost-effective in hypertrophic cardiomyopathy and disease-specific interventions are now available for specific conditions. Identification of a specific genetic disorder now allows for more precise medicine in the affected individual and more accurate preventive care for asymptomatic family members.

  13. Genetic heterogeneity in Alzheimer disease and implications for treatment strategies.

    Science.gov (United States)

    Ringman, John M; Goate, Alison; Masters, Colin L; Cairns, Nigel J; Danek, Adrian; Graff-Radford, Neill; Ghetti, Bernardino; Morris, John C

    2014-11-01

    Since the original publication describing the illness in 1907, the genetic understanding of Alzheimer's disease (AD) has advanced such that it is now clear that it is a genetically heterogeneous condition, the subtypes of which may not uniformly respond to a given intervention. It is therefore critical to characterize the clinical and preclinical stages of AD subtypes, including the rare autosomal dominant forms caused by known mutations in the PSEN1, APP, and PSEN2 genes that are being studied in the Dominantly Inherited Alzheimer Network study and its associated secondary prevention trial. Similar efforts are occurring in an extended Colombian family with a PSEN1 mutation, in APOE ε4 homozygotes, and in Down syndrome. Despite commonalities in the mechanisms producing the AD phenotype, there are also differences that reflect specific genetic origins. Treatment modalities should be chosen and trials designed with these differences in mind. Ideally, the varying pathological cascades involved in the different subtypes of AD should be defined so that both areas of overlap and of distinct differences can be taken into account. At the very least, clinical trials should determine the influence of known genetic factors in post hoc analyses.

  14. Genetic diversity in cultivated carioca common beans based on molecular marker analysis

    Directory of Open Access Journals (Sweden)

    Juliana Morini Küpper Cardoso Perseguini

    2011-01-01

    Full Text Available A wide array of molecular markers has been used to investigate the genetic diversity among common bean species. However, the best combination of markers for studying such diversity among common bean cultivars has yet to be determined. Few reports have examined the genetic diversity of the carioca bean, commercially one of the most important common beans in Brazil. In this study, we examined the usefulness of two molecular marker systems (simple sequence repeats - SSRs and amplified fragment length polymorphisms - AFLPs for assessing the genetic diversity of carioca beans. The amount of information provided by Roger's modified genetic distance was used to analyze SSR data and Jaccards similarity coefficient was used for AFLP data. Seventy SSRs were polymorphic and 20 AFLP primer combinations produced 635 polymorphic bands. Molecular analysis showed that carioca genotypes were quite diverse. AFLPs revealed greater genetic differentiation and variation within the carioca genotypes (Gst = 98% and Fst = 0.83, respectively than SSRs and provided better resolution for clustering the carioca genotypes. SSRs and AFLPs were both suitable for assessing the genetic diversity of Brazilian carioca genotypes since the number of markers used in each system provided a low coefficient of variation. However, fingerprint profiles were generated faster with AFLPs, making them a better choice for assessing genetic diversity in the carioca germplasm.

  15. Common genetic architecture underlying young children's food fussiness and liking for vegetables and fruit.

    Science.gov (United States)

    Fildes, Alison; van Jaarsveld, Cornelia H M; Cooke, Lucy; Wardle, Jane; Llewellyn, Clare H

    2016-04-01

    Food fussiness (FF) is common in early childhood and is often associated with the rejection of nutrient-dense foods such as vegetables and fruit. FF and liking for vegetables and fruit are likely all heritable phenotypes; the genetic influence underlying FF may explain the observed genetic influence on liking for vegetables and fruit. Twin analyses make it possible to get a broad-based estimate of the extent of the shared genetic influence that underlies these traits. We quantified the extent of the shared genetic influence that underlies FF and liking for vegetables and fruit in early childhood with the use of a twin design. Data were from the Gemini cohort, which is a population-based sample of twins born in England and Wales in 2007. Parents of 3-y-old twins (n= 1330 pairs) completed questionnaire measures of their children's food preferences (liking for vegetables and fruit) and the FF scale from the Children's Eating Behavior Questionnaire. Multivariate quantitative genetic modeling was used to estimate common genetic influences that underlie FF and liking for vegetables and fruit. Genetic correlations were significant and moderate to large in size between FF and liking for both vegetables (-0.65) and fruit (-0.43), which indicated that a substantial proportion of the genes that influence FF also influence liking. Common genes that underlie FF and liking for vegetables and fruit largely explained the observed phenotypic correlations between them (68-70%). FF and liking for fruit and vegetables in young children share a large proportion of common genetic factors. The genetic influence on FF may determine why fussy children typically reject fruit and vegetables.

  16. Genetics

    Science.gov (United States)

    ... Inheritance; Heterozygous; Inheritance patterns; Heredity and disease; Heritable; Genetic markers ... The chromosomes are made up of strands of genetic information called DNA. Each chromosome contains sections of ...

  17. The suggestion of common cause of disease, characteristics of human body, and medical treatment

    Directory of Open Access Journals (Sweden)

    Byung-Jun Cho

    2011-06-01

    Full Text Available Objectives & Methods: This suggestion was attempted to be elevated the recognition of common characteristics in disease. So, we performed to analyze the correlation of common cause of disease, characteristics of human body, and medical treatment. And the results are as follows. Results: 1. The cause of disease is consist of genetic factor, aging, habit, food of not good in health, weather, environment, deficit of the physical activity, stress and so on. 2. Generally, human has common and individual weakness. Individual weakness is appeared similar to the occurrence of volcano and lapse. 3. The correlation of disease and medical treatments is possible to explain using the quotation of the law of motion made by Isaac Newton, the great physicist. 4. When the process of the medical treatment was not progressed, the prognosis is determined by the correlation of the homeostasis(H' in human body and the homeostasis(H of disease. 5. The prognosis of disease is determined by the relationship between the energy of disease(F and medical treatment(F'. 6. The exact diagnosis is possible to predict the treatment sequence, and the facts that homeostasis in human body and disease, relationship between the energy of disease(F and medical treatment(F', action and reaction are important to determine the prognosis. 7. The careful observation of improving response and worsening action of disease becomes available for exact prognosis. Conclusion: The above described contents may be useful in clinical studies, and the concrete clinical reports about this will be made afterward.

  18. Association study of common genetic variants and HIV-1 acquisition in 6,300 infected cases and 7,200 controls

    DEFF Research Database (Denmark)

    McLaren, Paul J; Coulonges, Cédric; Ripke, Stephan

    2013-01-01

    Multiple genome-wide association studies (GWAS) have been performed in HIV-1 infected individuals, identifying common genetic influences on viral control and disease course. Similarly, common genetic correlates of acquisition of HIV-1 after exposure have been interrogated using GWAS, although...... that this association was due to the frailty bias in studies of lethal diseases. Further analyses including testing recessive genetic models, testing for bulk effects of non-genome-wide significant variants, stratifying by sexual or parenteral transmission risk and testing previously reported associations showed...... no evidence for genetic influence on HIV-1 acquisition (with the exception of CCR5Δ32 homozygosity). Thus, these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size....

  19. Complement regulators in human disease: lessons from modern genetics.

    Science.gov (United States)

    K Liszewski, M; Atkinson, J P

    2015-03-01

    First identified in human serum in the late 19th century as a 'complement' to antibodies in mediating bacterial lysis, the complement system emerged more than a billion years ago probably as the first humoral immune system. The contemporary complement system consists of nearly 60 proteins in three activation pathways (classical, alternative and lectin) and a terminal cytolytic pathway common to all. Modern molecular biology and genetics have not only led to further elucidation of the structure of complement system components, but have also revealed function-altering rare variants and common polymorphisms, particularly in regulators of the alternative pathway, that predispose to human disease by creating 'hyperinflammatory complement phenotypes'. To treat these 'complementopathies', a monoclonal antibody against the initiator of the membrane attack complex, C5, has received approval for use. Additional therapeutic reagents are on the horizon.

  20. Common Eye Diseases in Children in Saudi Arabia (Jazan)

    Science.gov (United States)

    Darraj, Abdulrahman; Barakat, Walid; Kenani, Mona; Shajry, Reem; Khawaji, Abdullah; Bakri, Sultan; Makin, Abdulrahman; Mohanna, Azza; Yassin, Abu Obaida

    2016-01-01

    BACKGROUND The rise in childhood eye diseases has become a matter of concern in Saudi Arabia, and hence a study has been conducted on the residents of Jazan. The aim of the research was to find out the root cause of such issues and provide a solution to prevent such circumstances for it may affect the vision of children. In this study, therefore, we aimed to determine the types of childhood eye diseases in Jazan and to discuss the best ways to prevent them or prevent their effect on the vision of our children. Our institutions are working toward the longevity and welfare of the residents, and healthcare is one of the important aspects in such a field. METHODS This is a retrospective review of all patients less than 18 years of age who presented to the pediatric ophthalmology clinic of Prince Mohammed Bin Nasser Hospital, Jazan, between October 2014 and October 2015. The data, collected on 385 cases, included the age at first presentation, sex, clinical diagnosis, refractive error (RE) if present, and whether the child had amblyopia. If the child did not undergo complete ophthalmic examination with cycloplegic refraction, he/she was excluded. All data were collected and analyzed using the software SPSS. A P-value sex among children with REs and squint. Trauma was seen more commonly among males and in the group aged 12–18 years. CONCLUSION In this retrospective study, the focus was on the common childhood eye diseases that were considerably high. Hypermetropia was the predominant RE, which is in contrast to other studies where myopia was more common. However, it is important to promote public education on the significance of early detection of strabismus, REs, and amblyopia and have periodic screening in schools. The discussion of the various issues is aimed at increasing the awareness and building a support for the cause by creating the knowledge base to treat things on time and acknowledging the severity of the issues. PMID:27679531

  1. Eukaryotic enhancers: common features, regulation, and participation in diseases.

    Science.gov (United States)

    Erokhin, Maksim; Vassetzky, Yegor; Georgiev, Pavel; Chetverina, Darya

    2015-06-01

    Enhancers are positive DNA regulatory sequences controlling temporal and tissue-specific gene expression. These elements act independently of their orientation and distance relative to the promoters of target genes. Enhancers act through a variety of transcription factors that ensure their correct match with target promoters and consequent gene activation. There is a growing body of evidence on association of enhancers with transcription factors, co-activators, histone chromatin marks, and lncRNAs. Alterations in enhancers lead to misregulation of gene expression, causing a number of human diseases. In this review, we focus on the common characteristics of enhancers required for transcription stimulation.

  2. Analysis of genetics and risk factors of Alzheimer's Disease.

    Science.gov (United States)

    Panpalli Ates, M; Karaman, Y; Guntekin, S; Ergun, M A

    2016-06-14

    Alzheimer's Disease is the leading neurodegenerative cause of dementia. The pathogenesis is not clearly understood yet, is believed to be the complex interaction between genetic and environmental factors. Consequently vascular risk factors and Apolipoprotein E genotyping are increasingly gaining importance. This study aimed at assessing the relationships between Alzheimer's Disease and Apolipoprotein E phenotype and vascular risk factors. Patients diagnosed with "possible Alzheimer's Disease" in the Gazi University, Department of Neurology, were included in the study and age-matched volunteer patients who attended the polyclinic were included as a control group. In this study, the risk factors including low education level, smoking, hyperlipidemia, higher serum total cholesterol levels, and hyperhomocysteinemia were found to be statistically significantly more common in the Alzheimer's Disease group in comparison to the Control Group, while all Apolipoprotein E ε4/ε4 genotypes were found in the Alzheimer's Disease group. The presence of the Apolipoprotein E ε4 allele is believed to increase vascular risk factors as well as to affect Alzheimer's Disease directly. The biological indicators which are used in identifying the patients' genes will be probably used in the treatment plan of the patients in the future.

  3. WNT2 Locus Is Involved in Genetic Susceptibility of Peyronie's Disease

    NARCIS (Netherlands)

    Dolmans, Guido H.; Werker, Paul M.; de Jong, Igle J.; Nijman, Rien J.; Wijmenga, Cisca; Ophoff, Roel A.

    Introduction. Peyronie's disease (PD) is a fibromatosis of the penis, with a pathology very similar to what is seen in the hand (palmar fascia) in Dupuytren's disease (DD). Recently, we performed a genome-wide association study and identified nine genetic loci containing common variants associated

  4. WNT2 Locus Is Involved in Genetic Susceptibility of Peyronie's Disease

    NARCIS (Netherlands)

    Dolmans, Guido H.; Werker, Paul M.; de Jong, Igle J.; Nijman, Rien J.; Wijmenga, Cisca; Ophoff, Roel A.

    2012-01-01

    Introduction. Peyronie's disease (PD) is a fibromatosis of the penis, with a pathology very similar to what is seen in the hand (palmar fascia) in Dupuytren's disease (DD). Recently, we performed a genome-wide association study and identified nine genetic loci containing common variants associated w

  5. Shared and Distinct Genetic Variants in Type 1 Diabetes and Celiac Disease

    NARCIS (Netherlands)

    Smyth, Deborah J.; Plagnol, Vincent; Walker, Neil M.; Cooper, Jason D.; Downes, Kate; Yang, Jennie H. M.; Howson, Joanna M. M.; Stevens, Helen; McManus, Ross; Wijmenga, Cisca; Heap, Graham A.; Dubois, Patrick C.; Clayton, David G.; Hunt, Karen A.; van Heel, David A.; Todd, John A.

    2008-01-01

    Background: Two inflammatory disorders, type 1 diabetes and celiac disease, cosegregate in populations, suggesting a common genetic origin. Since both diseases are associated with the HLA class II genes on chromosome 6p21, we tested whether non-HLA loci are shared. Methods: We evaluated the associat

  6. Genetic mapping of two genes conferring resistance to powdery mildew in common bean (Phaseolus vulgaris L.).

    Science.gov (United States)

    Pérez-Vega, Elena; Trabanco, Noemí; Campa, Ana; Ferreira, Juan José

    2013-06-01

    Powdery mildew (PM) is a serious disease in many legume species, including the common bean (Phaseolus vulgaris L.). This study investigated the genetic control behind resistance reaction to PM in the bean genotype, Cornell 49242. The results revealed evidence supporting a qualitative mode of inheritance for resistance and the involvement of two independent genes in the resistance reaction. The location of these resistance genes was investigated in a linkage genetic map developed for the XC RIL population. Contingency tests revealed significant associations for 28 loci out of a total of 329 mapped loci. Fifteen were isolated or formed groups with less than two loci. The thirteen remaining loci were located at three regions in linkage groups Pv04, Pv09, and Pv11. The involvement of Pv09 was discarded due to the observed segregation in the subpopulation obtained from the Xana genotype for the loci located in this region. In contrast, the two subpopulations obtained from the Xana genotype for the BM161 locus, linked to the Co-3/9 anthracnose resistance gene (Pv04), and from the Xana genotype for the SCAReoli locus, linked to the Co-2 anthracnose resistance gene (Pv11), exhibited monogenic segregations, suggesting that both regions were involved in the genetic control of resistance. A genetic dissection was carried out to verify the involvement of both regions in the reaction to PM. Two resistant recombinant lines were selected, according to their genotypes, for the block of loci included in the Co-2 and Co-3/9 regions, and they were crossed with the susceptible parent, Xana. Linkage analysis in the respective F2 populations supported the hypothesis that a dominant gene (Pm1) was located in the linkage group Pv11 and another gene (Pm2) was located in the linkage group Pv04. This is the first report showing the localization of resistance genes against powdery mildew in Phaseolus vulgaris and the results offer the opportunity to increase the efficiency of breeding

  7. Genetic control of human brain transcript expression in Alzheimer disease.

    Science.gov (United States)

    Webster, Jennifer A; Gibbs, J Raphael; Clarke, Jennifer; Ray, Monika; Zhang, Weixiong; Holmans, Peter; Rohrer, Kristen; Zhao, Alice; Marlowe, Lauren; Kaleem, Mona; McCorquodale, Donald S; Cuello, Cindy; Leung, Doris; Bryden, Leslie; Nath, Priti; Zismann, Victoria L; Joshipura, Keta; Huentelman, Matthew J; Hu-Lince, Diane; Coon, Keith D; Craig, David W; Pearson, John V; Heward, Christopher B; Reiman, Eric M; Stephan, Dietrich; Hardy, John; Myers, Amanda J

    2009-04-01

    We recently surveyed the relationship between the human brain transcriptome and genome in a series of neuropathologically normal postmortem samples. We have now analyzed additional samples with a confirmed pathologic diagnosis of late-onset Alzheimer disease (LOAD; final n = 188 controls, 176 cases). Nine percent of the cortical transcripts that we analyzed had expression profiles correlated with their genotypes in the combined cohort, and approximately 5% of transcripts had SNP-transcript relationships that could distinguish LOAD samples. Two of these transcripts have been previously implicated in LOAD candidate-gene SNP-expression screens. This study shows how the relationship between common inherited genetic variants and brain transcript expression can be used in the study of human brain disorders. We suggest that studying the transcriptome as a quantitative endo-phenotype has greater power for discovering risk SNPs influencing expression than the use of discrete diagnostic categories such as presence or absence of disease.

  8. 602 Cvid: A Common but Still Underdiagnosed Disease

    Science.gov (United States)

    Gallego, Claudia; González-Díaz, Sandra; del Carmen Zarate, Maria; Arias-Cruz, Alfredo; Garcia-Calderin, Diego; Yanneth Mejia Salas, Karla; Calva, Maricruz; Alfredo Dominguez Sansores, Luis

    2012-01-01

    Background Among the more than 150 different forms of Primary Immunodeficiency Diseases (PID) the CVID is the most common symptomatic primary immunodeficiency, present mainly in adults. There is a failure of B cells to develop and differentiate into plasma cells; at consequent a reduction of the production of one or more isotypes of antibody can also affected Cell-mediated immunity. Common manifestations included recurrent bacterial infections, that typically involve the upper and lower respiratory tract. Some patients are highly prone to autoimmune manifestations, lymphoid hyperplasia, and tumors. Methods We presented 3 cases of CVID with a variety of clinical presentation, evolution and complications related to delayed diagnosis. Results A 34 year old male presented chronic diarrhea, weight loss, malnutrition and recurrent upper respiratory infections; digestive tract endoscopy and biopsy was reported with villous atrophy, chronic inflammation and low grade non-Hodgkin's lymphoma B cell. Unfortunately this patient refused the use of gamma globulin treatment, had a high morbidity, and finally the patient died. The case of a nurse with clinical manifestation of recurrent rinosinusitis and pneumonia, which was diagnosed as IDCV 17 years later, after she developed pulmonary bronchiectasis. Fortunately the disease is under control and she is actually under treatment with intravenous immunoglobulin. Finally, the case of a 44 year old female, who suffered from recurrent upper respiratory infections, additionally had a thyroid gland tumor associated which affecting the thyroid function. Conclusions In the 3 cases had low levels of all immunoglobulin as a hallmark. The clinician must be suspecting this condition in all adults with recurrent infectious disease who have gastrointestinal symptoms or who are detected a malignant disease. Early diagnosis and correct treatment are critical in preventing tissue damage, long-term sequelae and death. Replacement with intravenous

  9. Treatment and Prevention of Common Complications of Chronic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Sheikh Salahuddin Ahmed

    2014-01-01

    Full Text Available Chronic kidney disease (CKD is a worldwide public health problem with an increasing incidence and prevalence. Outcomes of CKD include not only complications of decreased kidney function and cardiovascular disease but also kidney failure causing increased morbidity and mortality. Unfortunately, CKD is often undetected and undertreated because of its insidious onset, variable progression, and length of time to overt kidney failure. Diabetes is now the leading cause of CKD requiring renal replacement therapy in many parts of the world, and its prevalence is increasing disproportionately in the developing countries. This review article outlines the current recommendations from various clinical guidelines and research studies for treatment, prevention and delaying the progression of both CKD and its common complications such as hypertension, anemia, renal osteodystrophy, electrolyte and acid-base imbalance, and hyperlipidemia. Recommendations for nutrition in CKD and measures adopted for early diabetic kidney disease to prevent further progression have also been reviewed. There is strong evidence that early detection and management of CKD can prevent or reduce disease progression, decrease complications and improve outcomes. Evidence supports that achieving optimal glucose control, blood pressure, reduction in albuminuria with a multifactorial intervention slows the progression of CKD. Angiotensin-converting enzyme inhibitors and angiotensin-II receptor antagonists are most effective because of their unique ability to decrease proteinuria, a factor important for the progression of CKD.

  10. Salmonella Hepatitis: An Uncommon Complication of a Common Disease

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    Ritu Karoli

    2012-01-01

    Full Text Available Typhoid fever is a very common infectious disease of tropics, associated with high morbidity and mortality. Typhoid fever is often associated with hepatomegaly and mildly deranged liver functions; a clinical picture of acute hepatitis is a rare complication. We report a young patient who presented with fever and jaundice and was found to have acute hepatitis secondary to typhoid fever. Recognition of Salmonella hepatitis is of clinical importance as it can mimic acute viral hepatitis. Early institution of specific therapy can improve the prognosis in these patients.Typhoid fever is a very common infectious disease of tropics, associated with high morbidity and mortality. Typhoid fever is often associated with hepatomegaly and mildly deranged liver functions; a clinical picture of acute hepatitis is a rare complication. We report a young patient who presented with fever and jaundice and was found to have acute hepatitis secondary to typhoid fever. Recognition of Salmonella hepatitis is of clinical importance as it can mimic acute viral hepatitis. Early institution of specific therapy can improve the prognosis in these patients.

  11. Drug Induced Steatohepatitis: An Uncommon Culprit of a Common Disease

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    Liane Rabinowich

    2015-01-01

    Full Text Available Nonalcoholic fatty liver disease (NAFLD is a leading cause of liver disease in developed countries. Its frequency is increasing in the general population mostly due to the widespread occurrence of obesity and the metabolic syndrome. Although drugs and dietary supplements are viewed as a major cause of acute liver injury, drug induced steatosis and steatohepatitis are considered a rare form of drug induced liver injury (DILI. The complex mechanism leading to hepatic steatosis caused by commonly used drugs such as amiodarone, methotrexate, tamoxifen, valproic acid, glucocorticoids, and others is not fully understood. It relates not only to induction of the metabolic syndrome by some drugs but also to their impact on important molecular pathways including increased hepatocytes lipogenesis, decreased secretion of fatty acids, and interruption of mitochondrial β-oxidation as well as altered expression of genes responsible for drug metabolism. Better familiarity with this type of liver injury is important for early recognition of drug hepatotoxicity and crucial for preventing severe forms of liver injury and cirrhosis. Moreover, understanding the mechanisms leading to drug induced hepatic steatosis may provide much needed clues to the mechanism and potential prevention of the more common form of metabolic steatohepatitis.

  12. Comparative analysis of phenotypes features in two common genetic variants of limb-girdle muscular dystrophy

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    I. V. Sharkova

    2015-01-01

    Full Text Available The algorithm of differential diagnosis of the two most common genetic variants the limb-girdle muscular dystrophy (LGMD2A and DMD, developed on the basis of a comprehensive survey of 85 patients with a diagnosis specification using techniques of DNA analysis. It is shown that the accurate diagnosis of LGMD genetic types should be based on the results of the clinical and genealogical, biochemical and molecular genetic analysis. The proposed algorithm will significantly reduces the economic and time costs with expensive DNA testing.

