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.)

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

Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study.

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Kasperaviciūte, Dalia; Catarino, Claudia B; Heinzen, Erin L; Depondt, Chantal; Cavalleri, Gianpiero L; Caboclo, Luis O; Tate, Sarah K; Jamnadas-Khoda, Jenny; Chinthapalli, Krishna; Clayton, Lisa M S; Shianna, Kevin V; Radtke, Rodney A; Mikati, Mohamad A; Gallentine, William B; Husain, Aatif M; Alhusaini, Saud; Leppert, David; Middleton, Lefkos T; Gibson, Rachel A; Johnson, Michael R; Matthews, Paul M; Hosford, David; Heuser, Kjell; Amos, Leslie; Ortega, Marcos; Zumsteg, Dominik; Wieser, Heinz-Gregor; Steinhoff, Bernhard J; Krämer, Günter; Hansen, Jörg; Dorn, Thomas; Kantanen, Anne-Mari; Gjerstad, Leif; Peuralinna, Terhi; Hernandez, Dena G; Eriksson, Kai J; Kälviäinen, Reetta K; Doherty, Colin P; Wood, Nicholas W; Pandolfo, Massimo; Duncan, John S; Sander, Josemir W; Delanty, Norman; Goldstein, David B; Sisodiya, Sanjay M

2010-07-01

Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio<1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studies.

Genetics Home Reference: autoimmune Addison disease

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... common in particular ethnic groups? Genetic Changes The cause of autoimmune Addison disease is complex and not completely understood. A combination ... is not caused by an autoimmune reaction. Other causes include infections that ... adrenal glands. Addison disease can also be one of several features of ...

Twenty-First Century Diseases: Commonly Rare and Rarely Common?

Science.gov (United States)

Daunert, Sylvia; Sittampalam, Gurusingham Sitta; Goldschmidt-Clermont, Pascal J

2017-09-20

Alzheimer's drugs are failing at a rate of 99.6%, and success rate for drugs designed to help patients with this form of dementia is 47 times less than for drugs designed to help patients with cancers ( www.scientificamerican.com/article/why-alzheimer-s-drugs-keep-failing/2014 ). How can it be so difficult to produce a valuable drug for Alzheimer's disease? Each human has a unique genetic and epigenetic makeup, thus endowing individuals with a highly unique complement of genes, polymorphisms, mutations, RNAs, proteins, lipids, and complex sugars, resulting in distinct genome, proteome, metabolome, and also microbiome identity. This editorial is taking into account the uniqueness of each individual and surrounding environment, and stresses the point that a more accurate definition of a "common" disorder could be simply the amalgamation of a myriad of "rare" diseases. These rare diseases are being grouped together because they share a rather constant complement of common features and, indeed, generally respond to empirically developed treatments, leading to a positive outcome consistently. We make the case that it is highly unlikely that such treatments, despite their statistical success measured with large cohorts using standardized clinical research, will be effective on all patients until we increase the depth and fidelity of our understanding of the individual "rare" diseases that are grouped together in the "buckets" of common illnesses. Antioxid. Redox Signal. 27, 511-516.

Studying the Genetics of Resistance to CyHV-3 Disease Using Introgression from Feral to Cultured Common Carp Strains

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Tadmor-Levi, Roni; Asoulin, Efrat; Hulata, Gideon; David, Lior

2017-01-01

Sustainability and further development of aquaculture production are constantly challenged by outbreaks of fish diseases, which are difficult to prevent or control. Developing fish strains that are genetically resistant to a disease is a cost-effective and a sustainable solution to address this challenge. To do so, heritable genetic variation in disease resistance should be identified and combined together with other desirable production traits. Aquaculture of common carp has suffered substantial losses from the infectious disease caused by the cyprinid herpes virus type 3 (CyHV-3) virus and the global spread of outbreaks indicates that many cultured strains are susceptible. In this research, CyHV-3 resistance from the feral strain “Amur Sassan” was successfully introgressed into two susceptible cultured strains up to the first backcross (BC1) generation. Variation in resistance of families from F1 and BC1 generations was significantly greater compared to that among families of any of the susceptible parental lines, a good starting point for a family selection program. Considerable additive genetic variation was found for CyHV-3 resistance. This phenotype was transferable between generations with contributions to resistance from both the resistant feral and the susceptible cultured strains. Reduced scale coverage (mirror phenotype) is desirable and common in cultured strains, but so far, cultured mirror carp strains were found to be susceptible. Here, using BC1 families ranging from susceptible to resistant, no differences in resistance levels between fully scaled and mirror full-sib groups were found, indicating that CyHV-3 resistance was successfully combined with the desirable mirror phenotype. In addition, the CyHV-3 viral load in tissues throughout the infection of susceptible and resistant fish was followed. Although resistant fish get infected, viral loads in tissues of these fish are significantly lesser than in those of susceptible fish, allowing them

Genetics Home Reference: Paget disease of bone

Science.gov (United States)

... is most common in people of western European heritage. Early-onset Paget disease of bone is much rarer. This form of the disorder has been reported in only a few families. Related Information What information about a genetic condition can statistics provide? Why are some genetic ...

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.

Integrating common and rare genetic variation in diverse human populations.