  13. 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

    2011-12-01

    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 withthe 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.

  14. Maine Coon renal screening: ultrasonographical characterisation and preliminary genetic analysis for common genes in cats with renal cysts.

    Science.gov (United States)

    Gendron, Karine; Owczarek-Lipska, Marta; Lang, Johann; Leeb, Tosso

    2013-12-01

    The objective of this study was to assess the prevalence of renal cysts and other renal abnormalities in purebred Maine Coon cats, and to characterise these through genetic typing. Voluntary pre-breeding screening programmes for polycystic kidney disease (PKD) are offered for this breed throughout Switzerland, Germany and other northern European countries. We performed a retrospective evaluation of Maine Coon screening for renal disease at one institution over an 8-year period. Renal ultrasonography was performed in 187 healthy Maine Coon cats. Renal changes were observed in 27 of these cats. Renal cysts were found in seven cats, and were mostly single and unilateral (6/7, 85.7%), small (mean 3.6 mm) and located at the corticomedullary junction (4/6, 66.7%). Sonographical changes indicating chronic kidney disease (CKD) were observed in 10/187 (5.3%) cats and changes of unknown significance were documented in 11/187 (5.9%) cats. All six cats genetically tested for PKD1 were negative for the mutation, and gene sequencing of these cats did not demonstrate any common genetic sequences. Cystic renal disease occurs with a low prevalence in Maine Coons and is unrelated to the PKD observed in Persians and related breeds. Ultrasonographical findings compatible with CKD are not uncommon in juvenile Maine Coons.

  15. Pathogenesis of coronary artery disease: focus on genetic risk factors and identification of genetic variants

    Directory of Open Access Journals (Sweden)

    Sayols-Baixeras S

    2014-01-01

    Full Text Available Sergi Sayols-Baixeras, Carla Lluís-Ganella, Gavin Lucas, Roberto ElosuaCardiovascular Epidemiology and Genetics Research Group, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, SpainAbstract: Coronary artery disease (CAD is the leading cause of death and disability worldwide, and its prevalence is expected to increase in the coming years. CAD events are caused by the interplay of genetic and environmental factors, the effects of which are mainly mediated through cardiovascular risk factors. The techniques used to study the genetic basis of these diseases have evolved from linkage studies to candidate gene studies and genome-wide association studies. Linkage studies have been able to identify genetic variants associated with monogenic diseases, whereas genome-wide association studies have been more successful in determining genetic variants associated with complex diseases. Currently, genome-wide association studies have identified approximately 40 loci that explain 6% of the heritability of CAD. The application of this knowledge to clinical practice is challenging, but can be achieved using various strategies, such as genetic variants to identify new therapeutic targets, personal genetic information to improve disease risk prediction, and pharmacogenomics. The main aim of this narrative review is to provide a general overview of our current understanding of the genetics of coronary artery disease and its potential clinical utility.Keywords: coronary artery disease, pathogenesis, genetic risk factors, genetic variants

  16. Genetic Alterations in Intervertebral Disc Disease

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    Nikolay L. Martirosyan

    2016-11-01

    Full Text Available Background: Intervertebral disc degeneration (IVDD is considered a multifactorial disease. The last two decades of research strongly demonstrate that genetic factors contribute about 75% of the IVDD etiology. Recent total genome sequencing studies have shed light on the various single nucleotide polymorphisms (SNPs that are associated with IVDD.Aim: This review explores and presents updated information about the diversity of genetic factors in the inflammatory, degradative, homeostatic, and structural systems involved in the IVDD.Results: SNPs in the genes coding for structural proteins linked with IVDD or disc bulging include the Sp1 polymorphism of COL1A1, Trp3 polymorphism of COL9A3, several polymorphisms of COL11A1 and COL11A2, and a variable number tandem repeat polymorphism of ACAN. The rs4148941 SNP of CHST3 coding for an aggrecan sulfation enzyme is also associated with IVDD. The FokI, TaqI, and ApaI SNPs of the vitamin D receptor gene that is involved in chondrocyte functioning are also associated with IVDD. SNPs relevant to cytokine imbalance in IVDD include 889C/T of IL1a and 15T/A, as well as other SNPs (rs1800795, rs1800796, and rs1800797, of IL6, with effects limited to certain genders and populations. SNPs in collagenase genes include -1605G/D (guanine insertion/deletion of MMP1, -1306C/T of MMP2, -1562C/T and a 5-adenosine (5A variant (in the promotor region of MMP3, -1562C/T of MMP9, and -378T/C of MMP-14. SNPs in aggrecanase genes include 1877T/U of ADAMTS-4 and rs162509 of ADAMTS-5. Among the apoptosis-mediating genes, 1595T/C of the caspase 9 gene, 1525A/G and 1595T/C of the TRAIL gene, and 626C/G of the death receptor 4 gene (DR4 are SNPs associated with IVDD. Among the growth factors involved in disc homeostasis, the rs4871857 SNP of GDF5 was associated with IVDD. VEGF SNPs -2578C/A and -634G/C could foster neovascularization observed in IVDD.Conclusion: Improved understanding of the numerous genetic variants behind various

  17. Common immunologic mechanisms in inflammatory bowel disease and spondylarthropathies

    Institute of Scientific and Technical Information of China (English)

    Massimo C Fantini; Francesco Pallone; Giovanni Monteleone

    2009-01-01

    Spondyloarthropathies (SpA) are commonly observed extra-intestinal manifestations of both Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel diseases (IBD). However, the immunological link between these two clinical entities is still poorly understood. Several lines of evidence indicate that SpA may originate from the relocation to the joints of the immune process primarily induced in the gut. The transfer of the intestinal inflammatory process into the joints implicates that immune cells activated in the gut-draining lymph nodes can localize, at a certain point of the intestinal disease, either into the gut or into the joints. This is indicated by the overlapping expression of adhesion molecules observed on the surface of intestinal and synovial endothelial cells during inflammation. Moreover bacterial antigens and HLA-B27 expression may be implicated in the reactivation of T cells at the articular level. Finally, accumulating evidence indicates that a T helper 17 cell-mediated immune response may contribute to IBD and IBD-related SpA with a crucial role played by tumor necrosis factor-α in CD and to a lesser extent in UC.

  18. Epidemiology of the most common oral mucosal diseases in children.

    Science.gov (United States)

    Rioboo-Crespo, Maria del Rosario; Planells-del Pozo, Paloma; Rioboo-García, Rafael

    2005-01-01

    Dentists who treat children must be alert to the possibility of finding diseases of the oral mucosa, especially in younger children. The present study aimed to review the most updated information and the experience of our group in order to yield epidemiological data that assist diagnosis of the most common diseases of the oral mucosa in children. Recent epidemiologic studies have shown a wide variability in the prevalence of oral mucosal lesions in different regions of the world and have led researchers to draw disparate conclusions. Moreover, studies have not been designed using standard criteria, further explaining the wide variability in the percentage of different groups of children with oral lesions, which ranges from 4.1 to 52.6%. The lesions most frequently considered by authors and that most often appear in the different studies are: recurrent aphthous stomatitis (0.9-10.8%), labial herpes (0.78-5.2%), fissured tongue (1.49-23%), geographic tongue (0.60-9.8%), oral candidiasis (0.01-37%) and traumatic injury (0.09%-22.15%). Dentists must be able to detect any of the numerous possible disorders and perform the correct differential diagnosis, key to the treatment plan. The aim of this paper, based on a review of the different national and international studies, is to contribute data on the most important oral mucosal diseases in the paediatric population in terms of prevalence and differential diagnosis.

  19. The Evolution of Genetics: Alzheimer's and Parkinson's Diseases.

    Science.gov (United States)

    Singleton, Andrew; Hardy, John

    2016-06-15

    Genetic discoveries underlie the majority of the current thinking in neurodegenerative disease. This work has been driven by the significant gains made in identifying causal mutations; however, the translation of genetic causes of disease into pathobiological understanding remains a challenge. The application of a second generation of genetics methods allows the dissection of moderate and mild genetic risk factors for disease. This requires new thinking in two key areas: what constitutes proof of pathogenicity, and how do we translate these findings to biological understanding. Here we describe the progress and ongoing evolution in genetics. We describe a view that rejects the tradition that genetic proof has to be absolute before functional characterization and centers on a multi-dimensional approach integrating genetics, reference data, and functional work. We also argue that these challenges cannot be efficiently met by traditional hypothesis-driven methods but that high content system-wide efforts are required. Published by Elsevier Inc.

  20. Genome-wide association analysis of imputed rare variants: application to seven common complex diseases.

    Science.gov (United States)

    Mägi, Reedik; Asimit, Jennifer L; Day-Williams, Aaron G; Zeggini, Eleftheria; Morris, Andrew P

    2012-12-01

    Genome-wide association studies have been successful in identifying loci contributing effects to a range of complex human traits. The majority of reproducible associations within these loci are with common variants, each of modest effect, which together explain only a small proportion of heritability. It has been suggested that much of the unexplained genetic component of complex traits can thus be attributed to rare variation. However, genome-wide association study genotyping chips have been designed primarily to capture common variation, and thus are underpowered to detect the effects of rare variants. Nevertheless, we demonstrate here, by simulation, that imputation from an existing scaffold of genome-wide genotype data up to high-density reference panels has the potential to identify rare variant associations with complex traits, without the need for costly re-sequencing experiments. By application of this approach to genome-wide association studies of seven common complex diseases, imputed up to publicly available reference panels, we identify genome-wide significant evidence of rare variant association in PRDM10 with coronary artery disease and multiple genes in the major histocompatibility complex (MHC) with type 1 diabetes. The results of our analyses highlight that genome-wide association studies have the potential to offer an exciting opportunity for gene discovery through association with rare variants, conceivably leading to substantial advancements in our understanding of the genetic architecture underlying complex human traits.

  1. Genetic testing and Alzheimer's disease: implications for psychiatric-mental health nursing.

    Science.gov (United States)

    Schutte, Debra L

    2013-11-01

    Alzheimer's disease (AD), the most common cause of irreversible dementia, continues to grow in prevalence as well as public health impact. Extensive research into the genetic etiology of AD has yielded knowledge of some genetic factors that are causative and other genetic factors that increase risk for disease. Consequently, the possibility of genetic testing in individuals with or at risk for AD is a question that nurses may be asked. Psychiatric-mental health (PMH) professionals are in key positions to influence the care of individuals who are considering the effect of genetic information on their health care decisions. Whether by working within interdisciplinary genetic counseling teams to provide direct specialty services or by developing skills to identify and refer individuals at risk for or concerned about their risk for AD, PMH nurses can play an important role in the health care of individuals and families experiencing AD.

  2. The genetic architecture of the human immune system: a bioresource for autoimmunity and disease pathogenesis.

    Science.gov (United States)

    Roederer, Mario; Quaye, Lydia; Mangino, Massimo; Beddall, Margaret H; Mahnke, Yolanda; Chattopadhyay, Pratip; Tosi, Isabella; Napolitano, Luca; Terranova Barberio, Manuela; Menni, Cristina; Villanova, Federica; Di Meglio, Paola; Spector, Tim D; Nestle, Frank O

    2015-04-09

    Despite recent discoveries of genetic variants associated with autoimmunity and infection, genetic control of the human immune system during homeostasis is poorly understood. We undertook a comprehensive immunophenotyping approach, analyzing 78,000 immune traits in 669 female twins. From the top 151 heritable traits (up to 96% heritable), we used replicated GWAS to obtain 297 SNP associations at 11 genetic loci, explaining up to 36% of the variation of 19 traits. We found multiple associations with canonical traits of all major immune cell subsets and uncovered insights into genetic control for regulatory T cells. This data set also revealed traits associated with loci known to confer autoimmune susceptibility, providing mechanistic hypotheses linking immune traits with the etiology of disease. Our data establish a bioresource that links genetic control elements associated with normal immune traits to common autoimmune and infectious diseases, providing a shortcut to identifying potential mechanisms of immune-related diseases.

  3. Genetic and pharmacogenetic determinants of cardiovascular disease

    NARCIS (Netherlands)

    Verschuren, Jeffrey Johan Willem

    2013-01-01

    This thesis, titled ‘Genetic and pharmacogenetic determinants of cardiovascular disease’ is divided in three sections. In section one the genetic determinants of coronary restenosis are explored. In the first genome-wide association study on this condition, in the GENetic DEterminants of Restenosis

  4. Perceived genetic knowledge, attitudes towards genetic testing, and the relationship between these among patients with a chronic disease

    NARCIS (Netherlands)

    Morren, M.; Rijken, M.; Baanders, A.N.; Bensing, J.

    2007-01-01

    Objective: Genetics increasingly permeate everyday medicine. When patients want to make informed decisions about genetic testing, they require genetic knowledge. This study examined the genetic knowledge and attitudes of patients with chronic diseases, and the relationship between both. In addition,

  5. Perceived genetic knowledge, attitudes toward genetic testing, and the relationship between these among patients with a chronic disease.

    NARCIS (Netherlands)

    Morren, M.; Rijken, M.; Baanders, A.N.; Bensing, J.

    2007-01-01

    OBJECTIVE: Genetics increasingly permeate everyday medicine. When patients want to make informed decisions about genetic testing, they require genetic knowledge. This study examined the genetic knowledge and attitudes of patients with chronic diseases, and the relationship between both. In addition,

  6. Perceived genetic knowledge, attitudes towards genetic testing, and the relationship between these among patients with a chronic disease

    NARCIS (Netherlands)

    Morren, M.; Rijken, M.; Baanders, A.N.; Bensing, J.

    2007-01-01

    Objective: Genetics increasingly permeate everyday medicine. When patients want to make informed decisions about genetic testing, they require genetic knowledge. This study examined the genetic knowledge and attitudes of patients with chronic diseases, and the relationship between both. In addition,

  7. Perceived genetic knowledge, attitudes toward genetic testing, and the relationship between these among patients with a chronic disease.

    NARCIS (Netherlands)

    Morren, M.; Rijken, M.; Baanders, A.N.; Bensing, J.

    2007-01-01

    OBJECTIVE: Genetics increasingly permeate everyday medicine. When patients want to make informed decisions about genetic testing, they require genetic knowledge. This study examined the genetic knowledge and attitudes of patients with chronic diseases, and the relationship between both. In addition,

  8. Seewis virus, a genetically distinct hantavirus in the Eurasian common shrew (Sorex araneus

    Directory of Open Access Journals (Sweden)

    Hilbe Monika

    2007-10-01

    Full Text Available Abstract More than 20 years ago, hantaviral antigens were reported in tissues of the Eurasian common shrew (Sorex araneus, Eurasian water shrew (Neomys fodiens and common mole (Talpa europea, suggesting that insectivores, or soricomorphs, might serve as reservoirs of unique hantaviruses. Using RT-PCR, sequences of a genetically distinct hantavirus, designated Seewis virus (SWSV, were amplified from lung tissue of a Eurasian common shrew, captured in October 2006 in Graubünden, Switzerland. Pair-wise analysis of the full-length S and partial M and L segments of SWSV indicated approximately 55%–72% similarity with hantaviruses harbored by Murinae, Arvicolinae, Neotominae and Sigmodontinae rodents. Phylogenetically, SWSV grouped with other recently identified shrew-borne hantaviruses. Intensified efforts are underway to clarify the genetic diversity of SWSV throughout the geographic range of the Eurasian common shrew, as well as to determine its relevance to human health.

  9. Common genetic variants, acting additively, are a major source of risk for autism

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    Klei Lambertus

    2012-10-01

    Full Text Available Abstract Background Autism spectrum disorders (ASD are early onset neurodevelopmental syndromes typified by impairments in reciprocal social interaction and communication, accompanied by restricted and repetitive behaviors. While rare and especially de novo genetic variation are known to affect liability, whether common genetic polymorphism plays a substantial role is an open question and the relative contribution of genes and environment is contentious. It is probable that the relative contributions of rare and common variation, as well as environment, differs between ASD families having only a single affected individual (simplex versus multiplex families who have two or more affected individuals. Methods By using quantitative genetics techniques and the contrast of ASD subjects to controls, we estimate what portion of liability can be explained by additive genetic effects, known as narrow-sense heritability. We evaluate relatives of ASD subjects using the same methods to evaluate the assumptions of the additive model and partition families by simplex/multiplex status to determine how heritability changes with status. Results By analyzing common variation throughout the genome, we show that common genetic polymorphism exerts substantial additive genetic effects on ASD liability and that simplex/multiplex family status has an impact on the identified composition of that risk. As a fraction of the total variation in liability, the estimated narrow-sense heritability exceeds 60% for ASD individuals from multiplex families and is approximately 40% for simplex families. By analyzing parents, unaffected siblings and alleles not transmitted from parents to their affected children, we conclude that the data for simplex ASD families follow the expectation for additive models closely. The data from multiplex families deviate somewhat from an additive model, possibly due to parental assortative mating. Conclusions Our results, when viewed in the context

  10. Genetics of inflammatory bowel diseases--past, present, and future.

    NARCIS (Netherlands)

    Pena, A.S.

    2003-01-01

    In this review, the evidence to support the multifactorial and polygenic nature of the disease is briefly described. The past of genetics of inflammatory bowel disease (IBD) is characterized by unfulfilled promises and is now closed with a new vision and a new promise coming from a genetic

  11. Dopaminergic Neuronal Imaging in Genetic Parkinson's Disease: Insights into Pathogenesis

    NARCIS (Netherlands)

    A. McNeill (Alisdair); R-M. Wu (Ruey-Meei); K.-Y. Tzen (Kai-Yuan); P.C. Aguiar (Patricia); J.M. Arbelo (Jose); P. Barone (Paolo); K.P. Bhatia (Kailash); O.G. Barsottini (Orlando); V. Bonifati (Vincenzo); S. Bostantjopoulou (Sevasti); R.A. Bressan (Rodrigo); G. Cossu (Giovanni); P. Cortelli (Pietro); A.C. Felicio (Andre); H.B. Ferraz (Henrique); J. Herrera (Joanna); H. Houlden (Henry); M. Hoexter (Marcelo); C. Isla (Concepcion); A.J. Lees (Andrew); O. Lorenzo-Betancor (Oswaldo); N.E. Mencacci (Niccolo); P. Pastor (Pau); S. Pappata (Sabina); M.T. Pellecchia (Maria Teresa); L. Silveria-Moriyama (Laura); A. Varrone (Andrea); T. Foltynie (Thomas); A.H.V. Schapira (Anthony)

    2013-01-01

    textabstractObjectives:To compare the dopaminergic neuronal imaging features of different subtypes of genetic Parkinson's Disease.Methods:A retrospective study of genetic Parkinson's diseases cases in which DaTSCAN (123I-FP-CIT) had been performed. Specific non-displaceable binding was calculated fo

  12. Dopaminergic Neuronal Imaging in Genetic Parkinson's Disease: Insights into Pathogenesis

    NARCIS (Netherlands)

    A. McNeill (Alisdair); R-M. Wu (Ruey-Meei); K.-Y. Tzen (Kai-Yuan); P.C. Aguiar (Patricia); J.M. Arbelo (Jose); P. Barone (Paolo); K.P. Bhatia (Kailash); O.G. Barsottini (Orlando); V. Bonifati (Vincenzo); S. Bostantjopoulou (Sevasti); R.A. Bressan (Rodrigo); G. Cossu (Giovanni); P. Cortelli (Pietro); A.C. Felicio (Andre); H.B. Ferraz (Henrique); J. Herrera (Joanna); H. Houlden (Henry); M. Hoexter (Marcelo); C. Isla (Concepcion); A.J. Lees (Andrew); O. Lorenzo-Betancor (Oswaldo); N.E. Mencacci (Niccolo); P. Pastor (Pau); S. Pappata (Sabina); M.T. Pellecchia (Maria Teresa); L. Silveria-Moriyama (Laura); A. Varrone (Andrea); T. Foltynie (Thomas); A.H.V. Schapira (Anthony)

    2013-01-01

    textabstractObjectives:To compare the dopaminergic neuronal imaging features of different subtypes of genetic Parkinson's Disease.Methods:A retrospective study of genetic Parkinson's diseases cases in which DaTSCAN (123I-FP-CIT) had been performed. Specific non-displaceable binding was calculated

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

    NARCIS (Netherlands)

    C.M. van Duijn (Cock)

    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? Are

  14. Dopaminergic Neuronal Imaging in Genetic Parkinson's Disease: Insights into Pathogenesis

    NARCIS (Netherlands)

    A. McNeill (Alisdair); R-M. Wu (Ruey-Meei); K.-Y. Tzen (Kai-Yuan); P.C. Aguiar (Patricia); J.M. Arbelo (Jose); P. Barone (Paolo); K.P. Bhatia (Kailash); O.G. Barsottini (Orlando); V. Bonifati (Vincenzo); S. Bostantjopoulou (Sevasti); R.A. Bressan (Rodrigo); G. Cossu (Giovanni); P. Cortelli (Pietro); A.C. Felicio (Andre); H.B. Ferraz (Henrique); J. Herrera (Joanna); H. Houlden (Henry); M. Hoexter (Marcelo); C. Isla (Concepcion); A.J. Lees (Andrew); O. Lorenzo-Betancor (Oswaldo); N.E. Mencacci (Niccolo); P. Pastor (Pau); S. Pappata (Sabina); M.T. Pellecchia (Maria Teresa); L. Silveria-Moriyama (Laura); A. Varrone (Andrea); T. Foltynie (Thomas); A.H.V. Schapira (Anthony)

    2013-01-01

    textabstractObjectives:To compare the dopaminergic neuronal imaging features of different subtypes of genetic Parkinson's Disease.Methods:A retrospective study of genetic Parkinson's diseases cases in which DaTSCAN (123I-FP-CIT) had been performed. Specific non-displaceable binding was calculated fo

  15. Cardioviruses Are Genetically Diverse and Cause Common Enteric Infections in South Asian Children▿

    Science.gov (United States)

    Blinkova, Olga; Kapoor, Amit; Victoria, Joseph; Jones, Morris; Wolfe, Nathan; Naeem, Asif; Shaukat, Shahzad; Sharif, Salmaan; Alam, Muhammad Masroor; Angez, Mehar; Zaidi, Sohail; Delwart, Eric L.

    2009-01-01

    Cardioviruses cause enteric infections in mice and rats which when disseminated have been associated with myocarditis, type 1 diabetes, encephalitis, and multiple sclerosis-like symptoms. Cardioviruses have also been detected at lower frequencies in other mammals. The Cardiovirus genus within the Picornaviridae family is currently made up of two viral species, Theilovirus and Encephalomyocarditis virus. Until recently, only a single strain of cardioviruses (Vilyuisk virus within the Theilovirus species) associated with a geographically restricted and prevalent encephalitis-like condition had been reported to occur in humans. A second theilovirus-related cardiovirus (Saffold virus [SAFV]) was reported in 2007 and subsequently found in respiratory secretions from children with respiratory problems and in stools of both healthy and diarrheic children. Using viral metagenomics, we identified RNA fragments related to SAFV in the stools of Pakistani and Afghani children with nonpolio acute flaccid paralysis (AFP). We sequenced three near-full-length genomes, showing the presence of divergent strains of SAFV and preliminary evidence of a distant recombination event between the ancestors of the Theiler-like viruses of rats and those of human SAFV. Further VP1 sequencing showed the presence of five new SAFV genotypes, doubling the reported genetic diversity of human and animal theiloviruses combined. Both AFP patients and healthy children in Pakistan were found to be excreting SAFV at high frequencies of 9 and 12%, respectively. Further studies are needed to examine the roles of these highly common and diverse SAFV genotypes in nonpolio AFP and other human diseases. PMID:19193786

  16. Cardioviruses are genetically diverse and cause common enteric infections in South Asian children.

    Science.gov (United States)

    Blinkova, Olga; Kapoor, Amit; Victoria, Joseph; Jones, Morris; Wolfe, Nathan; Naeem, Asif; Shaukat, Shahzad; Sharif, Salmaan; Alam, Muhammad Masroor; Angez, Mehar; Zaidi, Sohail; Delwart, Eric L

    2009-05-01

    Cardioviruses cause enteric infections in mice and rats which when disseminated have been associated with myocarditis, type 1 diabetes, encephalitis, and multiple sclerosis-like symptoms. Cardioviruses have also been detected at lower frequencies in other mammals. The Cardiovirus genus within the Picornaviridae family is currently made up of two viral species, Theilovirus and Encephalomyocarditis virus. Until recently, only a single strain of cardioviruses (Vilyuisk virus within the Theilovirus species) associated with a geographically restricted and prevalent encephalitis-like condition had been reported to occur in humans. A second theilovirus-related cardiovirus (Saffold virus [SAFV]) was reported in 2007 and subsequently found in respiratory secretions from children with respiratory problems and in stools of both healthy and diarrheic children. Using viral metagenomics, we identified RNA fragments related to SAFV in the stools of Pakistani and Afghani children with nonpolio acute flaccid paralysis (AFP). We sequenced three near-full-length genomes, showing the presence of divergent strains of SAFV and preliminary evidence of a distant recombination event between the ancestors of the Theiler-like viruses of rats and those of human SAFV. Further VP1 sequencing showed the presence of five new SAFV genotypes, doubling the reported genetic diversity of human and animal theiloviruses combined. Both AFP patients and healthy children in Pakistan were found to be excreting SAFV at high frequencies of 9 and 12%, respectively. Further studies are needed to examine the roles of these highly common and diverse SAFV genotypes in nonpolio AFP and other human diseases.

  17. Novel insights into thyroid hormones from the study of common genetic variation.

    Science.gov (United States)

    Dayan, Colin M; Panicker, Vijay

    2009-04-01

    Effects of thyroid hormones in individual tissues are determined by many factors beyond their serum levels, including local deiodination and expression and activity of thyroid hormone transporters. These effects are difficult to examine by traditional techniques, but a novel approach that exploits the existence of common genetic variants has yielded new and surprising insights. Convincing evidence indicates a role of type 1 iodothyronine deiodinase (D1) in determining the serum T(4):T(3) ratio and a role of phosphodiesterase 8B in determining TSH levels. In addition, studies of type 2 iodothyronine deiodinase (D2) variants have shown that thyroid hormones contribute to osteoarthritis and these variants influence Intelligence quotient alterations associated with iodine deficiency. Preliminary evidence suggests associations between TSH-receptor variants and fasting glucose level, D1 variants and insulin-like growth factor I production, and D2 variants and hypertension, psychological well-being and response to T(3) or T(4) treatment. Intriguingly, most of these associations are independent of serum thyroid hormone levels, which highlights the importance of local regulation of thyroid hormones in tissues. Future research might reveal novel roles for thyroid hormones in obesity, cardiovascular disease, osteoporosis and depression and could have implications for interpretation of thyroid function tests and individualization of thyroid hormone replacement therapy.

  18. A rapid genetic assay for the identification of the most common Pocillopora damicornis genetic lineages on the Great Barrier Reef.

    Directory of Open Access Journals (Sweden)

    Gergely Torda

    Full Text Available Pocillopora damicornis (Linnaeus, 1758; Scleractinia, Pocilloporidae has recently been found to comprise at least five distinct genetic lineages in Eastern Australia, some of which likely represent cryptic species. Due to similar and plastic gross morphology of these lineages, field identification is often difficult. Here we present a quick, cost effective genetic assay as well as three novel microsatellite markers that distinguish the two most common lineages found on the Great Barrier Reef. The assay is based on PCR amplification of two regions within the mitochondrial putative control region, which show consistent and easily identifiable fragment size differences for the two genetic lineages after Alu1 restriction enzyme digestion of the amplicons.

  19. A robust GWSS method to simultaneously detect rare and common variants for complex disease.

    Directory of Open Access Journals (Sweden)

    Chung-Feng Kao

    Full Text Available The rapid advances in sequencing technologies and the resulting next-generation sequencing data provide the opportunity to detect disease-associated variants with a better solution, in particular for low-frequency variants. Although both common and rare variants might exert their independent effects on the risk for the trait of interest, previous methods to detect the association effects rarely consider them simultaneously. We proposed a class of test statistics, the generalized weighted-sum statistic (GWSS, to detect disease associations in the presence of common and rare variants with a case-control study design. Information of rare variants was aggregated using a weighted sum method, while signal directions and strength of the variants were considered at the same time. Permutations were performed to obtain the empirical p-values of the test statistics. Our simulation showed that, compared to the existing methods, the GWSS method had better performance in most of the scenarios. The GWSS (in particular VDWSS-t method is particularly robust for opposite association directions, association strength, and varying distributions of minor-allele frequencies. It is therefore promising for detecting disease-associated loci. For empirical data application, we also applied our GWSS method to the Genetic Analysis Workshop 17 data, and the results were consistent with the simulation, suggesting good performance of our method. As re-sequencing studies become more popular to identify putative disease loci, we recommend the use of this newly developed GWSS to detect associations with both common and rare variants.

  20. Genetic testing and counselling in inherited eye disease

    DEFF Research Database (Denmark)

    Brøndum-Nielsen, Karen; Jensen, Hanne; Timshel, Susanne

    2013-01-01

    Advances in genetics have made genetic testing in patients with inherited eye disease increasingly accessible, and the initiation of clinical intervention trials makes it increasingly clinically relevant. Based on a multidisciplinary collaboration between ophthalmologists and clinical geneticists......, the extensive register of families with monogenic inherited eye diseases at the National Eye Clinic of the Kennedy Center in Denmark provides a valuable asset waiting to be exploited in the global effort to reduce blindness caused by genetic defects....

  1. Genetic counseling and testing for Alzheimer disease: joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors.

    Science.gov (United States)

    Goldman, Jill S; Hahn, Susan E; Catania, Jennifer Williamson; LaRusse-Eckert, Susan; Butson, Melissa Barber; Rumbaugh, Malia; Strecker, Michelle N; Roberts, J Scott; Burke, Wylie; Mayeux, Richard; Bird, Thomas

    2011-06-01

    Alzheimer disease is the most common cause of dementia. It occurs worldwide and affects all ethnic groups. The incidence of Alzheimer disease is increasing due, in part, to increased life expectancy and the aging baby boomer generation. The average lifetime risk of developing Alzheimer disease is 10-12%. This risk at least doubles with the presence of a first-degree relative with the disorder. Despite its limited utility, patients express concern over their risk and, in some instances, request testing. Furthermore, research has demonstrated that testing individuals for apolipoprotein E can be valuable and safe in certain contexts. However, because of the complicated genetic nature of the disorder, few clinicians are prepared to address the genetic risks of Alzheimer disease with their patients. Given the increased awareness in family history thanks to family history campaigns, the increasing incidence of Alzheimer disease, and the availability of direct to consumer testing, patient requests for information is increasing. This practice guideline provides clinicians with a framework for assessing their patients' genetic risk for Alzheimer disease, identifying which individuals may benefit from genetic testing, and providing the key elements of genetic counseling for AD.

  2. Ancient Humans Influenced the Current Spatial Genetic Structure of Common Walnut Populations in Asia.

    Directory of Open Access Journals (Sweden)

    Paola Pollegioni

    Full Text Available Common walnut (Juglans regia L is an economically important species cultivated worldwide for its wood and nuts. It is generally accepted that J. regia survived and grew spontaneously in almost completely isolated stands in its Asian native range after the Last Glacial Maximum. Despite its natural geographic isolation, J. regia evolved over many centuries under the influence of human management and exploitation. We evaluated the hypothesis that the current distribution of natural genetic resources of common walnut in Asia is, at least in part, the product of ancient anthropogenic dispersal, human cultural interactions, and afforestation. Genetic analysis combined with ethno-linguistic and historical data indicated that ancient trade routes such as the Persian Royal Road and Silk Road enabled long-distance dispersal of J. regia from Iran and Trans-Caucasus to Central Asia, and from Western to Eastern China. Ancient commerce also disrupted the local spatial genetic structure of autochthonous walnut populations between Tashkent and Samarkand (Central-Eastern Uzbekistan, where the northern and central routes of the Northern Silk Road converged. A significant association between ancient language phyla and the genetic structure of walnut populations is reported even after adjustment for geographic distances that could have affected both walnut gene flow and human commerce over the centuries. Beyond the economic importance of common walnut, our study delineates an alternative approach for understanding how the genetic resources of long-lived perennial tree species may be affected by the interaction of geography and human history.

  3. Erectile Dysfunction ia a common problem in Interstitial Lung Disease

    DEFF Research Database (Denmark)

    Fløe, Andreas; Hilberg, Ole; Wijsenbeek, Marlies

    .6%) had co-morbid heart disease and/or manifest atherosclerosis, and 6 (11.8%) had diabetes mellitus (DM). 39 (76.5%) had fibrosing ILD on high-resolution CT-scan or lung biopsy (IPF n=24, Fibrosing NSIP n=7, unclassifiable ILD with fibrosis n=8). 35 ILD patients (70%) had ED, and 22 (44%) hereof had...... severe ED. Having a co-morbidity was not associated with increased risk of ED (OR 0,94, P=0,74).  Conclusion: Our data clearly demonstrate that ED is a common problem in ILD. Almost half of all patients in this study had severe ED. This is, to our knowledge, the first study to report on the occurrence...... of sexual problems among male patients with ILD. The rate of ED was comparable to that found among COPD patients in prior studies. Further research is needed in order to identify specific risk factors for ED among ILD patients....

  4. Genetic diagnosis of Huntington's disease: cases report

    Institute of Scientific and Technical Information of China (English)

    Liao Ting-ting; Wu Wei; Wan Qi; Cui Yu-gui; Liu Jia-yin

    2011-01-01

    Objective:To assess the efficiency of the PCR combined DNA sequencing to ascertain CAG repeat size of Huntington's disease(HD)gene as for gene diagnosis of HD.Method:Three patients with HD were diagnosed genetically with the technology of polymerase chain reaction (PCR) and polyacrylamide gel electrophoresis by assessing the CAG repeat size of HD gene.DNA sequencing then was used as verification test for HD gene.Results:Nine members of three nuclear families were included in this study,three patients were HD proband.In those families,CAG repeats of all spouse of propositus were in normal range.CAG repeats of all propositus and their descendants with the normal allele were in normal range,while CAG copy number of the other mobigenous allele was obviously abnormal.Conclusion:PCR combined DNA sequencing can be used to effectively ascertain CAG repeat of HD gene.CAG-repeat expansion mutations were accounted for 99% of HD cases,so HD can be accurately diagnosed by this method.

  5. Common biological networks underlie genetic risk for alcoholism in African- and European-American populations.

    Science.gov (United States)

    Kos, M Z; Yan, J; Dick, D M; Agrawal, A; Bucholz, K K; Rice, J P; Johnson, E O; Schuckit, M; Kuperman, S; Kramer, J; Goate, A M; Tischfield, J A; Foroud, T; Nurnberger, J; Hesselbrock, V; Porjesz, B; Bierut, L J; Edenberg, H J; Almasy, L

    2013-07-01

    Alcohol dependence (AD) is a heritable substance addiction with adverse physical and psychological consequences, representing a major health and economic burden on societies worldwide. Genes thus far implicated via linkage, candidate gene and genome-wide association studies (GWAS) account for only a small fraction of its overall risk, with effects varying across ethnic groups. Here we investigate the genetic architecture of alcoholism and report on the extent to which common, genome-wide SNPs collectively account for risk of AD in two US populations, African-Americans (AAs) and European-Americans (EAs). Analyzing GWAS data for two independent case-control sample sets, we compute polymarker scores that are significantly associated with alcoholism (P = 1.64 × 10(-3) and 2.08 × 10(-4) for EAs and AAs, respectively), reflecting the small individual effects of thousands of variants derived from patterns of allelic architecture that are population specific. Simulations show that disease models based on rare and uncommon causal variants (MAF gene location and examined for constituent biological networks, gene enrichment is observed for several cellular processes and functions in both EA and AA populations, transcending their underlying allelic differences. Our results reveal key insights into the complex etiology of AD, raising the possibility of an important role for rare and uncommon variants, and identify polygenic mechanisms that encompass a spectrum of disease liability, with some, such as chloride transporters and glycine metabolism genes, displaying subtle, modifying effects that are likely to escape detection in most GWAS designs.

  6. Common genetic variants in NEFL influence gene expression and neuroblastoma risk.

    Science.gov (United States)

    Capasso, Mario; Diskin, Sharon; Cimmino, Flora; Acierno, Giovanni; Totaro, Francesca; Petrosino, Giuseppe; Pezone, Lucia; Diamond, Maura; McDaniel, Lee; Hakonarson, Hakon; Iolascon, Achille; Devoto, Marcella; Maris, John M

    2014-12-01

    The genetic etiology of sporadic neuroblastoma is still largely obscure. In a genome-wide association study, we identified single-nucleotide polymorphisms (SNP) associated with neuroblastoma at the CASC15, BARD1, LMO1, DUSP12, HSD17B12, HACE1, and LIN28B gene loci, but these explain only a small fraction of neuroblastoma heritability. Other neuroblastoma susceptibility genes are likely hidden among signals discarded by the multiple testing corrections. In this study, we evaluated eight additional genes selected as candidates for further study based on proven involvement in neuroblastoma differentiation. SNPs at these candidate genes were tested for association with disease susceptibility in 2,101 cases and 4,202 controls, with the associations found replicated in an independent cohort of 459 cases and 809 controls. Replicated associations were further studied for cis-effect using gene expression, transient overexpression, silencing, and cellular differentiation assays. The neurofilament gene NEFL harbored three SNPs associated with neuroblastoma (rs11994014: Pcombined = 0.0050; OR, 0.88; rs2979704: Pcombined = 0.0072; OR, 0.87; rs1059111: Pcombined = 0.0049; OR, 0.86). The protective allele of rs1059111 correlated with increased NEFL expression. Biologic investigations showed that ectopic overexpression of NEFL inhibited cell growth specifically in neuroblastoma cells carrying the protective allele. NEFL overexpression also enhanced differentiation and impaired the proliferation and anchorage-independent growth of cells with protective allele and basal NEFL expression, while impairing invasiveness and proliferation of cells homozygous for the risk genotype. Clinically, high levels of NEFL expression in primary neuroblastoma specimens were associated with better overall survival (P = 0.03; HR, 0.68). Our results show that common variants of NEFL influence neuroblastoma susceptibility and they establish that NEFL expression influences disease initiation and

  7. Genetic similarity between cancers and comorbid Mendelian diseases identifies candidate driver genes.

    Science.gov (United States)

    Melamed, Rachel D; Emmett, Kevin J; Madubata, Chioma; Rzhetsky, Andrey; Rabadan, Raul

    2015-04-30

    Despite large-scale cancer genomics studies, key somatic mutations driving cancer, and their functional roles, remain elusive. Here, we propose that analysis of comorbidities of Mendelian diseases with cancers provides a novel, systematic way to discover new cancer genes. If germline genetic variation in Mendelian loci predisposes bearers to common cancers, the same loci may harbour cancer-associated somatic variation. Compilations of clinical records spanning over 100 million patients provide an unprecedented opportunity to assess clinical associations between Mendelian diseases and cancers. We systematically compare these comorbidities against recurrent somatic mutations from more than 5,000 patients across many cancers. Using multiple measures of genetic similarity, we show that a Mendelian disease and comorbid cancer indeed have genetic alterations of significant functional similarity. This result provides a basis to identify candidate drivers in cancers including melanoma and glioblastoma. Some Mendelian diseases demonstrate 'pan-cancer' comorbidity and shared genetics across cancers.

  8. Complete loss of MHC genetic diversity in the Common Hamster (Cricetus cricetus ) population in The Netherlands

    NARCIS (Netherlands)

    Smulders, M.J.M.; Snoek, L.B.; Booy, G.; Vosman, B.

    2003-01-01

    The Common Hamster (Cricetus cricetus L.) has suffered from changes in agricultural practices. In some Western European countries the populations have become so small and scattered that they are threatened with extinction. We studied the genetic diversity of mitochondrial and major histoincompatibil

  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 (Linetta); 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 (G.); 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 l

  10. Neuroinformatic analyses of common and distinct genetic components associated with major neuropsychiatric disorders

    OpenAIRE

    Lotan, Amit; Fenckova, Michaela; Bralten, Janita; Alttoa, Aet; Dixson, Luanna; Williams, Robert W.; van der Voet, Monique

    2014-01-01

    Major neuropsychiatric disorders are highly heritable, with mounting evidence suggesting that these disorders share overlapping sets of molecular and cellular underpinnings. In the current article we systematically test the degree of genetic commonality across six major neuropsychiatric disorders—attention deficit hyperactivity disorder (ADHD), anxiety disorders (Anx), autistic spectrum disorders (ASD), bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ). We curate...

  11. Common genetic variants and modification of penetrance of BRCA2-associated breast cancer

    DEFF Research Database (Denmark)

    Gaudet, Mia M; Kirchhoff, Tomas; Green, Todd

    2010-01-01

    The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carri...

  12. Common genetic variants associated with cognitive performance identified using the proxy-phenotype method

    NARCIS (Netherlands)

    C.A. Rietveld (Niels); T. Esko (Tõnu); G. Davies (Gail); T.H. Pers (Tune); P. Turley (Patrick); B. Benyamin (Beben); C.F. Chabris (Christopher F.); V. Emilsson (Valur); A.D. Johnson (Andrew); J.J. Lee (James J.); C. de Leeuw (Christiaan); R.E. Marioni (Riccardo); S.E. Medland (Sarah Elizabeth); M. Miller (Mike); O. Rostapshova (Olga); S. van der Lee (Sven); A.A.E. Vinkhuyzen (Anna A.); N. Amin (Najaf); D. Conley (Dalton); J. Derringer; C.M. van Duijn (Cock); R.S.N. Fehrmann (Rudolf); L. Franke (Lude); E.L. Glaeser (Edward L.); N.K. Hansell (Narelle); C. Hayward (Caroline); W.G. Iacono (William); C.A. Ibrahim-Verbaas (Carla); V.W.V. Jaddoe (Vincent); J. Karjalainen (Juha); D. Laibson (David); P. Lichtenstein (Paul); D.C. Liewald (David C.); P.K. Magnusson (Patrik); N.G. Martin (Nicholas); M. McGue (Matt); G. Mcmahon (George); N.L. Pedersen (Nancy); S. Pinker (Steven); D.J. Porteous (David J.); D. Posthuma (Danielle); F. Rivadeneira Ramirez (Fernando); B.H. Smithk (Blair H.); J.M. Starr (John); H.W. Tiemeier (Henning); N.J. Timpsonm (Nicholas J.); M. Trzaskowskin (Maciej); A.G. Uitterlinden (André); F.C. Verhulst (Frank); M.E. Ward (Mary); M.J. Wright (Margaret); G.D. Smith; I.J. Deary (Ian J.); M. Johannesson (Magnus); R. Plomin (Robert); P.M. Visscher (Peter); D.J. Benjamin (Daniel J.); D. Cesarini (David); Ph.D. Koellinger (Philipp)

    2014-01-01

    textabstractWe identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxyphenotype method. First, we conduct a genome-wide association study of educational attainment in a large sample (n = 106,736), which produces a set of 69 education

  13. Common genetic variants and modification of penetrance of BRCA2-associated breast cancer

    NARCIS (Netherlands)

    M.M. Gaudet (Mia); T. Kircchoff (Tomas); T. Green (Todd); J. Vijai (Joseph); J.M. Korn (Joshua); C. Guiducci (Candace); A.V. Segrè (Ayellet); K. McGee (Kate); L. McGuffog (Lesley); C. Kartsonaki (Christiana); J. Morrison (Jonathan); S. Healey (Sue); O. Sinilnikova (Olga); D. Stoppa-Lyonnet (Dominique); S. Mazoyer (Sylvie); M. Gauthier-Villars (Marion); H. Sobol (Hagay); M. Longy (Michel); M. Frenay (Marc); F.B.L. Hogervorst (Frans); M.A. Rookus (Matti); J.M. Collée (Margriet); N. Hoogerbrugge (Nicoline); K.E. van Roozendaal (Kees); M. Piedemonte (Marion); W.S. Rubinstein (Wendy); S. Nerenstone (Stacy); L. van Le (Linda); S.V. Blank (Stephanie); T. Caldes (Trinidad); M. de La Hoya (Miguel); H. Nevanlinna (Heli); K. Aittomäki (Kristiina); C. Lazaro (Conxi); I. Blanco (Ignacio); A. Arason (Adalgeir); O.T. Johannson (Oskar); R.B. Barkardottir (Rosa); P. Devilee (Peter); O.I. Olopade (Olofunmilayo); S.L. Neuhausen (Susan); X. Wang (Xianshu); Z. Fredericksen (Zachary); P. Peterlongo (Paolo); S. Manoukian (Siranoush); M. Barile (Monica); A. Viel (Alessandra); P. Radice (Paolo); C. Phelan (Catherine); S. Narod (Steven); G. Rennert (Gad); F. Lejbkowicz (Flavio); A. Flugelman (Anath); I.L. Andrulis (Irene); G. Glendon (Gord); H. Ozcelik (Hilmi); A.E. Toland (Amanda); M. Montagna (Marco); E. D'Andrea (Emma); E. Friedman (Eitan); Y. Laitman (Yael); Å. Borg (Åke); M.S. Beattie (Mary); S.J. Ramus (Susan); S.M. Domchek (Susan); K.L. Nathanson (Katherine); R. Rebbeck (Timothy); A.B. Spurdle (Amanda); X. Chen (Xiaoqing); H. Holland (Helene); E.M. John (Esther); J. Hopper (John); S.S. Buys (Saundra); M.B. Daly (Mary); M.C. Southey (Melissa); M-B. Terry (Mary-beth); N. Tung (Nadine); T.V.O. Hansen (Thomas); F.C. Nielsen (Finn); M.H. Greene (Mark); P.L. Mai (Phuong); A. Osorio (Ana); M. Duran; R. Andres (Raquel); J. Benítez (Javier); J.N. Weitzel (Jeffrey); J. Garber (Judy); U. Hamann (Ute); S. Peock (Susan); M. Cook (Margaret); C.T. Oliver (Clare); D. Frost (Debra); R. Platte (Radka); D.G. Evans (Gareth); F. Lalloo (Fiona); R. Eeles (Rosalind); L. Izatt (Louise); L.J. Walker (Lisa); J. Eason (Jacqueline); J. Barwell (Julian); A.K. Godwin (Andrew); R.K. Schmutzler (Rita); B. Wapenschmidt (Barbara); S. Engert (Stefanie); N. Arnold (Norbert); D. Gadzicki (Dorothea); M. Dean (Michael Emmans); B. Gold (Bert); R.J. Klein (Robert); F.J. Couch (Fergus); G. Chenevix-Trench (Georgia); D.F. Easton (Douglas); M.J. Daly (Mark); A.C. Antoniou (Antonis); D. Altshuler (David); K. Offit (Kenneth)