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Altshuler, David M; Gibbs, Richard A; Peltonen, Leena; Altshuler, David M; Gibbs, Richard A; Peltonen, Leena; Dermitzakis, Emmanouil; Schaffner, Stephen F; Yu, Fuli; Peltonen, Leena; Dermitzakis, Emmanouil; Bonnen, Penelope E; Altshuler, David M; Gibbs, Richard A; de Bakker, Paul I W; Deloukas, Panos; Gabriel, Stacey B; Gwilliam, Rhian; Hunt, Sarah; Inouye, Michael; Jia, Xiaoming; Palotie, Aarno; Parkin, Melissa; Whittaker, Pamela; Yu, Fuli; Chang, Kyle; Hawes, Alicia; Lewis, Lora R; Ren, Yanru; Wheeler, David; Gibbs, Richard A; Muzny, Donna Marie; Barnes, Chris; Darvishi, Katayoon; Hurles, Matthew; Korn, Joshua M; Kristiansson, Kati; Lee, Charles; McCarrol, Steven A; Nemesh, James; Dermitzakis, Emmanouil; Keinan, Alon; Montgomery, Stephen B; Pollack, Samuela; Price, Alkes L; Soranzo, Nicole; Bonnen, Penelope E; Gibbs, Richard A; Gonzaga-Jauregui, Claudia; Keinan, Alon; Price, Alkes L; Yu, Fuli; Anttila, Verneri; Brodeur, Wendy; Daly, Mark J; Leslie, Stephen; McVean, Gil; Moutsianas, Loukas; Nguyen, Huy; Schaffner, Stephen F; Zhang, Qingrun; Ghori, Mohammed J R; McGinnis, Ralph; McLaren, William; Pollack, Samuela; Price, Alkes L; Schaffner, Stephen F; Takeuchi, Fumihiko; Grossman, Sharon R; Shlyakhter, Ilya; Hostetter, Elizabeth B; Sabeti, Pardis C; Adebamowo, Clement A; Foster, Morris W; Gordon, Deborah R; Licinio, Julio; Manca, Maria Cristina; Marshall, Patricia A; Matsuda, Ichiro; Ngare, Duncan; Wang, Vivian Ota; Reddy, Deepa; Rotimi, Charles N; Royal, Charmaine D; Sharp, Richard R; Zeng, Changqing; Brooks, Lisa D; McEwen, Jean E

2010-09-02

Despite great progress in identifying genetic variants that influence human disease, most inherited risk remains unexplained. A more complete understanding requires genome-wide studies that fully examine less common alleles in populations with a wide range of ancestry. To inform the design and interpretation of such studies, we genotyped 1.6 million common single nucleotide polymorphisms (SNPs) in 1,184 reference individuals from 11 global populations, and sequenced ten 100-kilobase regions in 692 of these individuals. This integrated data set of common and rare alleles, called 'HapMap 3', includes both SNPs and copy number polymorphisms (CNPs). We characterized population-specific differences among low-frequency variants, measured the improvement in imputation accuracy afforded by the larger reference panel, especially in imputing SNPs with a minor allele frequency of disease, and serves as a step towards a high-resolution map of the landscape of human genetic variation.

The genetics of Alzheimer's disease.

Science.gov (United States)

Bertram, Lars; Tanzi, Rudolph E

2012-01-01

Genetic factors play a major role in determining a person's risk to develop Alzheimer's disease (AD). Rare mutations transmitted in a Mendelian fashion within affected families, for example, APP, PSEN1, and PSEN2, cause AD. In the absence of mutations in these genes, disease risk is largely determined by common polymorphisms that, in concert with each other and nongenetic risk factors, modestly impact risk for AD (e.g., the ε4-allele in APOE). Recent genome-wide screening approaches have revealed several additional AD susceptibility loci and more are likely to be discovered over the coming years. In this chapter, we review the current state of AD genetics research with a particular focus on loci that now can be considered established disease genes. In addition to reviewing the potential pathogenic relevance of these genes, we provide an outlook into the future of AD genetics research based on recent advances in high-throughput sequencing technologies. Copyright © 2012 Elsevier Inc. All rights reserved.

The Molecular Genetics of von Willebrand Disease

Directory of Open Access Journals (Sweden)

Ergül Berber

2012-12-01

Full Text Available Quantitative and/or qualitative deficiency of von Willebrand factor (vWF is associated with the most common inherited bleeding disease von Willebrand disease (vWD. vWD is a complex disease with clinical and genetic heterogeneity. Incomplete penetrance and variable expression due to genetic and environmental factors contribute to its complexity. vWD also has a complex molecular pathogenesis. Some vWF gene mutations are associated with the affected vWF biosynthesis and multimerization, whereas others are associated with increased clearance and functional impairment. Moreover, in addition to a particular mutation, type O blood may result in the more severe phenotype. The present review aimed to provide a summary of the current literature on the molecular genetics of vWD.

The molecular genetics of von Willebrand disease.

Science.gov (United States)

Berber, Ergül

2012-12-01

Quantitative and/or qualitative deficiency of von Willebrand factor (vWF) is associated with the most common inherited bleeding disease von Willebrand disease (vWD). vWD is a complex disease with clinical and genetic heterogeneity. Incomplete penetrance and variable expression due to genetic and environmental factors contribute to its complexity. vWD also has a complex molecular pathogenesis. Some vWF gene mutations are associated with the affected vWF biosynthesis and multimerization, whereas others are associated with increased clearance and functional impairment. Moreover, in addition to a particular mutation, type O blood may result in the more severe phenotype. The present review aimed to provide a summary of the current literature on the molecular genetics of vWD. None declared.