    2010-01-01

    textabstractThe considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2

  14. Common genetic variants and modification of penetrance of BRCA2-associated breast cancer

    NARCIS (Netherlands)

    M.M. Gaudet (Mia); T. Kircchoff (Tomas); T. Green (Todd); J. Vijai (Joseph); J.M. Korn (Joshua); C. Guiducci (Candace); A.V. Segrè (Ayellet); K. McGee (Kate); L. McGuffog (Lesley); C. Kartsonaki (Christiana); J. Morrison (Jonathan); S. Healey (Sue); O. Sinilnikova (Olga); D. Stoppa-Lyonnet (Dominique); S. Mazoyer (Sylvie); M. Gauthier-Villars (Marion); H. Sobol (Hagay); M. Longy (Michel); M. Frenay (Marc); F.B.L. Hogervorst (Frans); M.A. Rookus (Matti); J.M. Collée (Margriet); N. Hoogerbrugge (Nicoline); K.E. van Roozendaal (Kees); M. Piedemonte (Marion); W.S. Rubinstein (Wendy); S. Nerenstone (Stacy); L. van Le (Linda); S.V. Blank (Stephanie); T. Caldes (Trinidad); M. de La Hoya (Miguel); H. Nevanlinna (Heli); K. Aittomäki (Kristiina); C. Lazaro (Conxi); I. Blanco (Ignacio); A. Arason (Adalgeir); O.T. Johannson (Oskar); R.B. Barkardottir (Rosa); P. Devilee (Peter); O.I. Olopade (Olofunmilayo); S.L. Neuhausen (Susan); X. Wang (Xianshu); Z. Fredericksen (Zachary); P. Peterlongo (Paolo); S. Manoukian (Siranoush); M. Barile (Monica); A. Viel (Alessandra); P. Radice (Paolo); C. Phelan (Catherine); S. Narod (Steven); G. Rennert (Gad); F. Lejbkowicz (Flavio); A. Flugelman (Anath); I.L. Andrulis (Irene); G. Glendon (Gord); H. Ozcelik (Hilmi); A.E. Toland (Amanda); M. Montagna (Marco); E. D'Andrea (Emma); E. Friedman (Eitan); Y. Laitman (Yael); Å. Borg (Åke); M.S. Beattie (Mary); S.J. Ramus (Susan); S.M. Domchek (Susan); K.L. Nathanson (Katherine); R. Rebbeck (Timothy); A.B. Spurdle (Amanda); X. Chen (Xiaoqing); H. Holland (Helene); E.M. John (Esther); J. Hopper (John); S.S. Buys (Saundra); M.B. Daly (Mary); M.C. Southey (Melissa); M-B. Terry (Mary-beth); N. Tung (Nadine); T.V.O. Hansen (Thomas); F.C. Nielsen (Finn); M.H. Greene (Mark); P.L. Mai (Phuong); A. Osorio (Ana); M. Duran; R. Andres (Raquel); J. Benítez (Javier); J.N. Weitzel (Jeffrey); J. Garber (Judy); U. Hamann (Ute); S. Peock (Susan); M. Cook (Margaret); C.T. Oliver (Clare); D. Frost (Debra); R. Platte (Radka); D.G. Evans (Gareth); F. Lalloo (Fiona); R. Eeles (Rosalind); L. Izatt (Louise); L.J. Walker (Lisa); J. Eason (Jacqueline); J. Barwell (Julian); A.K. Godwin (Andrew); R.K. Schmutzler (Rita); B. Wapenschmidt (Barbara); S. Engert (Stefanie); N. Arnold (Norbert); D. Gadzicki (Dorothea); M. Dean (Michael Emmans); B. Gold (Bert); R.J. Klein (Robert); F.J. Couch (Fergus); G. Chenevix-Trench (Georgia); D.F. Easton (Douglas); M.J. Daly (Mark); A.C. Antoniou (Antonis); D. Altshuler (David); K. Offit (Kenneth)

    2010-01-01

    textabstractThe considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutat

  15. 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 (G.); 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 l

  16. Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer

    NARCIS (Netherlands)

    Gaudet, Mia M.; Kirchhoff, Tomas; Green, Todd; Vijai, Joseph; Korn, Joshua M.; Guiducci, Candace; Segre, Ayellet V.; McGee, Kate; McGuffog, Lesley; Kartsonaki, Christiana; Morrison, Jonathan; Healey, Sue; Sinilnikova, Olga M.; Stoppa-Lyonnet, Dominique; Mazoyer, Sylvie; Gauthier-Villars, Marion; Sobol, Hagay; Longy, Michel; Frenay, Marc; Hogervorst, Frans B. L.; Rookus, Matti A.; Collee, J. Margriet; Hoogerbrugge, Nicoline; van Roozendaal, Kees E. P.; Piedmonte, Marion; Rubinstein, Wendy; Nerenstone, Stacy; Van Le, Linda; Blank, Stephanie V.; Caldes, Trinidad; de la Hoya, Miguel; Nevanlinna, Heli; Aittomaki, Kristiina; Lazaro, Conxi; Blanco, Ignacio; Arason, Adalgeir; Johannsson, Oskar T.; Barkardottir, Rosa B.; Devilee, Peter; Olopade, Olofunmilayo I.; Neuhausen, Susan L.; Wang, Xianshu; Fredericksen, Zachary S.; Peterlongo, Paolo; Manoukian, Siranoush; Barile, Monica; Viel, Alessandra; Radice, Paolo; Phelan, Catherine M.; Narod, Steven; Rennert, Gad; Lejbkowicz, Flavio; Flugelman, Anath; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Toland, Amanda E.; Montagna, Marco; D'Andrea, Emma; Friedman, Eitan; Laitman, Yael; Borg, Ake; Beattie, Mary; Ramus, Susan J.; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Tim; Spurdle, Amanda B.; Chen, Xiaoqing; Holland, Helene; John, Esther M.; Hopper, John L.; Buys, Saundra S.; Daly, Mary B.; Southey, Melissa C.; Terry, Mary Beth; Tung, Nadine; Hansen, Thomas V. Overeem; Nielsen, Finn C.; Greene, Mark I.; Mai, Phuong L.; Osorio, Ana; Duran, Mercedes; Andres, Raquel; Benitez, Javier; Weitzel, Jeffrey N.; Garber, Judy; Hamann, Ute; Peock, Susan; Cook, Margaret; Oliver, Clare; Frost, Debra; Platte, Radka; Evans, D. Gareth; Lalloo, Fiona; Eeles, Ros; Izatt, Louise; Walker, Lisa; Eason, Jacqueline; Barwell, Julian; Godwin, Andrew K.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Engert, Stefanie; Arnold, Norbert; Gadzicki, Dorothea; Dean, Michael; Gold, Bert; Klein, Robert J.; Couch, Fergus J.; Chenevix-Trench, Georgia; Easton, Douglas F.; Daly, Mark J.; Antoniou, Antonis C.; Altshuler, David M.; Offit, Kenneth

    2010-01-01

    The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers

  17. Common Genetic and Environmental Influences on Major Depressive Disorder and Conduct Disorder

    Science.gov (United States)

    Subbarao, Anjali; Rhee, Soo Hyun; Young, Susan E.; Ehringer, Marissa A.; Corley, Robin P.; Hewitt, John K.

    2008-01-01

    The evidence for common genetic and environmental influences on conduct disorder (CD) and major depressive disorder (MDD) in adolescents was examined. A sample of 570 monozygotic twin pairs, 592 dizygotic twin pairs, and 426 non-twin siblings, aged 12-18 years, was recruited from the Colorado Twin Registry. For the past year data, there was a…

  18. 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 (G.); 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

  19. Geographical genetic diversity and divergence of common wild rice (O. rufipogon Griff.) in China

    Institute of Scientific and Technical Information of China (English)

    WANG MeiXing; LIChen; LI ZiChao; ZHANG HongLiang; ZHANG DongLing; PAN DaJian; LI DaoYuan; FAN ZhiLan; QI YongWen; SUN JunLi; YANG QingWen

    2008-01-01

    Using 36 SSR markers and 889 accessions of common wild rice in China, the genetic diversity and the divergence among different geographical populations are investigated. Guangdong Province has the largest number of alleles, which account for 84% of the total alleles detected in the study, followed by Guangxi Province. The Nei's gone diversity indices, from high to low, are in the sequence of Hainan, Guangdong, Guangxi, Fujian, Hunan, Jiangxi, and Yunnan provinces. Two genetic diversity centers of Chinese common wild rice are detected on the basis of geographic analysis, i.e., the region covering Boluo, Zijin, Lufeng, Haifeng, Huidong and Huiyang counties of Guangdong Province and the region covering Yongning, Longan, Laibin and Guigang counties of Guangxi Province. The common wild rice in Yunnan, Hunan, Jiangxi, and Fujian provinces are diverged into respectively independent popula-tions with relatively large genetic distances, whereas, those in Hainan, Guangdong and Guangxi prov-inces have relatively low genetic divergence. Under the condition of geographic separation, natural selection is considered as one of the primary forces contributing to the divergence of common wild rice in China.

  20. Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer

    NARCIS (Netherlands)

    Gaudet, Mia M.; Kirchhoff, Tomas; Green, Todd; Vijai, Joseph; Korn, Joshua M.; Guiducci, Candace; Segre, Ayellet V.; McGee, Kate; McGuffog, Lesley; Kartsonaki, Christiana; Morrison, Jonathan; Healey, Sue; Sinilnikova, Olga M.; Stoppa-Lyonnet, Dominique; Mazoyer, Sylvie; Gauthier-Villars, Marion; Sobol, Hagay; Longy, Michel; Frenay, Marc; Hogervorst, Frans B. L.; Rookus, Matti A.; Collee, J. Margriet; Hoogerbrugge, Nicoline; van Roozendaal, Kees E. P.; Piedmonte, Marion; Rubinstein, Wendy; Nerenstone, Stacy; Van Le, Linda; Blank, Stephanie V.; Caldes, Trinidad; de la Hoya, Miguel; Nevanlinna, Heli; Aittomaki, Kristiina; Lazaro, Conxi; Blanco, Ignacio; Arason, Adalgeir; Johannsson, Oskar T.; Barkardottir, Rosa B.; Devilee, Peter; Olopade, Olofunmilayo I.; Neuhausen, Susan L.; Wang, Xianshu; Fredericksen, Zachary S.; Peterlongo, Paolo; Manoukian, Siranoush; Barile, Monica; Viel, Alessandra; Radice, Paolo; Phelan, Catherine M.; Narod, Steven; Rennert, Gad; Lejbkowicz, Flavio; Flugelman, Anath; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Toland, Amanda E.; Montagna, Marco; D'Andrea, Emma; Friedman, Eitan; Laitman, Yael; Borg, Ake; Beattie, Mary; Ramus, Susan J.; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Tim; Spurdle, Amanda B.; Chen, Xiaoqing; Holland, Helene; John, Esther M.; Hopper, John L.; Buys, Saundra S.; Daly, Mary B.; Southey, Melissa C.; Terry, Mary Beth; Tung, Nadine; Hansen, Thomas V. Overeem; Nielsen, Finn C.; Greene, Mark I.; Mai, Phuong L.; Osorio, Ana; Duran, Mercedes; Andres, Raquel; Benitez, Javier; Weitzel, Jeffrey N.; Garber, Judy; Hamann, Ute; Peock, Susan; Cook, Margaret; Oliver, Clare; Frost, Debra; Platte, Radka; Evans, D. Gareth; Lalloo, Fiona; Eeles, Ros; Izatt, Louise; Walker, Lisa; Eason, Jacqueline; Barwell, Julian; Godwin, Andrew K.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Engert, Stefanie; Arnold, Norbert; Gadzicki, Dorothea; Dean, Michael; Gold, Bert; Klein, Robert J.; Couch, Fergus J.; Chenevix-Trench, Georgia; Easton, Douglas F.; Daly, Mark J.; Antoniou, Antonis C.; Altshuler, David M.; Offit, Kenneth

    2010-01-01

    The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers

  1. Common genetic variants and modification of penetrance of BRCA2-associated breast cancer

    NARCIS (Netherlands)

    M.M. Gaudet (Mia); T. Kircchoff (Tomas); T. Green (Todd); J. Vijai (Joseph); J.M. Korn (Joshua); C. Guiducci (Candace); A.V. Segrè (Ayellet); K. McGee (Kate); L. McGuffog (Lesley); C. Kartsonaki (Christiana); J. Morrison (Jonathan); S. Healey (Sue); O. Sinilnikova (Olga); D. Stoppa-Lyonnet (Dominique); S. Mazoyer (Sylvie); M. Gauthier-Villars (Marion); H. Sobol (Hagay); M. Longy (Michel); M. Frenay (Marc); F.B.L. Hogervorst (Frans); M.A. Rookus (Matti); J.M. Collée (Margriet); N. Hoogerbrugge (Nicoline); K.E. van Roozendaal (Kees); M. Piedemonte (Marion); W.S. Rubinstein (Wendy); S. Nerenstone (Stacy); L. van Le (Linda); S.V. Blank (Stephanie); T. Caldes (Trinidad); M. de La Hoya (Miguel); H. Nevanlinna (Heli); K. Aittomäki (Kristiina); C. Lazaro (Conxi); I. Blanco (Ignacio); A. Arason (Adalgeir); O.T. Johannson (Oskar); R.B. Barkardottir (Rosa); P. Devilee (Peter); O.I. Olopade (Olofunmilayo); S.L. Neuhausen (Susan); X. Wang (Xianshu); Z. Fredericksen (Zachary); P. Peterlongo (Paolo); S. Manoukian (Siranoush); M. Barile (Monica); A. Viel (Alessandra); P. Radice (Paolo); C. Phelan (Catherine); S. Narod (Steven); G. Rennert (Gad); F. Lejbkowicz (Flavio); A. Flugelman (Anath); I.L. Andrulis (Irene); G. Glendon (Gord); H. Ozcelik (Hilmi); A.E. Toland (Amanda); M. Montagna (Marco); E. D'Andrea (Emma); E. Friedman (Eitan); Y. Laitman (Yael); Å. Borg (Åke); M.S. Beattie (Mary); S.J. Ramus (Susan); S.M. Domchek (Susan); K.L. Nathanson (Katherine); R. Rebbeck (Timothy); A.B. Spurdle (Amanda); X. Chen (Xiaoqing); H. Holland (Helene); E.M. John (Esther); J. Hopper (John); S.S. Buys (Saundra); M.B. Daly (Mary); M.C. Southey (Melissa); M-B. Terry (Mary-beth); N. Tung (Nadine); T.V.O. Hansen (Thomas); F.C. Nielsen (Finn); M.H. Greene (Mark); P.L. Mai (Phuong); A. Osorio (Ana); M. Duran; R. Andres (Raquel); J. Benítez (Javier); J.N. Weitzel (Jeffrey); J. Garber (Judy); U. Hamann (Ute); S. Peock (Susan); M. Cook (Margaret); C.T. Oliver (Clare); D. Frost (Debra); R. Platte (Radka); D.G. Evans (Gareth); F. Lalloo (Fiona); R. Eeles (Rosalind); L. Izatt (Louise); L.J. Walker (Lisa); J. Eason (Jacqueline); J. Barwell (Julian); A.K. Godwin (Andrew); R.K. Schmutzler (Rita); B. Wapenschmidt (Barbara); S. Engert (Stefanie); N. Arnold (Norbert); D. Gadzicki (Dorothea); M. Dean (Michael Emmans); B. Gold (Bert); R.J. Klein (Robert); F.J. Couch (Fergus); G. Chenevix-Trench (Georgia); D.F. Easton (Douglas); M.J. Daly (Mark); A.C. Antoniou (Antonis); D. Altshuler (David); K. Offit (Kenneth)

    2010-01-01

    textabstractThe considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutat

  2. Common genetic variants and modification of penetrance of BRCA2-associated breast cancer

    DEFF Research Database (Denmark)

    Gaudet, Mia M; Kirchhoff, Tomas; Green, Todd;

    2010-01-01

    The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation...

  3. Effects of common germ-line genetic variation in cell cycle genes on ovarian cancer survival

    DEFF Research Database (Denmark)

    Song, H.; Hogdall, E.; Ramus, S.J.

    2008-01-01

    PURPOSE: Somatic alterations have been shown to correlate with ovarian cancer prognosis and survival, but less is known about the effects on survival of common inherited genetic variation. Of particular interest are genes involved in cell cycle pathways, which regulate cell division and could pla...

  4. 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...

  5. The effects of common genetic variants in oncogenes on ovarian cancer survival

    DEFF Research Database (Denmark)

    Quaye, L.; Gayther, S.A.; Ramus, S.J.

    2008-01-01

    PURPOSE: The 5-year survival rate for invasive epithelial ovarian cancer is <35%. It has been suggested that common, germline genetic variation may influence survival after cancer diagnoses, which might enable the prediction of response to treatment and survival in the clinical setting. The aim o...

  6. Common genetic variants associated with cognitive performance identified using the proxy-phenotype method

    NARCIS (Netherlands)

    Rietveld, Cornelius A; Esko, Tõnu; Davies, Gail; Pers, Tune H; Turley, Patrick; Benyamin, Beben; Chabris, Christopher F; Emilsson, Valur; Johnson, Andrew D; Lee, James J; de Leeuw, Christiaan; Marioni, Riccardo E; Medland, Sarah E; Miller, Michael B; Rostapshova, Olga; van der Lee, Sven J; Vinkhuyzen, Anna A E; Amin, Najaf; Conley, Dalton; Derringer, Jaime; van Duijn, Cornelia M; Fehrmann, Rudolf; Franke, Lude; Glaeser, Edward L; Hansell, Narelle K; Hayward, Caroline; Iacono, William G; Ibrahim-Verbaas, Carla; Jaddoe, Vincent; Karjalainen, Juha; Laibson, David; Lichtenstein, Paul; Liewald, David C; Magnusson, Patrik K E; Martin, Nicholas G; McGue, Matt; McMahon, George; Pedersen, Nancy L; Pinker, Steven; Porteous, David J; Posthuma, Danielle; Rivadeneira, Fernando; Smith, Blair H; Starr, John M; Tiemeier, Henning; Timpson, Nicholas J; Trzaskowski, Maciej; Uitterlinden, André G; Verhulst, Frank C; Ward, Mary E; Wright, Margaret J; Davey Smith, George; Deary, Ian J; Johannesson, Magnus; Plomin, Robert; Visscher, Peter M; Benjamin, Daniel J; Cesarini, David; Koellinger, Philipp D

    2014-01-01

    We identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxy-phenotype method. First, we conduct a genome-wide association study of educational attainment in a large sample (n = 106,736), which produces a set of 69 education-associated

  7. Common genetic variants associated with cognitive performance identified using the proxy-phenotype method

    NARCIS (Netherlands)

    Rietveld, Cornelius A; Esko, Tõnu; Davies, Gail; Pers, Tune H; Turley, Patrick; Benyamin, Beben; Chabris, Christopher F; Emilsson, Valur; Johnson, Andrew D; Lee, James J; de Leeuw, Christiaan; Marioni, Riccardo E; Medland, Sarah E; Miller, Michael B; Rostapshova, Olga; van der Lee, Sven J; Vinkhuyzen, Anna A E; Amin, Najaf; Conley, Dalton; Derringer, Jaime; van Duijn, Cornelia M; Fehrmann, Rudolf; Franke, Lude; Glaeser, Edward L; Hansell, Narelle K; Hayward, Caroline; Iacono, William G; Ibrahim-Verbaas, Carla; Jaddoe, Vincent; Karjalainen, Juha; Laibson, David; Lichtenstein, Paul; Liewald, David C; Magnusson, Patrik K E; Martin, Nicholas G; McGue, Matt; McMahon, George; Pedersen, Nancy L; Pinker, Steven; Porteous, David J; Posthuma, Danielle; Rivadeneira, Fernando; Smith, Blair H; Starr, John M; Tiemeier, Henning; Timpson, Nicholas J; Trzaskowski, Maciej; Uitterlinden, André G; Verhulst, Frank C; Ward, Mary E; Wright, Margaret J; Davey Smith, George; Deary, Ian J; Johannesson, Magnus; Plomin, Robert; Visscher, Peter M; Benjamin, Daniel J; Cesarini, David; Koellinger, Philipp D

    2014-01-01

    We identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxy-phenotype method. First, we conduct a genome-wide association study of educational attainment in a large sample (n = 106,736), which produces a set of 69 education-associated

  8. Common genetic variants associated with cognitive performance identified using the proxy-phenotype method

    NARCIS (Netherlands)

    C.A. Rietveld (Niels); T. Esko (Tõnu); G. Davies (Gail); T.H. Pers (Tune); P. Turley (Patrick); B. Benyamin (Beben); C.F. Chabris (Christopher F.); V. Emilsson (Valur); A.D. Johnson (Andrew); J.J. Lee (James J.); C. de Leeuw (Christiaan); R.E. Marioni (Riccardo); S.E. Medland (Sarah Elizabeth); M. Miller (Mike); O. Rostapshova (Olga); S. van der Lee (Sven); A.A.E. Vinkhuyzen (Anna A.); N. Amin (Najaf); D. Conley (Dalton); J. Derringer; C.M. van Duijn (Cock); R.S.N. Fehrmann (Rudolf); L. Franke (Lude); E.L. Glaeser (Edward L.); N.K. Hansell (Narelle); C. Hayward (Caroline); W.G. Iacono (William); C.A. Ibrahim-Verbaas (Carla); V.W.V. Jaddoe (Vincent); J. Karjalainen (Juha); D. Laibson (David); P. Lichtenstein (Paul); D.C. Liewald (David C.); P.K. Magnusson (Patrik); N.G. Martin (Nicholas); M. McGue (Matt); G. Mcmahon (George); N.L. Pedersen (Nancy); S. Pinker (Steven); D.J. Porteous (David J.); D. Posthuma (Danielle); F. Rivadeneira Ramirez (Fernando); B.H. Smithk (Blair H.); J.M. Starr (John); H.W. Tiemeier (Henning); N.J. Timpsonm (Nicholas J.); M. Trzaskowskin (Maciej); A.G. Uitterlinden (André); F.C. Verhulst (Frank); M.E. Ward (Mary); M.J. Wright (Margaret); G.D. Smith; I.J. Deary (Ian J.); M. Johannesson (Magnus); R. Plomin (Robert); P.M. Visscher (Peter); D.J. Benjamin (Daniel J.); D. Cesarini (David); Ph.D. Koellinger (Philipp)

    2014-01-01

    textabstractWe identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxyphenotype method. First, we conduct a genome-wide association study of educational attainment in a large sample (n = 106,736), which produces a set of 69 education

  9. Current Views on Genetics and Epigenetics of Cholesterol Gallstone Disease

    Directory of Open Access Journals (Sweden)

    Agostino Di Ciaula

    2013-01-01

    Full Text Available Cholesterol gallstone disease, one of the commonest digestive diseases in western countries, is induced by an imbalance in cholesterol metabolism, which involves intestinal absorption, hepatic biosynthesis, and biliary output of cholesterol, and its conversion to bile acids. Several components of the metabolic syndrome (e.g., obesity, type 2 diabetes, dyslipidemia, and hyperinsulinemia are also well-known risk factors for gallstones, suggesting the existence of interplay between common pathophysiological pathways influenced by insulin resistance, genetic, epigenetic, and environmental factors. Cholesterol gallstones may be enhanced, at least in part, by the abnormal expression of a set of the genes that affect cholesterol homeostasis and lead to insulin resistance. Additionally, epigenetic mechanisms (mainly DNA methylation, histone acetylation/deacetylation, and noncoding microRNAs may modify gene expression in the absence of an altered DNA sequence, in response to different lithogenic environmental stimuli, such as diet, lifestyle, pollutants, also occurring in utero before birth. In this review, we will comment on various steps of the pathogenesis of cholesterol gallstones and interaction between environmental and genetic factors. The epigenomic approach may offer new options for therapy of gallstones and better possibilities for primary prevention in subjects at risk.