Genetics of Congenital Heart Disease: Past and Present.

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Muntean, Iolanda; Togănel, Rodica; Benedek, Theodora

2017-04-01

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.

Population genetic structure of a common host predicts the spread of white-nose syndrome, an emerging infectious disease in bats.

Science.gov (United States)

Wilder, Aryn P; Kunz, Thomas H; Sorenson, Michael D

2015-11-01

Landscape complexity influences patterns of animal dispersal, which in turn may affect both gene flow and the spread of pathogens. White-nose syndrome (WNS) is an introduced fungal disease that has spread rapidly throughout eastern North America, causing massive mortality in bat populations. We tested for a relationship between the population genetic structure of the most common host, the little brown myotis (Myotis lucifugus), and the geographic spread of WNS to date by evaluating logistic regression models of WNS risk among hibernating colonies in eastern North America. We hypothesized that risk of WNS to susceptible host colonies should increase with both geographic proximity and genetic similarity, reflecting historical connectivity, to infected colonies. Consistent with this hypothesis, inclusion of genetic distance between infected and susceptible colonies significantly improved models of disease spread, capturing heterogeneity in the spatial expansion of WNS despite low levels of genetic differentiation among eastern populations. Expanding our genetic analysis to the continental range of little brown myotis reveals strongly contrasting patterns of population structure between eastern and western North America. Genetic structure increases markedly moving westward into the northern Great Plains, beyond the current distribution of WNS. In western North America, genetic differentiation of geographically proximate populations often exceeds levels observed across the entire eastern region, suggesting infrequent and/or locally restricted dispersal, and thus relatively limited opportunities for pathogen introduction in western North America. Taken together, our analyses suggest a possibly slower future rate of spread of the WNS pathogen, at least as mediated by little brown myotis. © 2015 John Wiley & Sons Ltd.

Genetics and Rheumatic Disease

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... 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 ...

Additional mechanisms conferring genetic susceptibility to Alzheimer's disease

Directory of Open Access Journals (Sweden)

Miguel eCalero

2015-04-01

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

Genetic divergence of common bean cultivars.

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Veloso, J S; Silva, W; Pinheiro, L R; Dos Santos, J B; Fonseca, N S; Euzebio, M P

2015-09-22

The aim of this study was to evaluate genetic divergence in the 'Carioca' (beige with brown stripes) common bean cultivar used by different institutions and in 16 other common bean cultivars used in the Rede Cooperativa de Pesquisa de Feijão (Cooperative Network of Common Bean Research), by using simple sequence repeats associated with agronomic traits that are highly distributed in the common bean genome. We evaluated 22 polymorphic loci using bulks containing DNA from 30 plants. There was genetic divergence among the Carioca cultivar provided by the institutions. Nevertheless, there was lower divergence among them than among the other cultivars. The cultivar used by Instituto Agronômico do Paraná was the most divergent in relation to the Carioca samples. The least divergence was observed among the samples used by Universidade Federal de Lavras and by Embrapa Arroz e Feijão. Of all the cultivars, 'CNFP 10104' and 'BRSMG Realce' showed the greatest dissimilarity. The cultivars were separated in two groups of greatest similarity using the Structure software. Genetic variation among cultivars was greater than the variation within or between the groups formed. This fact, together with the high estimate of heterozygosity observed and the genetic divergence of the samples of the Carioca cultivar in relation to the original provided by Instituto Agronômico de Campinas, indicates a mixture of cultivars. The high divergence among cultivars provides potential for the utilization of this genetic variability in plant breeding.

Human Genetic Variation and Parkinson’s Disease

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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.

Genetic influences in caries and periodontal diseases.

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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

[Leprosy, a pillar of human genetics of infectious diseases].

Science.gov (United States)

Gaschignard, J; Scurr, E; Alcaïs, A

2013-06-01

Despite a natural reservoir of Mycobacterium leprae limited to humans and free availability of an effective antibiotic treatment, more than 200,000 people develop leprosy each year. This disease remains a major cause of disability and social stigma worldwide. The cause of this constant incidence is currently unknown and indicates that important aspects of the complex relationship between the pathogen and its human host remain to be discovered. An important contribution of host genetics to susceptibility to leprosy has long been suggested to account for the considerable variability between individuals sustainably exposed to M. leprae. Given the inability to cultivate M. leprae in vitro and in the absence of relevant animal model, genetic epidemiology is the main strategy used to identify the genes and, consequently, the immunological pathways involved in protective immunity to M. leprae. Recent genome-wide studies have identified new pathophysiological pathways which importance is only beginning to be understood. In addition, the prism of human genetics placed leprosy at the crossroads of other common diseases such as Crohn's disease, asthma or myocardial infarction. Therefore, novel lights on the pathogenesis of many common diseases could eventually emerge from the detailed understanding of a disease of the shadows. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

The genetics of Alzheimer disease.

Science.gov (United States)

Tanzi, Rudolph E

2012-10-01

Family history is the second strongest risk factor for Alzheimer disease (AD) following advanced age. Twin and family studies indicate that genetic factors are estimated to play a role in at least 80% of AD cases. The inheritance of AD exhibits a dichotomous pattern. On one hand, rare mutations in APP, PSEN1, and PSEN2 virtually guarantee early-onset (<60 years) familial AD, which represents ∼5% of AD. On the other hand, common gene polymorphisms, such as the ε4 and ε2 variants of the APOE gene, can influence susceptibility for ∼50% of the common late-onset AD. These four genes account for 30%-50% of the inheritability of AD. Genome-wide association studies have recently led to the identification of 11 additional AD candidate genes. This paper reviews the past, present, and future attempts to elucidate the complex and heterogeneous genetic underpinnings of AD.

Common variants in mendelian kidney disease genes and their association with renal function

NARCIS (Netherlands)

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

2013-01-01

textabstractMany common genetic variants identified by genome-wide association studies for complex traitsmap 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

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...... to the number of patients suffering from the disease. This hypothesis is based on a study of bipolar disorder....

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...... identified. Furthermore, a total of 202 independent signals in 109 loci have achieved a false discovery rate (qgenetic risk scores that can improve risk prediction beyond conventional 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...

Alkaptonuria: An example of a "fundamental disease"--A rare disease with important lessons for more common disorders.

Science.gov (United States)

Gallagher, James A; Dillon, Jane P; Sireau, Nicolas; Timmis, Oliver; Ranganath, Lakshminarayan R

2016-04-01

"Fundamental diseases" is a term introduced by the charity Findacure to describe rare genetic disorders that are gateways to understanding common conditions and human physiology. The concept that rare diseases have important lessons for biomedical science has been recognised by some of the great figures in the history of medical research, including Harvey, Bateson and Garrod. Here we describe some of the recently discovered lessons from the study of the iconic genetic disease alkaptonuria (AKU), which have shed new light on understanding the pathogenesis of osteoarthritis. In AKU, ochronotic pigment is deposited in cartilage when collagen fibrils become susceptible to attack by homogentisic acid (HGA). When HGA binds to collagen, cartilage matrix becomes stiffened, resulting in the aberrant transmission of loading to underlying subchondral bone. Aberrant loading leads to the formation of pathophysiological structures including trabecular excrescences and high density mineralised protrusions (HDMPs). These structures initially identified in AKU have subsequently been found in more common osteoarthritis and appear to play a role in joint destruction in both diseases. Copyright © 2016 Elsevier Ltd. All rights reserved.

Human genetics of infectious diseases: a unified theory

OpenAIRE

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 predispos...

Public attitudes towards preventive genomics and personal interest in genetic testing to prevent disease: a survey study

NARCIS (Netherlands)

Vermeulen, E.; Henneman, L.; van El, C.G.; Cornel, M.C.

2014-01-01

Background: Genetic testing and family history assessment can be used as an aid in the prevention of common chronic diseases. The aim of this study was to determine public attitudes and interests towards offering genetic testing and family history-based risk assessment for common chronic disease

Genetics of common forms of heart failure: challenges and potential solutions.

Science.gov (United States)

Rau, Christoph D; Lusis, Aldons J; Wang, Yibin

2015-05-01

In contrast to many other human diseases, the use of genome-wide association studies (GWAS) to identify genes for heart failure (HF) has had limited success. We will discuss the underlying challenges as well as potential new approaches to understanding the genetics of common forms of HF. Recent research using intermediate phenotypes, more detailed and quantitative stratification of HF symptoms, founder populations and novel animal models has begun to allow researchers to make headway toward explaining the genetics underlying HF using GWAS techniques. By expanding analyses of HF to improved clinical traits, additional HF classifications and innovative model systems, the intractability of human HF GWAS should be ameliorated significantly.

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

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

2015-04-09

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.

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

KAUST Repository

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

2015-01-01

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

Common variants in Mendelian kidney disease genes and their association with renal function.

Science.gov (United States)

Parsa, Afshin; 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, Asa; 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

2013-12-01

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.

Genetic Parameters of Common Wheat in Nepal

OpenAIRE

Bal Krishna Joshi; Dhruba Bahadur Thapa; Madan Raj Bhatta

2015-01-01

Knowledge on variation within traits and their genetics are prerequisites in crop improvement program. Thus, in present paper we aimed to estimate genetic and environmental indices of common wheat genotypes. For the purpose, eight quantitative traits were measured from 30 wheat genotypes, which were in randomized complete block design with 3 replicates. Components of variance and covariance were estimated along with heritability, genetic gain, realized heritability, coheritability and correla...

Pathway analysis of GWAS provides new insights into genetic susceptibility to 3 inflammatory diseases.

Directory of Open Access Journals (Sweden)

Hariklia Eleftherohorinou

2009-11-01

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.

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.

Delivery of genomic medicine for common chronic adult diseases: a systematic review.