  10. Neanderthal and Denisova genetic affinities with contemporary humans: introgression versus common ancestral polymorphisms.

    Science.gov (United States)

    Lowery, Robert K; Uribe, Gabriel; Jimenez, Eric B; Weiss, Mark A; Herrera, Kristian J; Regueiro, Maria; Herrera, Rene J

    2013-11-01

    Analyses of the genetic relationships among modern humans, Neanderthals and Denisovans have suggested that 1-4% of the non-Sub-Saharan African gene pool may be Neanderthal derived, while 6-8% of the Melanesian gene pool may be the product of admixture between the Denisovans and the direct ancestors of Melanesians. In the present study, we analyzed single nucleotide polymorphism (SNP) diversity among a worldwide collection of contemporary human populations with respect to the genetic constitution of these two archaic hominins and Pan troglodytes (chimpanzee). We partitioned SNPs into subsets, including those that are derived in both archaic lineages, those that are ancestral in both archaic lineages and those that are only derived in one archaic lineage. By doing this, we have conducted separate examinations of subsets of mutations with higher probabilities of divergent phylogenetic origins. While previous investigations have excluded SNPs from common ancestors in principal component analyses, we included common ancestral SNPs in our analyses to visualize the relative placement of the Neanderthal and Denisova among human populations. To assess the genetic similarities among the various hominin lineages, we performed genetic structure analyses to provide a comparison of genetic patterns found within contemporary human genomes that may have archaic or common ancestral roots. Our results indicate that 3.6% of the Neanderthal genome is shared with roughly 65.4% of the average European gene pool, which clinally diminishes with distance from Europe. Our results suggest that Neanderthal genetic associations with contemporary non-Sub-Saharan African populations, as well as the genetic affinities observed between Denisovans and Melanesians most likely result from the retention of ancient mutations in these populations.

  11. Charcot-Marie-Tooth disease: frequency of genetic subtypes and guidelines for genetic testing.

    LENUS (Irish Health Repository)

    Murphy, Sinead M

    2012-07-01

    Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous group of diseases with approximately 45 different causative genes described. The aims of this study were to determine the frequency of different genes in a large cohort of patients with CMT and devise guidelines for genetic testing in practice.

  12. Identification of susceptibility genes and genetic modifiers of human diseases

    Science.gov (United States)

    Abel, Kenneth; Kammerer, Stefan; Hoyal, Carolyn; Reneland, Rikard; Marnellos, George; Nelson, Matthew R.; Braun, Andreas

    2005-03-01

    The completion of the human genome sequence enables the discovery of genes involved in common human disorders. The successful identification of these genes is dependent on the availability of informative sample sets, validated marker panels, a high-throughput scoring technology, and a strategy for combining these resources. We have developed a universal platform technology based on mass spectrometry (MassARRAY) for analyzing nucleic acids with high precision and accuracy. To fuel this technology, we generated more than 100,000 validated assays for single nucleotide polymorphisms (SNPs) covering virtually all known and predicted human genes. We also established a large DNA sample bank comprised of more than 50,000 consented healthy and diseased individuals. This combination of reagents and technology allows the execution of large-scale genome-wide association studies. Taking advantage of MassARRAY"s capability for quantitative analysis of nucleic acids, allele frequencies are estimated in sample pools containing large numbers of individual DNAs. To compare pools as a first-pass "filtering" step is a tremendous advantage in throughput and cost over individual genotyping. We employed this approach in numerous genome-wide, hypothesis-free searches to identify genes associated with common complex diseases, such as breast cancer, osteoporosis, and osteoarthritis, and genes involved in quantitative traits like high density lipoproteins cholesterol (HDL-c) levels and central fat. Access to additional well-characterized patient samples through collaborations allows us to conduct replication studies that validate true disease genes. These discoveries will expand our understanding of genetic disease predisposition, and our ability for early diagnosis and determination of specific disease subtype or progression stage.

  13. Genetic Characterization of Legionella pneumophila Isolated from a Common Watershed in Comunidad Valenciana, Spain.

    Science.gov (United States)

    Sánchez-Busó, Leonor; Coscollá, Mireia; Pinto-Carbó, Marta; Catalán, Vicente; González-Candelas, Fernando

    2013-01-01

    Legionella pneumophila infects humans to produce legionellosis and Pontiac fever only from environmental sources. In order to establish control measures and study the sources of outbreaks it is essential to know extent and distribution of strain variants of this bacterium in the environment. Sporadic and outbreak-related cases of legionellosis have been historically frequent in the Comunidad Valenciana region (CV, Spain), with a high prevalence in its Southeastern-most part (BV). Environmental investigations for the detection of Legionella pneumophila are performed in this area routinely. We present a population genetics study of 87 L. pneumophila strains isolated in 13 different localities of the BV area irrigated from the same watershed and compare them to a dataset of 46 strains isolated in different points of the whole CV. Our goal was to compare environmental genetic variation at two different geographic scales, at county and regional levels. Genetic diversity, recombination and population structure were analyzed with Sequence-Based Typing data and three intergenic regions. The results obtained reveal a low, but detectable, level of genetic differentiation between both datasets, mainly, but not only, attributed to the occurrence of unusual variants of the neuA locus present in the BV populations. This differentiation is still detectable when the 10 loci considered are analyzed independently, despite the relatively high incidence of the most common genetic variant in this species, sequence type 1 (ST-1). However, when the genetic data are considered without their associated geographic information, four major groups could be inferred at the genetic level which did not show any correlation with sampling locations. The overall results indicate that the population structure of these environmental samples results from the joint action of a global, widespread ST-1 along with genetic differentiation at shorter geographic distances, which in this case are related to

  14. Molecular genetics and mechanisms of disease in distal hereditary motor neuropathies: insights directing future genetic studies.

    Science.gov (United States)

    Drew, A P; Blair, I P; Nicholson, G A

    2011-11-01

    The distal hereditary motor neuropathies (dHMNs) are a clinically and genetically heterogeneous group of disorders that primarily affect motor neurons, without significant sensory involvement. New dHMN genes continue to be identified. There are now 11 causative genes described for dHMN, and an additional five genetic loci with unidentified genes. This genetic heterogeneity has further delineated the classification of dHMN, which was previously classified according to mode of inheritance, age at onset, and additional complicating features. Some overlap between phenotypically distinct forms of dHMN is also apparent. The mutated genes identified to-date in dHMN include HSPB1, HSPB8, HSPB3, DCTN1, GARS, PLEKHG5, BSCL2, SETX, IGHMBP2, ATP7A and TRPV4. The pathogenesis of mutations remains to be fully elucidated, however common pathogenic mechanisms are emerging. These include disruption of axonal transport, RNA processing defects, protein aggregation and inclusion body formation, disrupted calcium channel activity, and loss of neuroprotective signalling. Some of these dHMN genes are also mutated in Charcot-Marie-Tooth (CMT) disease and spinal muscular atrophy (SMA). This review examines the growing number of identified dHMN genes, discusses recent insights into the functions of these genes and possible pathogenic mechanisms, and looks at the increasing overlap between dHMN and the other neuropathies CMT2 and SMA.

  15. Genetic variants in diseases of the extrapyramidal system.

    Science.gov (United States)

    Oczkowska, Anna; Kozubski, Wojciech; Lianeri, Margarita; Dorszewska, Jolanta

    2014-02-01

    Knowledge on the genetics of movement disorders has advanced significantly in recent years. It is now recognized that disorders of the basal ganglia have genetic basis and it is suggested that molecular genetic data will provide clues to the pathophysiology of normal and abnormal motor control. Progress in molecular genetic studies, leading to the detection of genetic mutations and loci, has contributed to the understanding of mechanisms of neurodegeneration and has helped clarify the pathogenesis of some neurodegenerative diseases. Molecular studies have also found application in the diagnosis of neurodegenerative diseases, increasing the range of genetic counseling and enabling a more accurate diagno-sis. It seems that understanding pathogenic processes and the significant role of genetics has led to many experiments that may in the future will result in more effective treatment of such diseases as Parkinson's or Huntington's. Currently used molecular diagnostics based on DNA analysis can identify 9 neurodegenerative diseases, including spinal cerebellar ataxia inherited in an autosomal dominant manner, dentate-rubro-pallido-luysian atrophy, Friedreich's disease, ataxia with ocu-lomotorapraxia, Huntington's disease, dystonia type 1, Wilson's disease, and some cases of Parkinson's disease.

  16. Oral pathology in a group of Mexican patients with genetic diseases.

    Science.gov (United States)

    Montoya Pérez, Luis A; Arenas Sordo, María de la Luz; Hernández Zamora, Edgar; Aldape Barrios, Beatriz C

    2007-03-01

    Without considering infectious and traumatic diseases, the great majority of oral cavity diseases have a genetic base, in some cases identifiable, in others not. For the stomatologists it is of great importance to know the clinical characteristics and type of alteration that go with genetic etiology syndromes to be able to offer patients an adequate multidisciplinary treatment. Intentional search and description of oral pathology in patients with diverse genetic diseases. An observational and descriptive 4 month study of 62 patients from the Genetics Department of the National Institute of Rehabilitation, was done. Taken into consideration, aside from oral manifestations and genetic disease, were age, sex, consanguinity and inbreeding. The majority of patients who have genetic pathology do not have curative treatment, but they can receive other treatments to improve their quality of life, among these are dental treatments. The more common diseases we found were hereditary peripheral neuropathies, skeletal dysplasias, limb malformation and muscular dystrophies. Diverse features were described, registered and grouped according to their location. Presently it is important to look for the genetic etiology of all diseases to seek specific treatments and prevent them. This will change the practice of medicine and dentistry.

  17. [Genetic Structure of Urban Population of the Common Hamster (Cricetus cricetus)].

    Science.gov (United States)

    Feoktistova, N Yu; Meschersky, I G; Surov, A V; Bogomolov, P L; Tovpinetz, N N; Poplavskaya, N S

    2016-02-01

    Over the past half-century, the common hamster (Cricetus cricetus), along with range-wide decline of natural populations, has actively populated the cities. The study of the genetic structure of urban populations of common hamster may shed light on features of the habitation of this species in urban landscapes. This article is focused on the genetic structure of common hamster populations in Simferopol (Crimea), one of the largest known urban populations of this species. On the basis of the analysis of nucleotide sequences of the cytochrome b gene and mtDNA control region, and the allelic composition of ten microsatellite loci of nDNA, we revealed that, despite the fact that some individuals can move throughout the city at considerable distances, the entire population of the city is represented by separate demes confined to different areas. These demes are characterized by a high degree of the genetic isolation and reduced genetic diversity compared to that found for the city as a whole.

  18. Reverse genetics of Newcastle disease virus

    Science.gov (United States)

    Reverse genetics allows the generation of recombinant viruses or vectors used in functional studies, vaccine development, and gene therapy. This technique allows genetic manipulation and cloning of viral genomes, mutation through site-directed mutagenesis, and gene insertion or deletion, among othe...

  19. Genetic structure of the Common Eider in the western Aleutian Islands prior to fox eradication

    Science.gov (United States)

    Sonsthagen, Sarah A.; Talbot, Sandra L.; Wilson, Robert E.; Petersen, Margaret R.; Williams, Jeffrey C.; Byrd, G. Vernon; McCracken, Kevin G.

    2013-01-01

    Since the late 18th century bird populations residing in the Aleutian Archipelago have been greatly reduced by introduced arctic foxes (Alopex lagopus). We analyzed data from microsatellite, nuclear intron, and mitochondrial (mtDNA) loci to examine the spatial genetic structure, demography, and gene flow among four Aleutian Island populations of the Common Eider (Somateria mollissima) much reduced by introduced foxes. In mtDNA, we found high levels of genetic structure within and between island groups (ΦST = 0.643), but we found no population subdivision in microsatellites or nuclear introns. Differences in genetic structure between the mitochondrial and nuclear genomes are consistent with the Common Eider's breeding and winter biology, as females are highly philopatric and males disperse. Nevertheless, significant differences between islands in the mtDNA of males and marginal significance (P =0.07) in the Z-linked locus Smo 1 suggest that males may also have some level of fidelity to island groups. Severe reduction of populations by the fox, coupled with females' high philopatry, may have left the genetic signature of a bottleneck effect, resulting in the high levels of genetic differentiation observed in mtDNA (ΦST = 0.460–0.807) between islands only 440 km apart. Reestablishment of the Common Eider following the fox's eradication was likely through recruitment from within the islands and bolstered by dispersal from neighboring islands, as suggested by the lack of genetic structure and asymmetry in gene flow between Attu and the other Near Islands.

  20. Infertility etiologies are genetically and clinically linked with other diseases in single meta-diseases.

    Science.gov (United States)

    Tarín, Juan J; García-Pérez, Miguel A; Hamatani, Toshio; Cano, Antonio

    2015-04-15

    The present review aims to ascertain whether different infertility etiologies share particular genes and/or molecular pathways with other pathologies and are associated with distinct and particular risks of later-life morbidity and mortality. In order to reach this aim, we use two different sources of information: (1) a public web server named DiseaseConnect ( http://disease-connect.org ) focused on the analysis of common genes and molecular mechanisms shared by diseases by integrating comprehensive omics and literature data; and (2) a literature search directed to find clinical comorbid relationships of infertility etiologies with only those diseases appearing after infertility is manifested. This literature search is performed because DiseaseConnect web server does not discriminate between pathologies emerging before, concomitantly or after infertility is manifested. Data show that different infertility etiologies not only share particular genes and/or molecular pathways with other pathologies but they have distinct clinical relationships with other diseases appearing after infertility is manifested. In particular, (1) testicular and high-grade prostate cancer in male infertility; (2) non-fatal stroke and endometrial cancer, and likely non-fatal coronary heart disease and ovarian cancer in polycystic ovary syndrome; (3) osteoporosis, psychosexual dysfunction, mood disorders and dementia in premature ovarian failure; (4) breast and ovarian cancer in carriers of BRCA1/2 mutations in diminished ovarian reserve; (5) clear cell and endometrioid histologic subtypes of invasive ovarian cancer, and likely low-grade serous invasive ovarian cancer, melanoma and non-Hodgkin lymphoma in endometriosis; and (6) endometrial and ovarian cancer in idiopathic infertility. The present data endorse the principle that the occurrence of a disease (in our case infertility) is non-random in the population and suggest that different infertility etiologies are genetically and clinically

  1. Disease and Polygenic Architecture: Avoid Trio Design and Appropriately Account for Unscreened Control Subjects for Common Disease

    Science.gov (United States)

    Peyrot, Wouter J.; Boomsma, Dorret I.; Penninx, Brenda W.J.H.; Wray, Naomi R.

    2016-01-01

    Genome-wide association studies (GWASs) are an optimal design for discovery of disease risk loci for diseases whose underlying genetic architecture includes many common causal loci of small effect (a polygenic architecture). We consider two designs that deserve careful consideration if the true underlying genetic architecture of the trait is polygenic: parent-offspring trios and unscreened control subjects. We assess these designs in terms of quantification of the total contribution of genome-wide genetic markers to disease risk (SNP heritability) and power to detect an associated risk allele. First, we show that trio designs should be avoided when: (1) the disease has a lifetime risk > 1%; (2) trio probands are ascertained from families with more than one affected sibling under which scenario the SNP heritability can drop by more than 50% and power can drop as much as from 0.9 to 0.15 for a sample of 20,000 subjects; or (3) assortative mating occurs (spouse correlation of the underlying liability to the disorder), which decreases the SNP heritability but not the power to detect a single locus in the trio design. Some studies use unscreened rather than screened control subjects because these can be easier to collect; we show that the estimated SNP heritability should then be scaled by dividing by (1 − K × u)2 for disorders with population prevalence K and proportion of unscreened control subjects u. When omitting to scale appropriately, the SNP heritability of, for example, major depressive disorder (K = 0.15) would be underestimated by 28% when none of the control subjects are screened. PMID:26849113

  2. Genetics of cardiovascular diseases: lessons learned from a decade of genomics research in Iceland.

    Science.gov (United States)

    Arnar, David O; Andersen, Karl; Thorgeirsson, Gudmundur

    In the past 10 years, large-scale genotyping has led to discoveries of sequence variants that confer the risk of many common and complex diseases. Due to pioneering work done, in large part, at deCODE genetics in Reykjavik, discoveries from Iceland have contributed substantially to key advances in population genetics. In cardiovascular medicine, a number of discoveries have been made, uncovering sequence variants that are associated with disorders such as coronary artery disease, atrial fibrillation, sick sinus syndrome, peripheral vascular disease, aortic aneurysm, and ischemic stroke. Thus, a wealth of genetic data has been accumulated in cardiology and has enhanced our understanding of a number of diseases. In many cases, these findings offer new mechanistic clues into the pathophysiology of complex cardiovascular diseases and may point toward novel therapeutic approaches in drug therapy. The next important step is to begin to transform these findings into practical clinical knowledge with the aim of improving the delivery of cardiovascular health care.

  3. Constraints on Biological Mechanism from Disease Comorbidity Using Electronic Medical Records and Database of Genetic Variants.

    Directory of Open Access Journals (Sweden)

    Steven C Bagley

    2016-04-01

    Full Text Available Patterns of disease co-occurrence that deviate from statistical independence may represent important constraints on biological mechanism, which sometimes can be explained by shared genetics. In this work we study the relationship between disease co-occurrence and commonly shared genetic architecture of disease. Records of pairs of diseases were combined from two different electronic medical systems (Columbia, Stanford, and compared to a large database of published disease-associated genetic variants (VARIMED; data on 35 disorders were available across all three sources, which include medical records for over 1.2 million patients and variants from over 17,000 publications. Based on the sources in which they appeared, disease pairs were categorized as having predominant clinical, genetic, or both kinds of manifestations. Confounding effects of age on disease incidence were controlled for by only comparing diseases when they fall in the same cluster of similarly shaped incidence patterns. We find that disease pairs that are overrepresented in both electronic medical record systems and in VARIMED come from two main disease classes, autoimmune and neuropsychiatric. We furthermore identify specific genes that are shared within these disease groups.

  4. Genetics Home Reference: microvillus inclusion disease

    Science.gov (United States)

    ... and Rare Diseases Information Center (1 link) Microvillus inclusion disease Additional NIH Resources (1 link) National Digestive Diseases Information Clearinghouse: Diarrhea Educational Resources (9 links) American Society for Parenteral and ...

  5. Genetics Home Reference: Tay-Sachs disease

    Science.gov (United States)

    ... Facebook Twitter Home Health Conditions Tay-Sachs disease Tay-Sachs disease Printable PDF Open All Close All ... Javascript to view the expand/collapse boxes. Description Tay-Sachs disease is a rare inherited disorder that ...

  6. Genetics Home Reference: critical congenital heart disease

    Science.gov (United States)

    ... Health Conditions critical congenital heart disease critical congenital heart disease Printable PDF Open All Close All Enable Javascript ... view the expand/collapse boxes. Description Critical congenital heart disease (CCHD) is a term that refers to a ...

  7. Genetics Home Reference: mitochondrial neurogastrointestinal encephalopathy disease

    Science.gov (United States)

    ... GI Motility MalaCards: mitochondrial neurogastrointestinal encephalopathy disease Neuromuscular Disease Center, Washington University Orphanet: Mitochondrial neurogastrointestinal encephalomyopathy Patient Support and Advocacy ...

  8. Genetic factors associated with the development of inflammatory bowel disease

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Crohn's disease (CD) and ulcerative colitis (UC) are complex polygenic disorders, characterized by several genes together with environmental factors contributing to the development of inflammatory bowel disease (IBD). Recent advances in research on genetic susceptibility have allowed the identification of diverse genes at different levels: (1) Innate immunity; (2) Antigen presentation molecules; (3) Epithelial integrity; (4) Drug transporter; (5) Cell adhesion. The application of genetic testing into clinical practice is close and all genetic markers may have several clinical implications: prediction of disease phenotype, molecular classification, prevention of complications, and prognosis.

  9. Citizens in the commons: blood and genetics in the making of the civic.

    Science.gov (United States)

    Reddy, Deepa S

    2013-01-01

    This essay is based on ethnographic fieldwork conducted with the Indian community in Houston, as part of a NIH/NHGRI-sponsored ethics study and sample collection initiative entitled 'Indian and Hindu Perspectives on Genetic Variation Research.' Taking a cue from my Indian interlocutors who largely support and readily respond to such initiatives on the grounds that they will undoubtedly serve 'humanity' and the common good, I explore notions of the commons that are created in the process of soliciting blood for genetic research. How does blood become the stuff of which a civic discourse is made? How do idealistic individual appeals to donate blood, ethics research protocols, open-source databases, debates on approaches to genetic research, patents and Intellectual Property regulations, markets and the nation-state itself variously engage, limit or further ideas of the common good? Moving much as my interlocutors do, between India and the United States, I explore the nature of the commons that is both imagined and pragmatically reckoned in both local and global diasporic contexts.

  10. Network medicine approaches to the genetics of complex diseases.

    Science.gov (United States)

    Silverman, Edwin K; Loscalzo, Joseph

    2012-08-01

    Complex diseases are caused by perturbations of biological networks. Genetic analysis approaches focused on individual genetic determinants are unlikely to characterize the network architecture of complex diseases comprehensively. Network medicine, which applies systems biology and network science to complex molecular networks underlying human disease, focuses on identifying the interacting genes and proteins which lead to disease pathogenesis. The long biological path between a genetic risk variant and development of a complex disease involves a range of biochemical intermediates, including coding and non-coding RNA, proteins, and metabolites. Transcriptomics, proteomics, metabolomics, and other -omics technologies have the potential to provide insights into complex disease pathogenesis, especially if they are applied within a network biology framework. Most previous efforts to relate genetics to -omics data have focused on a single -omics platform; the next generation of complex disease genetics studies will require integration of multiple types of -omics data sets in a network context. Network medicine may also provide insight into complex disease heterogeneity, serve as the basis for new disease classifications that reflect underlying disease pathogenesis, and guide rational therapeutic and preventive strategies.