Science.gov (United States)

Scheuner, Maren T; Sieverding, Pauline; Shekelle, Paul G

2008-03-19

The greatest public health benefit of advances in understanding the human genome may be realized for common chronic diseases such as cardiovascular disease, diabetes mellitus, and cancer. Attempts to integrate such knowledge into clinical practice are still in the early stages, and as a result, many questions surround the current state of this translation. To synthesize current information on genetic health services for common adult-onset conditions by examining studies that have addressed the outcomes, consumer information needs, delivery, and challenges in integrating these services. MEDLINE articles published between January 2000 and February 2008. Original research articles and systematic reviews dealing with common chronic adult-onset conditions were reviewed. A total of 3371 citations were reviewed, 170 articles retrieved, and 68 articles included in the analysis. Data were independently extracted by one reviewer and checked by another with disagreement resolved by consensus. Variables assessed included study design and 4 key areas: outcomes of genomic medicine, consumer information needs, delivery of genomic medicine, and challenges and barriers to integration of genomic medicine. Sixty-eight articles contributed data to the synthesis: 5 systematic reviews, 8 experimental studies, 35 surveys, 7 pre/post studies, 3 observational studies, and 10 qualitative reports. Three systematic reviews, 4 experimental studies, and 9 additional studies reported on outcomes of genetic services. Generally there were modest positive effects on psychological outcomes such as worry and anxiety, behavioral outcomes have shown mixed results, and clinical outcomes were less well studied. One systematic review, 1 randomized controlled trial, and 14 other studies assessed consumer information needs and found in general that genetics knowledge was reported to be low but that attitudes were generally positive. Three randomized controlled trials and 13 other studies assessed how

Genetic prion disease: no role for the immune system in disease pathogenesis?

Science.gov (United States)

Friedman-Levi, Yael; Binyamin, Orli; Frid, Kati; Ovadia, Haim; Gabizon, Ruth

2014-08-01

Prion diseases, which can manifest by transmissible, sporadic or genetic etiologies, share several common features, such as a fatal neurodegenerative outcome and the aberrant accumulation of proteinase K (PK)-resistant PrP forms in the CNS. In infectious prion diseases, such as scrapie in mice, prions first replicate in immune organs, then invade the CNS via ascending peripheral tracts, finally causing death. Accelerated neuroinvasion and death occurs when activated prion-infected immune cells infiltrate into the CNS, as is the case for scrapie-infected mice induced for experimental autoimmune encephalomyelitis (EAE), a CNS inflammatory insult. To establish whether the immune system plays such a central role also in genetic prion diseases, we induced EAE in TgMHu2ME199K mice, a line mimicking for late onset genetic Creutzfeldt Jacob disease (gCJD), a human prion disease. We show here that EAE induction of TgMHu2ME199K mice neither accelerated nor aggravated prion disease manifestation. Concomitantly, we present evidence that PK-resistant PrP forms were absent from CNS immune infiltrates, and most surprisingly also from lymph nodes and spleens of TgMHu2ME199K mice at all ages and stages of disease. These results imply that the mechanism of genetic prion disease differs widely from that of the infectious presentation, and that the conversion of mutant PrPs into PK resistant forms occurs mostly/only in the CNS. If the absence of pathogenic PrP forms form immune organs is also true for gCJD patients, it may suggest their blood is devoid of prion infectivity. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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.

[Parkinson's disease(s): recent insight into genetic factors

NARCIS (Netherlands)

Warrenburg, B.P.C. van de; Scheffer, H.; Heutink, P.; Bloem, B.R.

2007-01-01

In recent years, 5 genes have been identified that are unambiguously associated with genetic forms of Parkinson's disease. These genes probably explain less than 10% of all cases of Parkinson's disease. Clinically, these genetic forms can closely resemble idiopathic Parkinson's disease. Mutation

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...... not previously implicated in epilepsy and provides further evidence about the genetic architecture of these disorders, with the ultimate aim of assisting in disease classification and prognosis. The data suggest that specific loci can act pleiotropically raising risk for epilepsy broadly, or can have effects...... 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...

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

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......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...... endophenotypes showed moderate to high heritability (0.31-0.69) and small common environmental variance (0.05-0.21). In general, genetic and phenotypic correlations between the endophenotypes were strong only within sets of physiologically similar endophenotypes, but weak to moderate for other pairs...

Genetics of Alzheimer’s Disease: Lessons Learned in Two Decades

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Nilüfer Ertekin Taner

2010-03-01

Full Text Available Alzheimer’s disease (AD is the most common type of dementia. It is estimated that more than 35 million people worldwide will suffer from dementia in 2010. Without effective therapies, this epidemic is expected to affect more than 115 million patients worldwide by 2050. Genetic studies can help us understand the disease pathophysiology, thereby providing potential therapeutic, presymptomatic predictive and preventative avenues. Since 1990, there has been evidence for a substantial genetic component underlying the risk for AD. Three genes with autosomal dominant mutations lead to early-onset familial AD, which explains less than 1% of all AD. Apolipoprotein ε4, the only widely accepted genetic risk factor for late-onset AD, accounts for only a portion of this risk. Genetic linkage and association studies have identified multiple candidate gene regions, although many resulting candidate genes suffer from lack of replication, at least partially due to underpowered studies in the setting of genetic heterogeneity and small-tomoderate effect size. Genome-wide association studies that assess hundreds of thousands of single-nucleotide polymorphisms (SNPs in thousands of subjects have been viewed as a potentially powerful approach in uncovering common risk variations for genetically complex diseases such as AD. To date, 11 independent genome-wide association studies have been completed in late-onset AD (LOAD that led to candidate regions and genes for follow-up. These studies provide evidence for novel, plausible genetic risk factors for AD, but still fail to account for all of the estimated risk. Additional genetic risk factors of even smaller effect size, rare variants and/or structural DNA polymorphisms may exist, which may escape detection by conventional methods. Alternative approaches such as nextgeneration sequencing, use of quantitative endophenotypes, copy number variation analyses, and meta-analyses may be required. This review summarizes the