  11. Phenotype-Based Genetic Association Studies (PGAS)-Towards Understanding the Contribution of Common Genetic Variants to Schizophrenia Subphenotypes.

    Science.gov (United States)

    Ehrenreich, Hannelore; Nave, Klaus-Armin

    2014-02-27

    Neuropsychiatric diseases ranging from schizophrenia to affective disorders and autism are heritable, highly complex and heterogeneous conditions, diagnosed purely clinically, with no supporting biomarkers or neuroimaging criteria. Relying on these "umbrella diagnoses", genetic analyses, including genome-wide association studies (GWAS), were undertaken but failed to provide insight into the biological basis of these disorders. "Risk genotypes" of unknown significance with low odds ratios of mostly definition of biological subgroups of mental diseases. For that purpose, the GRAS (Göttingen Research Association for Schizophrenia) data collection was initiated in 2005. With >3000 phenotypical data points per patient, it comprises the world-wide largest currently available schizophrenia database (N > 1200), combining genome-wide SNP coverage and deep phenotyping under highly standardized conditions. First PGAS results on normal genetic variants, relevant for e.g., cognition or catatonia, demonstrated proof-of-concept. Presently, an autistic subphenotype of schizophrenia is being defined where an unfortunate accumulation of normal genotypes, so-called pro-autistic variants of synaptic genes, explains part of the phenotypical variance. Deep phenotyping and comprehensive clinical data sets, however, are expensive and it may take years before PGAS will complement conventional GWAS approaches in psychiatric genetics.

  12. The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease.

    Science.gov (United States)

    Astle, William J; Elding, Heather; Jiang, Tao; Allen, Dave; Ruklisa, Dace; Mann, Alice L; Mead, Daniel; Bouman, Heleen; Riveros-Mckay, Fernando; Kostadima, Myrto A; Lambourne, John J; Sivapalaratnam, Suthesh; Downes, Kate; Kundu, Kousik; Bomba, Lorenzo; Berentsen, Kim; Bradley, John R; Daugherty, Louise C; Delaneau, Olivier; Freson, Kathleen; Garner, Stephen F; Grassi, Luigi; Guerrero, Jose; Haimel, Matthias; Janssen-Megens, Eva M; Kaan, Anita; Kamat, Mihir; Kim, Bowon; Mandoli, Amit; Marchini, Jonathan; Martens, Joost H A; Meacham, Stuart; Megy, Karyn; O'Connell, Jared; Petersen, Romina; Sharifi, Nilofar; Sheard, Simon M; Staley, James R; Tuna, Salih; van der Ent, Martijn; Walter, Klaudia; Wang, Shuang-Yin; Wheeler, Eleanor; Wilder, Steven P; Iotchkova, Valentina; Moore, Carmel; Sambrook, Jennifer; Stunnenberg, Hendrik G; Di Angelantonio, Emanuele; Kaptoge, Stephen; Kuijpers, Taco W; Carrillo-de-Santa-Pau, Enrique; Juan, David; Rico, Daniel; Valencia, Alfonso; Chen, Lu; Ge, Bing; Vasquez, Louella; Kwan, Tony; Garrido-Martín, Diego; Watt, Stephen; Yang, Ying; Guigo, Roderic; Beck, Stephan; Paul, Dirk S; Pastinen, Tomi; Bujold, David; Bourque, Guillaume; Frontini, Mattia; Danesh, John; Roberts, David J; Ouwehand, Willem H; Butterworth, Adam S; Soranzo, Nicole

    2016-11-17

    Many common variants have been associated with hematological traits, but identification of causal genes and pathways has proven challenging. We performed a genome-wide association analysis in the UK Biobank and INTERVAL studies, testing 29.5 million genetic variants for association with 36 red cell, white cell, and platelet properties in 173,480 European-ancestry participants. This effort yielded hundreds of low frequency (<5%) and rare (<1%) variants with a strong impact on blood cell phenotypes. Our data highlight general properties of the allelic architecture of complex traits, including the proportion of the heritable component of each blood trait explained by the polygenic signal across different genome regulatory domains. Finally, through Mendelian randomization, we provide evidence of shared genetic pathways linking blood cell indices with complex pathologies, including autoimmune diseases, schizophrenia, and coronary heart disease and evidence suggesting previously reported population associations between blood cell indices and cardiovascular disease may be non-causal. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Resistance of genetically different common carp, Cyprinus carpio L., families against experimental bacterial challenge with Aeromonas hydrophila.

    Science.gov (United States)

    Jeney, G; Ardó, L; Rónyai, A; Bercsényi, M; Jeney, Z

    2011-01-01

    The objective of this study was to determine the differences in disease resistance against artificial infection with Aeromonas hydrophila between genetically different common carp families. Four strains differing in their origin and breeding history were selected from the live gene bank of common carp maintained at the Research Institute for Fisheries, Aquaculture and Irrigation (HAKI, Szarvas, Hungary) to establish families with wide genetic background: Szarvas 15 (15), an inbred mirror line; Tata (T) scaly noble carp; Duna (D), a Hungarian wild carp and Amur (A), an East Asian wild carp. A diallele mating structure was used to allow the assessment of genetic variation within and between the tested 96 families for a variety of traits. The existing technologies of fertilization and incubation of carp eggs, as well as larval and fingerling rearing had been modified because of the large number of baseline populations. Two challenge trials of the 96 families of carp with Aeromonas hydrophila were done. The 10 most resistant and 10 most susceptible families to A. hydrophila were identified from these two challenges. The crosses that produced the most resistant families were mainly those having parents from Tata and Szarvas 15 domesticated strains, while the most susceptible families were from the wild strains Duna and Amur.

  14. Genetic counseling and testing for Huntington's disease: A historical review.

    Science.gov (United States)

    Nance, Martha A

    2017-01-01

    This manuscript describes the ways in which genetic counseling has evolved since John Pearson and Sheldon Reed first promoted "a genetic education" in the 1950s as a voluntary, non-directive clinical tool for permitting individual decision making. It reviews how the emergence of Huntington's disease (HD) registries and patient support organizations, genetic testing, and the discovery of a disease-causing CAG repeat expansion changed the contours of genetic counseling for families with HD. It also reviews the guidelines, outcomes, ethical and laboratory challenges, and uptake of predictive, prenatal, and preimplantation testing, and it casts a vision for how clinicians can better make use of genetic counseling to reach a broader pool of families that may be affected by HD and to ensure that genetic counseling is associated with the best levels of care. © 2016 Wiley Periodicals, Inc.

  15. Study of the common genetic background for rheumatoid arthritis and systemic lupus erythematosus

    Science.gov (United States)

    Orozco, Gisela; Eyre, Steve; Hinks, Anne; Bowes, John; Morgan, Ann W; Wilson, Anthony G; Wordsworth, Paul; Steer, Sophia; Hocking, Lynne; Thomson, Wendy; Worthington, Jane; Barton, Anne

    2011-01-01

    Background Evidence is beginning to emerge that there may be susceptibility loci for rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) that are common to both diseases. Objective To investigate single nucleotide polymorphisms that have been reported to be associated with SLE in a UK cohort of patients with RA and controls. Methods 3962 patients with RA and 9275 controls were included in the study. Eleven SNPs mapping to confirmed SLE loci were investigated. These mapped to the TNFSF4, BANK1, TNIP1, PTTG1, UHRF1BP1, ATG5, JAZF1, BLK, KIAA1542, ITGAM and UBE2L3 loci. Genotype frequencies were compared between patients with RA and controls using the trend test. Results The SNPs mapping to the BLK and UBE2L3 loci showed significant evidence for association with RA. Two other SNPs, mapping to ATG5 and KIAA1542, showed nominal evidence for association with RA (p=0.02 and p=0.02, respectively) but these were not significant after applying a Bonferroni correction. Additionally, a significant global enrichment in carriage of SLE alleles in patients with RA compared with controls (p=9.1×10−7) was found. Meta-analysis of this and previous studies confirmed the association of the BLK and UBE2L3 gene with RA at genome-wide significance levels (p<5×10−8). Together, the authors estimate that the SLE and RA overlapping loci, excluding HLA-DRB1 alleles, identified so far explain ∼5.8% of the genetic susceptibility to RA as a whole. Conclusion The findings confirm the association of the BLK and UBE2L3 loci with RA, thus adding to the list of loci showing overlap between RA and SLE. PMID:21068098

  16. Role of common sarcomeric gene polymorphisms in genetic susceptibility to left ventricular dysfunction

    Indian Academy of Sciences (India)

    SURENDRA KUMAR; AVSHESH MISHRA; ANSHIKA SRIVASTAVA; MANSI BHATT; N. GARG; S. K. AGARWAL; SHANTANU PANDE; BALRAJ MITTAL

    2016-06-01

    Mutations in sarcomeric genes are common genetic cause of cardiomyopathies. An intronic 25-bp deletion in cardiac myosin binding protein C (MYBPC3) at 3' region is associated with dilated and hypertrophic cardiomyopathies in Southeast Asia. However, the frequency of sarcomeric gene polymorphisms and associated clinical presentation have not been established with left ventricular dysfunction (LVD). Therefore, the aim of the present study was to explore the association of MYBPC3 25-bp deletion, titin (TTN) 18 bp I/D, troponin T type 2 (TNNT2) 5 bp I/D and myospryn K2906N polymorphisms with LVD. This study includes 988 consecutive patients with angiographically confirmed coronary artery disease (CAD) and 300 healthy controls. Among the 988 CAD patients, 253 with reduced left ventricle ejection fraction (LVEF≤45%) were categorized as LVD. MYBPC3 25-bp deletion,TTN 18 bp I/D and TNNT25 bp I/D polymorphisms were determined by direct polymerase chain reaction method, while myospryn K2906N polymorphism by TaqMan assay. Our results showed that MYBPC3 25-bpdeletion polymorphism was significantly associated with elevated risk of LVD (LVEF <45) (healthy controls versus LVD: OR= 3.85,P<0.001; and nonLVD versus LVD: OR=1.65,P=0.035), while TTN 18 bp I/D, TNNT25bpI/Dand myospryn K2906N polymorphisms did not show any significant association with LVD. The results also showed that MYBPC3 25-bp deletion polymorphism was significantly associated with other parameters of LV remodelling, i.e. LV dimensions (LV end diastole dimension, LVEDD: P= 0.037 and LV end systolic dimension, LVESD: P= 0.032).Our data suggests that MYBPC3 25-bp deletion may play significant role in conferring LVD as well as CAD risk in north Indian population

  17. Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants

    Science.gov (United States)

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

    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. Methods: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates. Results: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer. Conclusions: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report. PMID:25855707

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

    Science.gov (United States)

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

    2015-05-01

    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. We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates. There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer. The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report. © The Author 2015. Published by Oxford University Press.

  19. Genetic variation in human disease and a new role for copy number variants.

    Science.gov (United States)

    Shelling, Andrew N; Ferguson, Lynnette R

    2007-09-01

    While complex diseases, such as inflammatory bowel disease, do not follow distinctive Mendelian inheritance patterns, there is now considerable evidence from twin and pedigree studies to show that there are significant genetic influences in the development of many such diseases. In times past, this type of information was considered to be interesting, and was used mainly to alert other members of the families that they may also be at increased risk of developing the disease. However, with the ability to evaluate the genetic basis of common disease, this information will have important consequences for the diagnosis, prevention and treatment of the disorder. The genetic basis for common disease is likely to be more complicated than we had previously anticipated, since we now recognise epigenetic causes of disease, and other subtle gene regulatory mechanisms. Copy number variants have been highlighted in this review, as being a phenomenon that we have known about for a long time, but that has not previously been clearly associated with human disease. As complex disease is related to changes in gene expression, any variation in the human genome that alters gene expression is now a candidate for being involved in the disease process.

  20. Minding the Genes: a Multidisciplinary Approach towards Genetic Assessment of Cardiovascular Disease.

    Science.gov (United States)

    Rhodes, Ashley; Rosman, Lindsey; Cahill, John; Ingles, Jodie; Murray, Brittney; Tichnell, Crystal; James, Cynthia A; Sears, Samuel F

    2017-04-01

    Genetic assessment for inherited cardiovascular disease (CVD) is increasingly available, due in part to rapid innovations in genetic sequencing technologies. While genetic testing is aimed at reducing uncertainty, it also produces awareness of potential medical conditions and can leave patients feeling uncertain about their risk, especially if there are ambiguous results. This uncertainty can produce psychological distress for patients and their families undergoing the assessment process. Additionally, patients may experience psychological distress related to living with inherited CVD. In order to more effectively manage the psychosocial challenges related to genetic assessment for CVD, a multidisciplinary model expanded to include psychologists and other allied health professionals is outlined. A case study is provided to illustrate how psychological distress can manifest in a patient living with inherited CVD, as well as proposed psychological management of this patient. Finally, a guide for genetic counselors is provided to aid in identifying and managing common psychological reactions to genetic assessment for CVD.

  1. Animal models for human genetic diseases

    African Journals Online (AJOL)

    Sharif Sons

    organisms are extensively used in applied research in agriculture, industry, and also in medicine, where they are ... in genetic disorder that is critical for embryonic .... by practical limitations and ethical concerns. ..... American journal of medical.

  2. Rare disease relations through common genes and protein interactions.

    Science.gov (United States)

    Fernandez-Novo, Sara; Pazos, Florencio; Chagoyen, Monica

    2016-06-01

    ODCs (Orphan Disease Connections), available at http://csbg.cnb.csic.es/odcs, is a novel resource to explore potential molecular relations between rare diseases. These molecular relations have been established through the integration of disease susceptibility genes and human protein-protein interactions. The database currently contains 54,941 relations between 3032 diseases.

  3. Role of Genetic Testing in Inherited Cardiovascular Disease: A Review.

    Science.gov (United States)

    Cirino, Allison L; Harris, Stephanie; Lakdawala, Neal K; Michels, Michelle; Olivotto, Iacopo; Day, Sharlene M; Abrams, Dominic J; Charron, Philippe; Caleshu, Colleen; Semsarian, Christopher; Ingles, Jodie; Rakowski, Harry; Judge, Daniel P; Ho, Carolyn Y

    2017-08-09

    Genetic testing is a valuable tool for managing inherited cardiovascular disease in patients and families, including hypertrophic, dilated, and arrhythmogenic cardiomyopathies and inherited arrhythmias. By identifying the molecular etiology of disease, genetic testing can improve diagnostic accuracy and refine family management. However, unique features associated with genetic testing affect the interpretation and application of results and differentiate it from traditional laboratory-based diagnostics. Clinicians and patients must have accurate and realistic expectations about the yield of genetic testing and its role in management. Familiarity with the rationale, implications, benefits, and limitations of genetic testing is essential to achieve the best possible outcomes. Successfully incorporating genetic testing into clinical practice requires (1) recognizing when inherited cardiovascular disease may be present, (2) identifying appropriate individuals in the family for testing, (3) selecting the appropriate genetic test, (4) understanding the complexities of result interpretation, and (5) effectively communicating the results and implications to the patient and family. Obtaining a detailed family history is critical to identify families who will benefit from genetic testing, determine the best strategy, and interpret results. Instead of focusing on an individual patient, genetic testing requires consideration of the family as a unit. Consolidation of care in centers with a high level of expertise is recommended. Clinicians without expertise in genetic testing will benefit from establishing referral or consultative networks with experienced clinicans in specialized multidisciplinary clinics. Genetic testing provides a foundation for transitioning to more precise and individualized management. By distinguishing phenotypic subgroups, identifying disease mechanisms, and focusing family care, gene-based diagnosis can improve management. Successful integration of

  4. Neuroinformatic Analyses of Common and Distinct Genetic Components Associated with Major Neuropsychiatric Disorders

    Directory of Open Access Journals (Sweden)

    Amit eLotan

    2014-11-01

    Full Text Available Major neuropsychiatric disorders are highly heritable, with mounting evidence suggesting that these disorders share overlapping sets of molecular and cellular underpinnings. In the current article we systematically test the degree of genetic commonality across six major neuropsychiatric disorders—attention deficit hyperactivity disorder, anxiety disorders, autistic spectrum disorders, bipolar disorder, major depressive disorder and schizophrenia. We curated a well-vetted list of genes based on large-scale human genetic studies and verified their appearance on the NHGRI catalog of published genome-wide association studies. A total of 180 genes were accepted into the analysis on the basis of low but liberal GWAS p-values (<10-5. 22% of genes overlapped two or more disorders. The most widely shared subset of genes—common to five of six disorders–included ANK3, AS3MT, CACNA1C, CACNB2, CNNM2, CSMD1, DPCR1, ITIH3, NT5C2, PPP1R11, SYNE1, TCF4, TENM4, TRIM26, and ZNRD1. Using a suite of neuroinformatic resources, we showed that many of the shared genes are implicated in the postsynaptic density, expressed in immune tissues and co-expressed in developing human brain.. Using a translational cross-species approach, we detected two distinct genetic components that were both shared by each of the six disorders; the 1st component is involved in CNS development, neural projections and synaptic transmission, while the 2nd is implicated in various cytoplasmic organelles and cellular processes. Combined, these genetic components account for 20–30% of the genetic load. The remaining risk is conferred by distinct, disorder-specific variants. Nevertheless, the convergence of different analytical approaches on similar targets may bear important implications. Thus, although adding mostly confirmatory findings, higher resolution of shared and unique genetic factors provided in this manuscript could ultimately translate into improved diagnosis and treatment of

  5. Genetic variation of common walnut (Juglans regia in Piedmont, Northwestern Italy

    Directory of Open Access Journals (Sweden)

    Ferrazzini D

    2007-12-01

    Full Text Available The European or common walnut is a large tree prized as a multipurpose species: it provides valuable timber and produces a high-quality edible nut. The diffusion of the species in Italy has been largely influenced by the human activity, mainly through germplasm movement, selection of genotypes most suited for wood or fruit production and adaptation induced on fruit crop reproductive materials. As a consequence, genetic variability has been reduced, so that programs aimed at its preservation appear of the utmost importance. 104 walnut plants growing in Piedmont, northwestern Italy, were investigated through genetic variation scored at RAPD loci, yielded by PCR amplification of 10 decamer primers. Among the 101 studied loci, only 53 were polymorphic, showing a low level of genetic variation within the studied material. Genetic differentiation was estimated both at individual and geographical area level. Only in few cases trees growing in the same area showed to be genetically similar, while the differentiation between areas accounted for about 10% of the total variation, according to AMOVA. No significant correlation was found between genetic and geographic distances. The results of the study showed that also in Piedmont (such as it was already demonstrated in other parts of Italy the distribution of common walnut is a direct consequence of the human activity. The selection of individual trees, to be used as basic materials for seed supply, should therefore be based mainly on phenotypic traits, rather than ecological features of the location: in species characterized by artificial diffusion, the adoption of Region of Provenance has a scarce significance and prominence should be given to the phenotype selection.

  6. Systems Genetics as a Tool to Identify Master Genetic Regulators in Complex Disease.

    Science.gov (United States)

    Moreno-Moral, Aida; Pesce, Francesco; Behmoaras, Jacques; Petretto, Enrico

    2017-01-01

    Systems genetics stems from systems biology and similarly employs integrative modeling approaches to describe the perturbations and phenotypic effects observed in a complex system. However, in the case of systems genetics the main source of perturbation is naturally occurring genetic variation, which can be analyzed at the systems-level to explain the observed variation in phenotypic traits. In contrast with conventional single-variant association approaches, the success of systems genetics has been in the identification of gene networks and molecular pathways that underlie complex disease. In addition, systems genetics has proven useful in the discovery of master trans-acting genetic regulators of functional networks and pathways, which in many cases revealed unexpected gene targets for disease. Here we detail the central components of a fully integrated systems genetics approach to complex disease, starting from assessment of genetic and gene expression variation, linking DNA sequence variation to mRNA (expression QTL mapping), gene regulatory network analysis and mapping the genetic control of regulatory networks. By summarizing a few illustrative (and successful) examples, we highlight how different data-modeling strategies can be effectively integrated in a systems genetics study.

  7. Dopaminergic neuronal imaging in genetic Parkinson's disease: insights into pathogenesis.

    Directory of Open Access Journals (Sweden)

    Alisdair McNeill

    Full Text Available OBJECTIVES: To compare the dopaminergic neuronal imaging features of different subtypes of genetic Parkinson's Disease. METHODS: A retrospective study of genetic Parkinson's diseases cases in which DaTSCAN (123I-FP-CIT had been performed. Specific non-displaceable binding was calculated for bilateral caudate and putamen for each case. The right:left asymmetry index and striatal asymmetry index was calculated. RESULTS: Scans were available from 37 cases of monogenetic Parkinson's disease (7 glucocerebrosidase (GBA mutations, 8 alpha-synuclein, 3 LRRK2, 7 PINK1, 12 Parkin. The asymmetry of radioligand uptake for Parkinson's disease with GBA or LRRK2 mutations was greater than that for Parkinson's disease with alpha synuclein, PINK1 or Parkin mutations. CONCLUSIONS: The asymmetry of radioligand uptake in Parkinsons disease associated with GBA or LRRK2 mutations suggests that interactions with additional genetic or environmental factors may be associated with dopaminergic neuronal loss.

  8. Genetics and behavioral medicine: Risk factors for cardiovascular disease

    NARCIS (Netherlands)

    Vogler, G.P.; McClearn, G.E.; Snieder, H.; Boomsma, D.I.; Palmer, R.; Knijff, P. de; Slagboom, P.E.

    1997-01-01

    This is the second in a series of three articles addressing the intersection of interests in behavioral genetics and behavioral medicine. In this article, we use risk factors for cardiovascular disease as a prototypical trait for which behavioral genetic approaches provide powerful tools for underst

  9. Genetics and behavioral medicine: Risk factors for cardiovascular disease

    NARCIS (Netherlands)

    Vogler, G.P.; McClearn, G.E.; Snieder, H.; Boomsma, D.I.; Palmer, R.; Knijff, P. de; Slagboom, P.E.

    1997-01-01

    This is the second in a series of three articles addressing the intersection of interests in behavioral genetics and behavioral medicine. In this article, we use risk factors for cardiovascular disease as a prototypical trait for which behavioral genetic approaches provide powerful tools for

  10. Neuroinformatic Analyses of Common and Distinct Genetic Components Associated with Major Neuropsychiatric Disorders

    OpenAIRE

    Amit eLotan; Michaela eFenckova; Janita eBralten; Aet eAlttoa; Luanna eDixson; Williams, Robert W.; Monique evan der Voet

    2014-01-01

    Major neuropsychiatric disorders are highly heritable, with mounting evidence suggesting that these disorders share overlapping sets of molecular and cellular underpinnings. In the current article we systematically test the degree of genetic commonality across six major neuropsychiatric disorders—attention deficit hyperactivity disorder, anxiety disorders, autistic spectrum disorders, bipolar disorder, major depressive disorder and schizophrenia. We curated a well-vetted list of genes based o...