Genetics of Alzheimer’s Disease: Lessons Learned in Two Decades

Directory of Open Access Journals (Sweden)

Nilüfer Ertekin Taner

2010-03-01

Full Text Available Alzheimer’s disease (AD is the most common type of dementia. It is estimated that more than 35 million people worldwide will suffer from dementia in 2010. Without effective therapies, this epidemic is expected to affect more than 115 million patients worldwide by 2050. Genetic studies can help us understand the disease pathophysiology, thereby providing potential therapeutic, presymptomatic predictive and preventative avenues. Since 1990, there has been evidence for a substantial genetic component underlying the risk for AD. Three genes with autosomal dominant mutations lead to early-onset familial AD, which explains less than 1% of all AD. Apolipoprotein ε4, the only widely accepted genetic risk factor for late-onset AD, accounts for only a portion of this risk. Genetic linkage and association studies have identified multiple candidate gene regions, although many resulting candidate genes suffer from lack of replication, at least partially due to underpowered studies in the setting of genetic heterogeneity and small-tomoderate effect size. Genome-wide association studies that assess hundreds of thousands of single-nucleotide polymorphisms (SNPs in thousands of subjects have been viewed as a potentially powerful approach in uncovering common risk variations for genetically complex diseases such as AD. To date, 11 independent genome-wide association studies have been completed in late-onset AD (LOAD that led to candidate regions and genes for follow-up. These studies provide evidence for novel, plausible genetic risk factors for AD, but still fail to account for all of the estimated risk. Additional genetic risk factors of even smaller effect size, rare variants and/or structural DNA polymorphisms may exist, which may escape detection by conventional methods. Alternative approaches such as nextgeneration sequencing, use of quantitative endophenotypes, copy number variation analyses, and meta-analyses may be required. This review summarizes the

The molecular genetics of inflammatory, autoimmune, and infectious diseases of the sinonasal tract: a review.

Science.gov (United States)

Montone, Kathleen T

2014-06-01

The sinonasal tract is frequently affected by a variety of nonneoplastic inflammatory disease processes that are often multifactorial in their etiology but commonly have a molecular genetic component. To review the molecular genetics of a variety of nonneoplastic inflammatory diseases of the sinonasal tract. Inflammatory lesions of the sinonasal tract can be divided into 3 main categories: (1) chronic rhinosinusitis, (2) infectious diseases, and (3) autoimmune diseases/vasculitides. The molecular diagnosis and pathways of a variety of these inflammatory lesions are currently being elucidated and will shed light on disease pathogenesis and treatment. The sinonasal tract is frequently affected by inflammatory lesions that arise through complex interactions of environmental, infectious, and genetic factors. Because these lesions are all inflammatory in nature, the molecular pathology surrounding them is most commonly due to upregulation and down-regulation of genes that affect inflammatory responses and immune regulation.

[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.

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.

A Common LPA Null Allele Associates With Lower Lipoprotein(a) Levels and Coronary Artery Disease Risk

NARCIS (Netherlands)

Kyriakou, Theodosios; Seedorf, Udo; Goel, Anuj; Hopewell, Jemma C.; Clarke, Robert; Watkins, Hugh; Farrall, Martin; van der Hout, A.H.

Objective-Increased levels of lipoprotein(a) are a highly heritable risk factor for coronary artery disease (CAD). The genetic determinants of lipoprotein(a) levels are mainly because of genetic variation in the apolipoprotein(a) gene (LPA). We have tested the association of a relatively common null

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....

Common genetic variants associated with disease from genome-wide association studies are mutually exclusive in prostate cancer and rheumatoid arthritis.

Science.gov (United States)

Orozco, Gisela; Goh, Chee L; Al Olama, Ali Amin; Benlloch-Garcia, Sara; Govindasami, Koveela; Guy, Michelle; Muir, Kenneth R; Giles, Graham G; Severi, Gianluca; Neal, David E; Hamdy, Freddie C; Donovan, Jenny L; Kote-Jarai, Zsofia; Easton, Douglas F; Eyre, Steve; Eeles, Rosalind A

2013-06-01

WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The link between inflammation and cancer has long been reported and inflammation is thought to play a role in the pathogenesis of many cancers, including prostate cancer (PrCa). Over the last 5 years, genome-wide association studies (GWAS) have reported numerous susceptibility loci that predispose individuals to many different traits. The present study aims to ascertain if there are common genetic risk profiles that might predispose individuals to both PrCa and the autoimmune inflammatory condition, rheumatoid arthritis. These results could have potential public heath impact in terms of screening and chemoprevention. To investigate if potential common pathways exist for the pathogenesis of autoimmune disease and prostate cancer (PrCa). To ascertain if the single nucleotide polymorphisms (SNPs) reported by genome-wide association studies (GWAS) as being associated with susceptibility to PrCa are also associated with susceptibility to the autoimmune disease rheumatoid arthritis (RA). The original Wellcome Trust Case Control Consortium (WTCCC) UK RA GWAS study was expanded to include a total of 3221 cases and 5272 controls. In all, 37 germline autosomal SNPs at genome-wide significance associated with PrCa risk were identified from a UK/Australian PrCa GWAS. Allele frequencies were compared for these 37 SNPs between RA cases and controls using a chi-squared trend test and corrected for multiple testing (Bonferroni). In all, 33 SNPs were able to be analysed in the RA dataset. Proxies could not be located for the SNPs in 3q26, 5p15 and for two SNPs in 17q12. After applying a Bonferroni correction for the number of SNPs tested, the SNP mapping to CCHCR1 (rs130067) retained statistically significant evidence for association (P = 6 × 10(-4) ; odds ratio [OR] = 1.15, 95% CI: 1.06-1.24); this has also been associated with psoriasis. However, further analyses showed that the association of this allele was due to

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

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

NARCIS (Netherlands)

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

2013-01-01

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

Genetic diversity and population structure of common bean ...

African Journals Online (AJOL)

The Ethiopian genetic center is considered to be one of the secondary centers of diversity for the common bean. This study was conducted to characterize the distribution of genetic diversity between and within ecological/geographical regions of Ethiopia. A germplasm sample of 116 landrace accessions was developed, ...

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....

Genotator: A disease-agnostic tool for genetic annotation of disease

Directory of Open Access Journals (Sweden)

Jung Jae-Yoon

2010-10-01

Full Text Available Abstract Background Disease-specific genetic information has been increasing at rapid rates as a consequence of recent improvements and massive cost reductions in sequencing technologies. Numerous systems designed to capture and organize this mounting sea of genetic data have emerged, but these resources differ dramatically in their disease coverage and genetic depth. With few exceptions, researchers must manually search a variety of sites to assemble a complete set of genetic evidence for a particular disease of interest, a process that is both time-consuming and error-prone. Methods We designed a real-time aggregation tool that provides both comprehensive coverage and reliable gene-to-disease rankings for any disease. Our tool, called Genotator, automatically integrates data from 11 externally accessible clinical genetics resources and uses these data in a straightforward formula to rank genes in order of disease relevance. We tested the accuracy of coverage of Genotator in three separate diseases for which there exist specialty curated databases, Autism Spectrum Disorder, Parkinson's Disease, and Alzheimer Disease. Genotator is freely available at http://genotator.hms.harvard.edu. Results Genotator demonstrated that most of the 11 selected databases contain unique information about the genetic composition of disease, with 2514 genes found in only one of the 11 databases. These findings confirm that the integration of these databases provides a more complete picture than would be possible from any one database alone. Genotator successfully identified at least 75% of the top ranked genes for all three of our use cases, including a 90% concordance with the top 40 ranked candidates for Alzheimer Disease. Conclusions As a meta-query engine, Genotator provides high coverage of both historical genetic research as well as recent advances in the genetic understanding of specific diseases. As such, Genotator provides a real-time aggregation of ranked

Genotator: a disease-agnostic tool for genetic annotation of disease.

Science.gov (United States)

Wall, Dennis P; Pivovarov, Rimma; Tong, Mark; Jung, Jae-Yoon; Fusaro, Vincent A; DeLuca, Todd F; Tonellato, Peter J

2010-10-29

Disease-specific genetic information has been increasing at rapid rates as a consequence of recent improvements and massive cost reductions in sequencing technologies. Numerous systems designed to capture and organize this mounting sea of genetic data have emerged, but these resources differ dramatically in their disease coverage and genetic depth. With few exceptions, researchers must manually search a variety of sites to assemble a complete set of genetic evidence for a particular disease of interest, a process that is both time-consuming and error-prone. We designed a real-time aggregation tool that provides both comprehensive coverage and reliable gene-to-disease rankings for any disease. Our tool, called Genotator, automatically integrates data from 11 externally accessible clinical genetics resources and uses these data in a straightforward formula to rank genes in order of disease relevance. We tested the accuracy of coverage of Genotator in three separate diseases for which there exist specialty curated databases, Autism Spectrum Disorder, Parkinson's Disease, and Alzheimer Disease. Genotator is freely available at http://genotator.hms.harvard.edu. Genotator demonstrated that most of the 11 selected databases contain unique information about the genetic composition of disease, with 2514 genes found in only one of the 11 databases. These findings confirm that the integration of these databases provides a more complete picture than would be possible from any one database alone. Genotator successfully identified at least 75% of the top ranked genes for all three of our use cases, including a 90% concordance with the top 40 ranked candidates for Alzheimer Disease. As a meta-query engine, Genotator provides high coverage of both historical genetic research as well as recent advances in the genetic understanding of specific diseases. As such, Genotator provides a real-time aggregation of ranked data that remains current with the pace of research in the disease

Common and Rare Variant Association Study for Plasma Lipids and Coronary Artery Disease.

Science.gov (United States)

Tada, Hayato; Kawashiri, Masa-aki; Konno, Tetsuo; Yamagishi, Masakazu; Hayashi, Kenshi

2016-01-01

Blood lipid levels are highly heritable and modifiable risk factors for coronary artery disease (CAD), and are the leading cause of death worldwide. These facts have motivated human genetic association studies that have the substantial potential to define the risk factors that are causal and to identify pathways and therapeutic targets for lipids and CAD.The success of the HapMap project that provided an extensive catalog of human genetic variations and the development of microarray based genotyping chips (typically containing variations with allele frequencies ＞ 5%) facilitated common variant association study (CVAS; formerly termed genome-wide association study, GWAS) identifying disease-associated variants in a genome-wide manner. To date, 157 loci associated with blood lipids and 46 loci with CAD have been successfully identified, accounting for approximately 12%-14% of heritability for lipids and 10% of heritability for CAD. However, there is yet a major challenge termed "missing heritability problem," namely the observation that loci detected by CVAS explain only a small fraction of the inferred genetic variations. To explain such missing portions, focuses in genetic association studies have shifted from common to rare variants. However, it is challenging to apply rare variant association study (RVAS) in an unbiased manner because such variants typically lack the sufficient number to be identified statistically.In this review, we provide a current understanding of the genetic architecture mostly derived from CVAS, and several updates on the progress and limitations of RVAS for lipids and CAD.