  11. Disentangling genetic vs. environmental causes of sex determination in the common frog, Rana temporaria

    OpenAIRE

    Merilä Juha; Miura Ikuo; Matsuba Chikako

    2008-01-01

    Abstract Background Understanding of sex ratio dynamics in a given species requires understanding its sex determination system, as well as access for reliable tools for sex identification at different life stages. As in the case of many other amphibians, the common frogs (Rana temporaria) do not have well differentiated sex chromosomes, and an identification of individuals' genetic sex may be complicated by sex reversals. Here, we report results of studies shedding light on the sex determinat...

  12. Common genetic variability in ESR1 and EGF in relation to endometrial cancer risk and survival

    OpenAIRE

    Einarsdóttir, K; Darabi, H; Czene, K.; Li, Y; Low, Y.L.; Y. Q. Li; Bonnard, C.; Wedrén, S.; Liu, E. T.; Hall, P; Liu, J; Humphreys, K.

    2009-01-01

    We investigated common genetic variation in the entire ESR1 and EGF genes in relation to endometrial cancer risk, myometrial invasion and endometrial cancer survival. We genotyped a dense set of single-nucleotide polymorphisms (SNPs) in both genes and selected haplotype tagging SNPs (tagSNPs). The tagSNPs were genotyped in 713 Swedish endometrial cancer cases and 1567 population controls and the results incorporated into logistic regression and Cox proportional hazards models. We found five a...

  13. Web-based, participant-driven studies yield novel genetic associations for common traits.

    OpenAIRE

    Nicholas Eriksson; J Michael Macpherson; Joyce Y Tung; Hon, Lawrence S.; Brian Naughton; Serge Saxonov; Linda Avey; Anne Wojcicki; Itsik Pe'er; Joanna Mountain

    2010-01-01

    Despite the recent rapid growth in genome-wide data, much of human variation remains entirely unexplained. A significant challenge in the pursuit of the genetic basis for variation in common human traits is the efficient, coordinated collection of genotype and phenotype data. We have developed a novel research framework that facilitates the parallel study of a wide assortment of traits within a single cohort. The approach takes advantage of the interactivity of the Web both to gather data and...

  14. Of mice and men: molecular genetics of congenital heart disease.

    Science.gov (United States)

    Andersen, Troels Askhøj; Troelsen, Karin de Linde Lind; Larsen, Lars Allan

    2014-04-01

    Congenital heart disease (CHD) affects nearly 1 % of the population. It is a complex disease, which may be caused by multiple genetic and environmental factors. Studies in human genetics have led to the identification of more than 50 human genes, involved in isolated CHD or genetic syndromes, where CHD is part of the phenotype. Furthermore, mapping of genomic copy number variants and exome sequencing of CHD patients have led to the identification of a large number of candidate disease genes. Experiments in animal models, particularly in mice, have been used to verify human disease genes and to gain further insight into the molecular pathology behind CHD. The picture emerging from these studies suggest that genetic lesions associated with CHD affect a broad range of cellular signaling components, from ligands and receptors, across down-stream effector molecules to transcription factors and co-factors, including chromatin modifiers.

  15. Genetics and mapping of a new anthracnose resistance locus in Andean common bean Paloma.

    Science.gov (United States)

    de Lima Castro, Sandra Aparecida; Gonçalves-Vidigal, Maria Celeste; Gilio, Thiago Alexandre Santana; Lacanallo, Giselly Figueiredo; Valentini, Giseli; da Silva Ramos Martins, Vanusa; Song, Qijian; Galván, Marta Zulema; Hurtado-Gonzales, Oscar P; Pastor-Corrales, Marcial Antonio

    2017-04-18

    The Andean cultivar Paloma is resistant to Mesoamerican and Andean races of Colletotrichum lindemuthianum, the fungal pathogen that causes the destructive anthracnose disease in common bean. Remarkably, Paloma is resistant to Mesoamerican races 2047 and 3481, which are among the most virulent races of the anthracnose pathogen. Most genes conferring anthracnose resistance in common bean are overcome by these races. The genetic mapping and the relationship between the resistant Co-Pa gene of Paloma and previously characterized anthracnose resistance genes can be a great contribution for breeding programs. The inheritance of resistance studies for Paloma was performed in F2 population from the cross Paloma (resistant) × Cornell 49-242 (susceptible) inoculated with race 2047, and in F2 and F2:3 generations from the cross Paloma (resistant) × PI 207262 (susceptible) inoculated with race 3481. The results of these studies demonstrated that a single dominant gene confers the resistance in Paloma. Allelism tests performed with multiple races of C. lindemuthianum showed that the resistance gene in Paloma, provisionally named Co-Pa, is independent from the anthracnose resistance genes Co-1, Co-2, Co-3, Co-4, Co-5, Co-6, Co-12, Co-13, Co-14, Co-15 and Co-16. Bulk segregant analysis using the SNP chip BARCBean6K_3 positioned the approximate location of Co-Pa in the lower arm of chromosome Pv01. Further mapping analysis located the Co-Pa gene at a 390 kb region of Pv01 flanked by SNP markers SS82 and SS83 at a distance of 1.3 and 2.1 cM, respectively. The results presented here showed that Paloma cultivar has a new dominant gene conferring resistance to anthracnose, which is independent from those genes previously described. The linkage between the Co-Pa gene and the SS82 and SS83 SNP markers will be extremely important for marker-assisted introgression of the gene into elite cultivars in order to enhance resistance.

  16. Multicollinearity in spatial genetics: separating the wheat from the chaff using commonality analyses.

    Science.gov (United States)

    Prunier, J G; Colyn, M; Legendre, X; Nimon, K F; Flamand, M C

    2015-01-01

    Direct gradient analyses in spatial genetics provide unique opportunities to describe the inherent complexity of genetic variation in wildlife species and are the object of many methodological developments. However, multicollinearity among explanatory variables is a systemic issue in multivariate regression analyses and is likely to cause serious difficulties in properly interpreting results of direct gradient analyses, with the risk of erroneous conclusions, misdirected research and inefficient or counterproductive conservation measures. Using simulated data sets along with linear and logistic regressions on distance matrices, we illustrate how commonality analysis (CA), a detailed variance-partitioning procedure that was recently introduced in the field of ecology, can be used to deal with nonindependence among spatial predictors. By decomposing model fit indices into unique and common (or shared) variance components, CA allows identifying the location and magnitude of multicollinearity, revealing spurious correlations and thus thoroughly improving the interpretation of multivariate regressions. Despite a few inherent limitations, especially in the case of resistance model optimization, this review highlights the great potential of CA to account for complex multicollinearity patterns in spatial genetics and identifies future applications and lines of research. We strongly urge spatial geneticists to systematically investigate commonalities when performing direct gradient analyses.

  17. Evaluation of Genetic Diversity of Sichuan Common Wheat Landraces in China by SSR Markers

    Institute of Scientific and Technical Information of China (English)

    LI Wei; BIAN Chun-mei; WEI Yu-ming; LIU An-jun; CHEN Guo-yue; PU Zhi-en; LIU Ya-xi; ZHENG You-liang

    2013-01-01

    Genetic diversity of 62 Sichuan wheat landraces accessions of China was investigated by agronomic traits and SSR markers. The landrace population showed the characters of higher tiller capability and more kernels/spike, especially tiller no./plant of six accessions was over 40 and kernels/spike of three accessions was more than 70. A total of 547 alleles in 124 polymorphic loci were detected with an average of 4.76 alleles per locus by 114 SSR markers. Parameters analysis indicated that the genetic diversity ranked as genome A>genome B>genome D, and the homoeologous groups ranked as 5>4>3>1>2>7>6 based on genetic richness (Ri). Furthermore, chromosomes 2A, 1B and 3D had more diversity than that of chromosomes 4A, 7A and 6B. The variation of SSR loci on chromosomes 1B, 2A, 2D, 3B, and 4B implied that, in the past, different selective pressures might have acted on different chromosome regions of these landraces. Our results suggested that Sichuan common wheat landraces is a useful genetic resource for genetic research and wheat improvement.

  18. Discriminatory power of common genetic variants in personalized breast cancer diagnosis

    Science.gov (United States)

    Wu, Yirong; Abbey, Craig K.; Liu, Jie; Ong, Irene; Peissig, Peggy; Onitilo, Adedayo A.; Fan, Jun; Yuan, Ming; Burnside, Elizabeth S.

    2016-03-01

    Technology advances in genome-wide association studies (GWAS) has engendered optimism that we have entered a new age of precision medicine, in which the risk of breast cancer can be predicted on the basis of a person's genetic variants. The goal of this study is to evaluate the discriminatory power of common genetic variants in breast cancer risk estimation. We conducted a retrospective case-control study drawing from an existing personalized medicine data repository. We collected variables that predict breast cancer risk: 153 high-frequency/low-penetrance genetic variants, reflecting the state-of-the-art GWAS on breast cancer, mammography descriptors and BI-RADS assessment categories in the Breast Imaging Reporting and Data System (BI-RADS) lexicon. We trained and tested naïve Bayes models by using these predictive variables. We generated ROC curves and used the area under the ROC curve (AUC) to quantify predictive performance. We found that genetic variants achieved comparable predictive performance to BI-RADS assessment categories in terms of AUC (0.650 vs. 0.659, p-value = 0.742), but significantly lower predictive performance than the combination of BI-RADS assessment categories and mammography descriptors (0.650 vs. 0.751, p-value < 0.001). A better understanding of relative predictive capability of genetic variants and mammography data may benefit clinicians and patients to make appropriate decisions about breast cancer screening, prevention, and treatment in the era of precision medicine.

  19. Genetic variability of the common Snook Centropomus undecimalis (Perciformes: Centropomidae) in connected marine and riverine environments.

    Science.gov (United States)

    Hernández-Vidal, Ulises; Lesher-Gordillo, Julia; Contreras-Sánchez, Wilfrido M; Chiappa-Carrara, Xavier

    2014-06-01

    The Common Snook, Centropomus undecimalis, inhabits riverine and marine areas of Southern Gulf of Mexico, where it is subject to intense use and exploitation. It has been reported that the genetic identification of fish stocks constitutes a valuable tool for wild population management; nevertheless, there is no available information on the genetic identification on fish stocks of this species in the region. The aim of this study was to determine the genetic relationship between C. undecimalis captured in marine and freshwater environments of the Gulf of Mexico and the San Pedro River. For this, muscle tissue samples of 79 specimens were obtained from areas located more than 300km apart. The genotype of each individual was determined using seven microsatellite primer pairs. Five primers amplified efficiently presenting between six and 28 alleles per locus. High levels of heterozygosis were observed in samples from both environments. Deviation from HWE due to an excess of heterozygotes was observed. The values of genetic difference indicate an absence of population structure (F(ST) = 0.0075 and R(ST) = (0.016, p = 0.051) and similarity in the allele frequencies, defined by Nei's index (0.805). Data showed the existence of a high gene flow due to the number of migrants (Nm = 18.7). Our results suggest that individuals living in these environments belong to the same genetic population. We suggest the development of management and protection plans for this fish species population in the wild.

  20. Genetic influences on chronic obstructive pulmonary disease - a twin study

    DEFF Research Database (Denmark)

    Sylvan Ingebrigtsen, Truls; Thomsen, Simon Francis; Vestbo, Jørgen

    2010-01-01

    Genes that contribute to the risk of developing Chronic Obstructive Pulmonary Disease (COPD) have been identified, but an attempt to accurately quantify the total genetic contribution to COPD has to our knowledge never been conducted.......Genes that contribute to the risk of developing Chronic Obstructive Pulmonary Disease (COPD) have been identified, but an attempt to accurately quantify the total genetic contribution to COPD has to our knowledge never been conducted....

  1. Genetic influences on Chronic Obstructive Pulmonary Disease - a twin study

    DEFF Research Database (Denmark)

    Ingebrigtsen, Truls; Thomsen, Simon F; Vestbo, Jørgen

    2010-01-01

    Genes that contribute to the risk of developing Chronic Obstructive Pulmonary Disease (COPD) have been identified, but an attempt to accurately quantify the total genetic contribution to COPD has to our knowledge never been conducted.......Genes that contribute to the risk of developing Chronic Obstructive Pulmonary Disease (COPD) have been identified, but an attempt to accurately quantify the total genetic contribution to COPD has to our knowledge never been conducted....

  2. Views of Discrimination among Individuals Confronting Genetic Disease

    OpenAIRE

    Klitzman, Robert

    2010-01-01

    Though the US passed the Genetic Information Non-Discrimination Act, many questions remain of how individuals confronting genetic disease view and experience possible discrimination. We interviewed, for 2 hours each, 64 individuals who had, or were at risk for, Huntington’s Disease, breast cancer, or Alpha-1 antitrypsin deficiency. Discrimination can be implicit, indirect and subtle, rather than explicit, direct and overt; and be hard to prove. Patients may be treated “differently” and unfair...

  3. Currently Clinical Views on Genetics of Wilson′s Disease

    OpenAIRE

    Chen Chen; Bo Shen; Jia-Jia Xiao; Rong Wu; Sarah Jane Duff Canning; Xiao-Ping Wang

    2015-01-01

    Objective: The objective of this study was to review the research on clinical genetics of Wilson′s disease (WD). Data Sources: We searched documents from PubMed and Wanfang databases both in English and Chinese up to 2014 using the keywords WD in combination with genetic, ATP7B gene, gene mutation, genotype, phenotype. Study Selection: Publications about the ATP7B gene and protein function associated with clinical features were selected. Results: Wilson′s disease, also named hepat...

  4. A dense genetic linkage map for common carp and its integration with a BAC-based physical map.

    Directory of Open Access Journals (Sweden)

    Lan Zhao

    Full Text Available BACKGROUND: Common carp (Cyprinus carpio is one of the most important aquaculture species with an annual global production of 3.4 million metric tons. It is also an important ornamental species as well as an important model species for aquaculture research. To improve the economically important traits of this fish, a number of genomic resources and genetic tools have been developed, including several genetic maps and a bacterial artificial chromosome (BAC-based physical map. However, integrated genetic and physical maps are not available to study quantitative trait loci (QTL and assist with fine mapping, positional cloning and whole genome sequencing and assembly. The objective of this study was to integrate the currently available BAC-based physical and genetic maps. RESULTS: The genetic map was updated with 592 novel markers, including 312 BAC-anchored microsatellites and 130 SNP markers, and contained 1,209 genetic markers on 50 linkage groups, spanning 3,565.9 cM in the common carp genome. An integrated genetic and physical map of the common carp genome was then constructed, which was composed of 463 physical map contigs and 88 single BACs. Combined lengths of the contigs and single BACs covered a physical length of 498.75 Mb, or around 30% of the common carp genome. Comparative analysis between common carp and zebrafish genomes was performed based on the integrated map, providing more insights into the common carp specific whole genome duplication and segmental rearrangements in the genome. CONCLUSION: We integrated a BAC-based physical map to a genetic linkage map of common carp by anchoring BAC-associated genetic markers. The density of the genetic linkage map was significantly increased. The integrated map provides a tool for both genetic and genomic studies of common carp, which will help us to understand the genomic architecture of common carp and facilitate fine mapping and positional cloning of economically important traits for

  5. Advances in the genetically-complex autoinflammatory diseases

    Science.gov (United States)

    Ombrello, Michael J.

    2015-01-01

    Monogenic diseases usually demonstrate Mendelian inheritance and are caused by highly penetrant genetic variants of a single gene. In contrast, genetically-complex diseases arise from a combination of multiple genetic and environmental factors. The concept of autoinflammation originally emerged from the identification of individual, activating lesions of the innate immune system as the molecular basis of the hereditary periodic fever syndromes. In addition to these rare, monogenic forms of autoinflammation, genetically-complex autoinflammatory diseases like the periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome, chronic recurrent multifocal osteomyelitis (CRMO), Behçet’s disease, and systemic arthritis also fulfill the definition of autoinflammatory diseases - namely the development of apparently unprovoked episodes of inflammation without identifiable exogenous triggers and in the absence of autoimmunity. Interestingly, investigations of these genetically-complex autoinflammatory diseases have implicated both innate and adaptive immune abnormalities, blurring the line between autoinflammation and autoimmunity. This reinforces the paradigm of concerted innate and adaptive immune dysfunction leading to genetically-complex autoinflammatory phenotypes. PMID:26077134

  6. Common Membrane Trafficking Defects of Disease Associated Dynamin 2 Mutations

    OpenAIRE

    Liu, Ya-Wen; Lukiyanchuk, Vasyl; Schmid, Sandra L.

    2011-01-01

    Dynamin (Dyn) is a multidomain and multifunctional GTPase best known for its essential role in clathrin-mediated endocytosis (CME). Dyn2 mutations have been linked to two human diseases, Centronuclear Myopathy (CNM) and Charcot-Marie-Tooth (CMT) disease. Paradoxically, although Dyn2 is ubiquitously expressed and essential for embryonic development, the disease-associated Dyn2 mutants are autosomal dominant, but result in slowly progressing and tissue-specific diseases. Thus, although the cell...

  7. [The application of genetic risk score in genetic studies of complex human diseases].

    Science.gov (United States)

    Dayan, Niu; Weili, Yan

    2015-12-01

    Complex diseases such as cardiovascular disease, type 2 diabetes, essential hypertension, asthma, obesity and cancer have spread across the globe and become the predominant cause of death. There are growing concerns over the role of genetic susceptibility in pathogenesis of complex diseases. However, the related susceptibility genes and sequence variations are still unknown. To elucidate the genetic basis of complex diseases, researchers have identified a large number of genetic variants associated with complex diseases through genome-wide association studies (GWAS) and candidate gene studies recently. The identification of these causal and/or associated variants promotes the development of approaches for complex diseases prediction and prevention. Genetic risk score (GRS), an emerging method for exploring correlation between single nucleotide polymorphisms (SNPs) and clinical phenotypes of complex diseases, integrates weak effects of multiple SNPs and dramatically enhances predictability of complex diseases by gene polymorphisms. This method has been applied successfully in genetic studies of many complex diseases. Here we focus on the introduction of the computational methods and evaluation criteria of GRS, enumerate a series of achievements through GRS application, discuss some limitations during application, and finally prospect the future of GRS.

  8. Clinical subtypes and genetic heterogeneity: of lumping and splitting in Parkinson disease.

    Science.gov (United States)

    von Coelln, Rainer; Shulman, Lisa M

    2016-12-01

    Recent studies on clinical, genetic and pathological heterogeneity of Parkinson disease have renewed the old debate whether we should think of Parkinson disease as one disease with variations, or as a group of independent diseases that happen to present with similar phenotypes. Here, we provide an overview of where the debate is coming from, and how recent findings in clinical subtyping, genetics and clinico-pathological correlation have shaped this controversy over the last few years. New and innovative clinical diagnostic criteria for Parkinson disease have been proposed and await validation. Studies using functional imaging or wearable biosensors, as well as biomarker studies, provide new support for the validity of the traditional clinical subtypes of Parkinson disease (tremor-dominant versus akinetic-rigid or postural instability/gait difficulty). A recent cluster analysis (as unbiased data-driven approach to subtyping) included a wide spectrum of nonmotor variables, and showed correlation of the proposed subtypes with disease progression in a longitudinal analysis. New genetic factors contributing to Parkinson disease susceptibility continue to be identified, including rare mutations causing monogenetic disease, common variants with small effect size and risk factors (like mutations in the gene for glucocerebrosidase) that fall in between the two other categories. Recent studies show some limited correlation between genetic factors and clinical heterogeneity. Despite some variations in patterns of pathology, Lewy bodies are still the hallmark of Parkinson disease, including the vast majority of genetic subgroups. Evidence of clinical, genetic and pathological heterogeneity of Parkinson disease continues to emerge, but clearly defined subtypes that hold up in more than one of these domains remain elusive. For research to identify such subtypes, splitting is likely the way forward; until then, for clinical practice, lumping remains the more pragmatic approach.

  9. The role of genetics in fisheries management under the E.U. common fisheries policy.

    Science.gov (United States)

    Casey, J; Jardim, E; Martinsohn, J Th

    2016-12-01

    Exploitation of fish and shellfish stocks by the European Union fishing fleet is managed under the Common Fisheries Policy (CFP), which aims to ensure that fishing and aquaculture are environmentally, economically and socially sustainable and that they provide a source of healthy food for E.U. citizens. A notable feature of the CFP is its legally enshrined requirement for sound scientific advice to underpin its objectives. The CFP was first conceived in 1970 when it formed part of the Common Agricultural Policy. Its formal inception as a stand-alone regulation occurred in 1983 and since that time, the CFP has undergone reforms in 1992, 2002 and 2013, each time bringing additional challenges to the scientific advisory process as the scope of the advice increased in response to changing objectives arising from E.U. regulations and commitments to international agreements. This paper reviews the influence that genetics has had on fish stock assessments and the provision of management advice for European fisheries under successive reforms of the CFP. The developments in genetics since the inception of the CFP have given rise to a diverse and versatile set of genetic techniques that have the potential to provide significant added value to fisheries assessments and the scientific advisory process. While in some cases, notably Pacific salmon Oncorhynchus spp., genetics appear to be very well integrated into existing management schemes, it seems that for marine fishes, discussions on the use of genetics and genomics for fisheries management are often driven by the remarkable technological progress in this field, rather than imminent needs emerging from policy frameworks. An example is the recent suggestion to use environmental (e)DNA for monitoring purposes. While there is no denying that state-of-the-art genetic and genomic approaches can and will be of value to address a number of issues relevant for the management and conservation of marine renewable natural resources, a

  10. Pathway analysis of GWAS provides new insights into genetic susceptibility to 3 inflammatory diseases.

    Directory of Open Access Journals (Sweden)

    Hariklia Eleftherohorinou

    Full Text Available Although the introduction of genome-wide association studies (GWAS have greatly increased the number of genes associated with common diseases, only a small proportion of the predicted genetic contribution has so far been elucidated. Studying the cumulative variation of polymorphisms in multiple genes acting in functional pathways may provide a complementary approach to the more common single SNP association approach in understanding genetic determinants of common disease. We developed a novel pathway-based method to assess the combined contribution of multiple genetic variants acting within canonical biological pathways and applied it to data from 14,000 UK individuals with 7 common diseases. We tested inflammatory pathways for association with Crohn's disease (CD, rheumatoid arthritis (RA and type 1 diabetes (T1D with 4 non-inflammatory diseases as controls. Using a variable selection algorithm, we identified variants responsible for the pathway association and evaluated their use for disease prediction using a 10 fold cross-validation framework in order to calculate out-of-sample area under the Receiver Operating Curve (AUC. The generalisability of these predictive models was tested on an independent birth cohort from Northern Finland. Multiple canonical inflammatory pathways showed highly significant associations (p 10(-3-10(-20 with CD, T1D and RA. Variable selection identified on average a set of 205 SNPs (149 genes for T1D, 350 SNPs (189 genes for RA and 493 SNPs (277 genes for CD. The pattern of polymorphisms at these SNPS were found to be highly predictive of T1D (91% AUC and RA (85% AUC, and weakly predictive of CD (60% AUC. The predictive ability of the T1D model (without any parameter refitting had good predictive ability (79% AUC in the Finnish cohort. Our analysis suggests that genetic contribution to common inflammatory diseases operates through multiple genes interacting in functional pathways.

  11. Cumulative impact of common genetic variants and other risk factors on colorectal cancer risk in 42 103 individuals

    NARCIS (Netherlands)

    Dunlop, Malcolm G.; Tenesa, Albert; Farrington, Susan M.; Ballereau, Stephane; Brewster, David H.; Koessler, Thibaud; Pharoah, Paul; Schafmayer, Clemens; Hampe, Jochen; Voelzke, Henry; Chang-Claude, Jenny; Hoffmeister, Michael; Brenner, Hermann; von Holst, Susanna; Picelli, Simone; Lindblom, Annika; Jenkins, Mark A.; Hopper, John L.; Casey, Graham; Duggan, David; Newcomb, Polly A.; Abuli, Anna; Bessa, Xavier; Ruiz-Ponte, Clara; Castellvi-Bel, Sergi; Niittymaeki, Iina; Tuupanen, Sari; Karhu, Auli; Aaltonen, Lauri; Zanke, Brent; Hudson, Tom; Gallinger, Steven; Barclay, Ella; Martin, Lynn; Gorman, Maggie; Carvajal-Carmona, Luis; Walther, Axel; Kerr, David; Lubbe, Steven; Broderick, Peter; Chandler, Ian; Pittman, Alan; Penegar, Steven; Campbell, Harry; Tomlinson, Ian; Houlston, Richard S.

    2013-01-01

    Objective Colorectal cancer (CRC) has a substantial heritable component. Common genetic variation has been shown to contribute to CRC risk. A study was conducted in a large multi-population study to assess the feasibility of CRC risk prediction using common genetic variant data combined with other r

  12. The role of the inherited disorders of hemoglobin, the first "molecular diseases," in the future of human genetics.

    Science.gov (United States)

    Weatherall, David J

    2013-01-01

    Although the inherited hemoglobin disorders were the first genetic diseases to be explored at the molecular level, they still have important messages for the future of medical genetics. In particular, they can offer a better understanding of the evolutionary and population biology of genetic disease, the mechanisms that underlie the phenotypic diversity of monogenic disease, and how, by developing appropriate partnerships, richer countries can help low-income countries to evolve programs for the control and management of these diseases where, in many cases, they are particularly common.

  13. Optimal Trend Tests for Genetic Association Studies of Heterogeneous Diseases.

    Science.gov (United States)

    Lee, Wen-Chung

    2016-06-09

    The Cochran-Armitage trend test is a standard procedure in genetic association studies. It is a directed test with high power to detect genetic effects that follow the gene-dosage model. In this paper, the author proposes optimal trend tests for genetic association studies of heterogeneous diseases. Monte-Carlo simulations show that the power gain of the optimal trend tests over the conventional Cochran-Armitage trend test is striking when the genetic effects are heterogeneous. The easy-to-use R 3.1.2 software (R Foundation for Statistical Computing, Vienna, Austria) code is provided. The optimal trend tests are recommended for routine use.

  14. GWAS signals across the HLA regions: revealing a clue for common etiology underlying infectious tumors and other immunity diseases

    Institute of Scientific and Technical Information of China (English)

    Yin Yao Shugart; Ying Wang; Wei-Hua Jia; Yi-Xin Zeng

    2011-01-01

    Increasing evidence suggests that multiple genes in the human leukocyte antigen (HLA) regions play an important role in development of cancers and immunity disorders. However, the biological mechanisms of the HLA associations are not well understood. We recently conducted a survey of all genome-wide association studies (GWAS) with significant findings in the HLA regions and concluded that diseases such as cancer and immune disorders are more likely to be associated with genetic variants located in the HLA regions than other diseases. This finding is suggestive for testing a hypothesis of a common etiology of infectious tumors and other immunity diseases.

  15. Capitalizing on the Autophagic Response for Treatment of Liver Disease Caused by Alpha-1-Antitrypsin Deficiency and Other Genetic Diseases

    Directory of Open Access Journals (Sweden)

    Andrew S. Chu

    2014-01-01

    Full Text Available Alpha-1-antitrypsin deficiency (ATD is one of the most common genetic causes of liver disease and is a prototype of liver diseases caused by the pathologic accumulation of aggregated mutant alpha-1-antitrypsin Z (ATZ within liver cells. In the case of ATD-associated liver disease, the resulting “gain-of-function” toxicity can lead to serious clinical manifestations, including cirrhosis and hepatocellular carcinoma. Currently, the only definitive therapy for ATD-associated liver disease is liver transplantation, but recent efforts have demonstrated the exciting potential for novel therapies that target disposal of the mutant protein aggregates by harnessing a cellular homeostasis mechanism called autophagy. In this review, we will summarize research advances on autophagy and genetic liver diseases. We will discuss autophagy enhancer strategies for liver disease due to ATD and another genetic liver disease, inherited hypofibrinogenemia, caused by the proteotoxic effects of a misfolded protein. On the basis of recent evidence that autophagy plays a role in cellular lipid degradation, we also speculate about autophagy enhancer strategies for treatment of hepatic lipid storage diseases such as cholesterol ester storage disease.

  16. An atlas of genetic correlations across human diseases and traits

    DEFF Research Database (Denmark)

    Bulik-Sullivan, Brendan; Finucane, Hilary K; Anttila, Verneri;

    2015-01-01

    Identifying genetic correlations between complex traits and diseases can provide useful etiological insights and help prioritize likely causal relationships. The major challenges preventing estimation of genetic correlation from genome-wide association study (GWAS) data with current methods...... are the lack of availability of individual-level genotype data and widespread sample overlap among meta-analyses. We circumvent these difficulties by introducing a technique-cross-trait LD Score regression-for estimating genetic correlation that requires only GWAS summary statistics and is not biased by sample...... overlap. We use this method to estimate 276 genetic correlations among 24 traits. The results include genetic correlations between anorexia nervosa and schizophrenia, anorexia and obesity, and educational attainment and several diseases. These results highlight the power of genome-wide analyses...

  17. Maternal-Zygotic Epistasis and the Evolution of Genetic Diseases

    Directory of Open Access Journals (Sweden)

    Nicholas K. Priest

    2010-01-01

    Full Text Available Many birth defects and genetic diseases are expressed in individuals that do not carry the disease causing alleles. Genetic diseases observed in offspring can be caused by gene expression in mothers and by interactions between gene expression in mothers and offspring. It is not clear whether the underlying pattern of gene expression (maternal versus offspring affects the incidence of genetic disease. Here we develop a 2-locus population genetic model with epistatic interactions between a maternal gene and a zygotic gene to address this question. We show that maternal effect genes that affect disease susceptibility in offspring persist longer and at higher frequencies in a population than offspring genes with the same effects. We find that specific forms of maternal-zygotic epistasis can maintain disease causing alleles at high frequencies over a range of plausible values. Our findings suggest that the strength and form of epistasis and the underlying pattern of gene expression may greatly influence the prevalence of human genetic diseases.

  18. Genetics of liver disease: From pathophysiology to clinical practice.

    Science.gov (United States)

    Karlsen, Tom H; Lammert, Frank; Thompson, Richard J

    2015-04-01

    Paralleling the first 30 years of the Journal of Hepatology we have witnessed huge advances in our understanding of liver disease and physiology. Genetic advances have played no small part in that. Initial studies in the 1970s and 1980s identified the strong major histocompatibility complex associations in autoimmune liver diseases. During the 1990 s, developments in genomic technologies drove the identification of genes responsible for Mendelian liver diseases. Over the last decade, genome-wide association studies have allowed for the dissection of the genetic susceptibility to complex liver disorders, in which also environmental co-factors play important roles. Findings have allowed the identification and elaboration of pathophysiological processes, have indicated the need for reclassification of liver diseases and have already pointed to new disease treatments. In the immediate future genetics will allow further stratification of liver diseases and contribute to personalized medicine. Challenges exist with regard to clinical implementation of rapidly developing technologies and interpretation of the wealth of accumulating genetic data. The historical perspective of genetics in liver diseases illustrates the opportunities for future research and clinical care of our patients.

  19. Genetic Characterization of Insect Vectors of Disease.

    Science.gov (United States)

    1982-09-01

    populations, and is highest of all in the a subspecies. Some variation, -I- 3 especially for HLis found in Asian and New World populations. Tables 4-7...East Africa. Evoluion 33, 287-295.. Tabaohnibk, W.J. & Powell, J.R. (1978). Genetic structure of the East African domestic populations of Aedes a

  20. Genetics of intracranial aneurysms and related diseases

    NARCIS (Netherlands)

    van 't Hof, F.N.G.

    2017-01-01

    Intracranial aneurysms (IA) are dilatations of the vessel walls of cerebral arteries. Some can rupture and result in a subarachnoid hemorrhage (SAH), a severe subtype of stroke. This thesis is set out to elucidate the pathophysiology of IA from a genetic perspective. The main conclusions are: 1.

  1. New insights into mechanisms of small vessel disease stroke from genetics.

    Science.gov (United States)

    Tan, Rhea; Traylor, Matthew; Rutten-Jacobs, Loes; Markus, Hugh

    2017-04-01

    Cerebral small vessel disease (SVD) is a common cause of lacunar strokes, vascular cognitive impairment (VCI) and vascular dementia. SVD is thought to result in reduced cerebral blood flow, impaired cerebral autoregulation and increased blood-brain barrier (BBB) permeability. However, the molecular mechanisms underlying SVD are incompletely understood. Recent studies in monogenic forms of SVD, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and 'sporadic' SVD have shed light on possible disease mechanisms in SVD. Proteomic and biochemical studies in post-mortem monogenic SVD patients, as well as in animal models of monogenic disease have suggested that disease pathways are shared between different types of monogenic disease, often involving the impairment of extracellular matrix (ECM) function. In addition, genetic studies in 'sporadic' SVD have also shown that the disease is highly heritable, particularly among young-onset stroke patients, and that common variants in monogenic disease genes may contribute to disease processes in some SVD subtypes. Genetic studies in sporadic lacunar stroke patients have also suggested distinct genetic mechanisms between subtypes of SVD. Genome-wide association studies (GWAS) have also shed light on other potential disease mechanisms that may be shared with other diseases involving the white matter, or with pathways implicated in monogenic disease. This review brings together recent data from studies in monogenic SVD and genetic studies in 'sporadic' SVD. It aims to show how these provide new insights into the pathogenesis of SVD, and highlights the possible convergence of disease mechanisms in monogenic and sporadic SVD. © 2017 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

  2. CTLA-4 as a genetic determinant in autoimmune Addison's disease.

    Science.gov (United States)

    Wolff, A S B; Mitchell, A L; Cordell, H J; Short, A; Skinningsrud, B; Ollier, W; Badenhoop, K; Meyer, G; Falorni, A; Kampe, O; Undlien, D; Pearce, S H S; Husebye, E S

    2015-09-01

    In common with several other autoimmune diseases, autoimmune Addison's disease (AAD) is thought to be caused by a combination of deleterious susceptibility polymorphisms in several genes, together with undefined environmental factors and stochastic events. To date, the strongest genomic association with AAD has been with alleles at the HLA locus, DR3-DQ2 and DR4. The contribution of other genetic variants has been inconsistent. We have studied the association of 16 single-nucleotide polymorphisms (SNPs) within the CD28-CTLA-4-ICOS genomic locus, in a cohort comprising 691 AAD patients of Norwegian and UK origin with matched controls. We have also performed a meta-analysis including 1002 patients from European countries. The G-allele of SNP rs231775 in CTLA-4 is associated with AAD in Norwegian patients (odds ratio (OR)=1.35 (confidence interval (CI) 1.10-1.66), P=0.004), but not in UK patients. The same allele is associated with AAD in the total European population (OR=1.37 (CI 1.13-1.66), P=0.002). A three-marker haplotype, comprising PROMOTER_1661, rs231726 and rs1896286 was found to be associated with AAD in the Norwegian cohort only (OR 2.43 (CI 1.68-3.51), P=0.00013). This study points to the CTLA-4 gene as a susceptibility locus for the development of AAD, and refines its mapping within the wider genomic locus.

  3. Neuroinformatic analyses of common and distinct genetic components associated with major neuropsychiatric disorders.

    Science.gov (United States)

    Lotan, Amit; Fenckova, Michaela; Bralten, Janita; Alttoa, Aet; Dixson, Luanna; Williams, Robert W; van der Voet, Monique

    2014-01-01

    Major neuropsychiatric disorders are highly heritable, with mounting evidence suggesting that these disorders share overlapping sets of molecular and cellular underpinnings. In the current article we systematically test the degree of genetic commonality across six major neuropsychiatric disorders-attention deficit hyperactivity disorder (ADHD), anxiety disorders (Anx), autistic spectrum disorders (ASD), bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ). We curated a well-vetted list of genes based on large-scale human genetic studies based on the NHGRI catalog of published genome-wide association studies (GWAS). A total of 180 genes were accepted into the analysis on the basis of low but liberal GWAS p-values (NT5C2, PPP1R11, SYNE1, TCF4, TENM4, TRIM26, and ZNRD1. Using a suite of neuroinformatic resources, we showed that many of the shared genes are implicated in the postsynaptic density (PSD), expressed in immune tissues and co-expressed in developing human brain. Using a translational cross-species approach, we detected two distinct genetic components that were both shared by each of the six disorders; the 1st component is involved in CNS development, neural projections and synaptic transmission, while the 2nd is implicated in various cytoplasmic organelles and cellular processes. Combined, these genetic components account for 20-30% of the genetic load. The remaining risk is conferred by distinct, disorder-specific variants. Our systematic comparative analysis of shared and unique genetic factors highlights key gene sets and molecular processes that may ultimately translate into improved diagnosis and treatment of these debilitating disorders.

  4. Assessing Genetic Structure in Common but Ecologically Distinct Carnivores: The Stone Marten and Red Fox.

    Directory of Open Access Journals (Sweden)

    Mafalda P Basto

    Full Text Available The identification of populations and spatial genetic patterns is important for ecological and conservation research, and spatially explicit individual-based methods have been recognised as powerful tools in this context. Mammalian carnivores are intrinsically vulnerable to habitat fragmentation but not much is known about the genetic consequences of fragmentation in common species. Stone martens (Martes foina and red foxes (Vulpes vulpes share a widespread Palearctic distribution and are considered habitat generalists, but in the Iberian Peninsula stone martens tend to occur in higher quality habitats. We compared their genetic structure in Portugal to see if they are consistent with their differences in ecological plasticity, and also to illustrate an approach to explicitly delineate the spatial boundaries of consistently identified genetic units. We analysed microsatellite data using spatial Bayesian clustering methods (implemented in the software BAPS, GENELAND and TESS, a progressive partitioning approach and a multivariate technique (Spatial Principal Components Analysis-sPCA. Three consensus Bayesian clusters were identified for the stone marten. No consensus was achieved for the red fox, but one cluster was the most probable clustering solution. Progressive partitioning and sPCA suggested additional clusters in the stone marten but they were not consistent among methods and were geographically incoherent. The contrasting results between the two species are consistent with the literature reporting stricter ecological requirements of the stone marten in the Iberian Peninsula. The observed genetic structure in the stone marten may have been influenced by landscape features, particularly rivers, and fragmentation. We suggest that an approach based on a consensus clustering solution of multiple different algorithms may provide an objective and effective means to delineate potential boundaries of inferred subpopulations. sPCA and progressive

  5. Atherosclerosis and Alzheimer - diseases with a common cause? Inflammation, oxysterols, vasculature

    Science.gov (United States)

    2014-01-01

    Background Aging is accompanied by increasing vulnerability to pathologies such as atherosclerosis (ATH) and Alzheimer disease (AD). Are these different pathologies, or different presentations with a similar underlying pathoetiology? Discussion Both ATH and AD involve inflammation, macrophage infiltration, and occlusion of the vasculature. Allelic variants in common genes including APOE predispose to both diseases. In both there is strong evidence of disease association with viral and bacterial pathogens including herpes simplex and Chlamydophila. Furthermore, ablation of components of the immune system (or of bone marrow-derived macrophages alone) in animal models restricts disease development in both cases, arguing that both are accentuated by inflammatory/immune pathways. We discuss that amyloid β, a distinguishing feature of AD, also plays a key role in ATH. Several drugs, at least in mouse models, are effective in preventing the development of both ATH and AD. Given similar age-dependence, genetic underpinnings, involvement of the vasculature, association with infection, Aβ involvement, the central role of macrophages, and drug overlap, we conclude that the two conditions reflect different manifestations of a common pathoetiology. Mechanism Infection and inflammation selectively induce the expression of cholesterol 25-hydroxylase (CH25H). Acutely, the production of ‘immunosterol’ 25-hydroxycholesterol (25OHC) defends against enveloped viruses. We present evidence that chronic macrophage CH25H upregulation leads to catalyzed esterification of sterols via 25OHC-driven allosteric activation of ACAT (acyl-CoA cholesterol acyltransferase/SOAT), intracellular accumulation of cholesteryl esters and lipid droplets, vascular occlusion, and overt disease. Summary We postulate that AD and ATH are both caused by chronic immunologic challenge that induces CH25H expression and protection against particular infectious agents, but at the expense of longer-term pathology

  6. Atherosclerosis and Alzheimer--diseases with a common cause? Inflammation, oxysterols, vasculature.

    Science.gov (United States)

    Lathe, Richard; Sapronova, Alexandra; Kotelevtsev, Yuri

    2014-03-21

    Aging is accompanied by increasing vulnerability to pathologies such as atherosclerosis (ATH) and Alzheimer disease (AD). Are these different pathologies, or different presentations with a similar underlying pathoetiology? Both ATH and AD involve inflammation, macrophage infiltration, and occlusion of the vasculature. Allelic variants in common genes including APOE predispose to both diseases. In both there is strong evidence of disease association with viral and bacterial pathogens including herpes simplex and Chlamydophila. Furthermore, ablation of components of the immune system (or of bone marrow-derived macrophages alone) in animal models restricts disease development in both cases, arguing that both are accentuated by inflammatory/immune pathways. We discuss that amyloid β, a distinguishing feature of AD, also plays a key role in ATH. Several drugs, at least in mouse models, are effective in preventing the development of both ATH and AD. Given similar age-dependence, genetic underpinnings, involvement of the vasculature, association with infection, Aβ involvement, the central role of macrophages, and drug overlap, we conclude that the two conditions reflect different manifestations of a common pathoetiology. Infection and inflammation selectively induce the expression of cholesterol 25-hydroxylase (CH25H). Acutely, the production of 'immunosterol' 25-hydroxycholesterol (25OHC) defends against enveloped viruses. We present evidence that chronic macrophage CH25H upregulation leads to catalyzed esterification of sterols via 25OHC-driven allosteric activation of ACAT (acyl-CoA cholesterol acyltransferase/SOAT), intracellular accumulation of cholesteryl esters and lipid droplets, vascular occlusion, and overt disease. We postulate that AD and ATH are both caused by chronic immunologic challenge that induces CH25H expression and protection against particular infectious agents, but at the expense of longer-term pathology.

  7. A database of annotated promoters of genes associated with common respiratory and related diseases

    KAUST Repository

    Chowdhary, Rajesh

    2012-07-01

    Many genes have been implicated in the pathogenesis of common respiratory and related diseases (RRDs), yet the underlying mechanisms are largely unknown. Differential gene expression patterns in diseased and healthy individuals suggest that RRDs affect or are affected by modified transcription regulation programs. It is thus crucial to characterize implicated genes in terms of transcriptional regulation. For this purpose, we conducted a promoter analysis of genes associated with 11 common RRDs including allergic rhinitis, asthma, bronchiectasis, bronchiolitis, bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, emphysema, eczema, psoriasis, and urticaria, many of which are thought to be genetically related. The objective of the present study was to obtain deeper insight into the transcriptional regulation of these disease-associated genes by annotating their promoter regions with transcription factors (TFs) and TF binding sites (TFBSs). We discovered many TFs that are significantly enriched in the target disease groups including associations that have been documented in the literature. We also identified a number of putative TFs/TFBSs that appear to be novel. The results of our analysis are provided in an online database that is freely accessible to researchers at http://www.respiratorygenomics.com. Promoter-associated TFBS information and related genomic features, such as histone modification sites, microsatellites, CpG islands, and SNPs, are graphically summarized in the database. Users can compare and contrast underlying mechanisms of specific RRDs relative to candidate genes, TFs, gene ontology terms, micro-RNAs, and biological pathways for the conduct of metaanalyses. This database represents a novel, useful resource for RRD researchers. Copyright © 2012 by the American Thoracic Society.

  8. Investigation of the Genetics of Hematologic Diseases

    Science.gov (United States)

    2017-03-01

    Bone Marrow Failure Syndromes; Erythrocyte Disorder; Leukocyte Disorder; Hemostasis; Blood Coagulation Disorder; Sickle Cell Disease; Dyskeratosis Congenita; Diamond-Blackfan Anemia; Congenital Thrombocytopenia; Severe Congenital Neutropenia; Fanconi Anemia

  9. Advanced Role of Neutrophils in Common Respiratory Diseases

    Directory of Open Access Journals (Sweden)

    Jinping Liu

    2017-01-01

    Full Text Available Respiratory diseases, always being a threat towards the health of people all over the world, are most tightly associated with immune system. Neutrophils serve as an important component of immune defense barrier linking innate and adaptive immunity. They participate in the clearance of exogenous pathogens and endogenous cell debris and play an essential role in the pathogenesis of many respiratory diseases. However, the pathological mechanism of neutrophils remains complex and obscure. The traditional roles of neutrophils in severe asthma, chronic obstructive pulmonary diseases (COPD, pneumonia, lung cancer, pulmonary fibrosis, bronchitis, and bronchiolitis had already been reviewed. With the development of scientific research, the involvement of neutrophils in respiratory diseases is being brought to light with emerging data on neutrophil subsets, trafficking, and cell death mechanism (e.g., NETosis, apoptosis in diseases. We reviewed all these recent studies here to provide you with the latest advances about the role of neutrophils in respiratory diseases.

  10. Role of Th17 cells in common liver diseases

    Directory of Open Access Journals (Sweden)

    WEI Linlin

    2013-06-01

    Full Text Available In recent years, it has been found that T helper type 17 (Th17 cells are a new subset of CD4+ Th cells. Th17 cells play an important role in the onset and development of many liver diseases and have become the research focus in immunology. This paper summarizes the studies on the relationship between Th17 cells and various liver diseases in order to provide a new idea for the study and treatment of liver diseases.

  11. Comparative transcriptome analysis reveals the genetic basis of skin color variation in common carp.

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    Yanliang Jiang

    Full Text Available The common carp is an important aquaculture species that is widely distributed across the world. During the long history of carp domestication, numerous carp strains with diverse skin colors have been established. Skin color is used as a visual criterion to determine the market value of carp. However, the genetic basis of common carp skin color has not been extensively studied.In this study, we performed Illumina sequencing on two common carp strains: the reddish Xingguo red carp and the brownish-black Yellow River carp. A total of 435,348,868 reads were generated, resulting in 198,781 assembled contigs that were used as reference sequences. Comparisons of skin transcriptome files revealed 2,012 unigenes with significantly different expression in the two common carp strains, including 874 genes that were up-regulated in Xingguo red carp and 1,138 genes that were up-regulated in Yellow River carp. The expression patterns of 20 randomly selected differentially expressed genes were validated using quantitative