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...

Evolution, revolution and heresy in the genetics of infectious disease susceptibility

Science.gov (United States)

Hill, Adrian V. S.

2012-01-01

Infectious pathogens have long been recognized as potentially powerful agents impacting on the evolution of human genetic diversity. Analysis of large-scale case–control studies provides one of the most direct means of identifying human genetic variants that currently impact on susceptibility to particular infectious diseases. For over 50 years candidate gene studies have been used to identify loci for many major causes of human infectious mortality, including malaria, tuberculosis, human immunodeficiency virus/acquired immunodeficiency syndrome, bacterial pneumonia and hepatitis. But with the advent of genome-wide approaches, many new loci have been identified in diverse populations. Genome-wide linkage studies identified a few loci, but genome-wide association studies are proving more successful, and both exome and whole-genome sequencing now offer a revolutionary increase in power. Opinions differ on the extent to which the genetic component to common disease susceptibility is encoded by multiple high frequency or rare variants, and the heretical view that most infectious diseases might even be monogenic has been advocated recently. Review of findings to date suggests that the genetic architecture of infectious disease susceptibility may be importantly different from that of non-infectious diseases, and it is suggested that natural selection may be the driving force underlying this difference. PMID:22312051

Evolution, revolution and heresy in the genetics of infectious disease susceptibility.

Science.gov (United States)

Hill, Adrian V S

2012-03-19

Infectious pathogens have long been recognized as potentially powerful agents impacting on the evolution of human genetic diversity. Analysis of large-scale case-control studies provides one of the most direct means of identifying human genetic variants that currently impact on susceptibility to particular infectious diseases. For over 50 years candidate gene studies have been used to identify loci for many major causes of human infectious mortality, including malaria, tuberculosis, human immunodeficiency virus/acquired immunodeficiency syndrome, bacterial pneumonia and hepatitis. But with the advent of genome-wide approaches, many new loci have been identified in diverse populations. Genome-wide linkage studies identified a few loci, but genome-wide association studies are proving more successful, and both exome and whole-genome sequencing now offer a revolutionary increase in power. Opinions differ on the extent to which the genetic component to common disease susceptibility is encoded by multiple high frequency or rare variants, and the heretical view that most infectious diseases might even be monogenic has been advocated recently. Review of findings to date suggests that the genetic architecture of infectious disease susceptibility may be importantly different from that of non-infectious diseases, and it is suggested that natural selection may be the driving force underlying this difference.

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

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

Science.gov (United States)

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

2009-06-09

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

Common Genetic Risk for Melanoma Encourages Preventive Behavior Change

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Lori Diseati

2015-02-01

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

Advances in the genetically complex autoinflammatory diseases.

Science.gov (United States)

Ombrello, Michael J

2015-07-01

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.

Type 2 Diabetes Mellitus and Cardiovascular Disease: Genetic and Epigenetic Links

Directory of Open Access Journals (Sweden)

Salvatore De Rosa

2018-01-01

Full Text Available Type 2 diabetes mellitus (DM is a common metabolic disorder predisposing to diabetic cardiomyopathy and atherosclerotic cardiovascular disease (CVD, which could lead to heart failure through a variety of mechanisms, including myocardial infarction and chronic pressure overload. Pathogenetic mechanisms, mainly linked to hyperglycemia and chronic sustained hyperinsulinemia, include changes in metabolic profiles, intracellular signaling pathways, energy production, redox status, increased susceptibility to ischemia, and extracellular matrix remodeling. The close relationship between type 2 DM and CVD has led to the common soil hypothesis, postulating that both conditions share common genetic and environmental factors influencing this association. However, although the common risk factors of both CVD and type 2 DM, such as obesity, insulin resistance, dyslipidemia, inflammation, and thrombophilia, can be identified in the majority of affected patients, less is known about how these factors influence both conditions, so that efforts are still needed for a more comprehensive understanding of this relationship. The genetic, epigenetic, and environmental backgrounds of both type 2 DM and CVD have been more recently studied and updated. However, the underlying pathogenetic mechanisms have seldom been investigated within the broader shared background, but rather studied in the specific context of type 2 DM or CVD, separately. As the precise pathophysiological links between type 2 DM and CVD are not entirely understood and many aspects still require elucidation, an integrated description of the genetic, epigenetic, and environmental influences involved in the concomitant development of both diseases is of paramount importance to shed new light on the interlinks between type 2 DM and CVD. This review addresses the current knowledge of overlapping genetic and epigenetic aspects in type 2 DM and CVD, including microRNAs and long non-coding RNAs, whose

Preimplantation Genetic Diagnosis Counseling in Autosomal Dominant Polycystic Kidney Disease.

Science.gov (United States)

Murphy, Erin L; Droher, Madeline L; DiMaio, Miriam S; Dahl, Neera K

2018-03-30

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common hereditary forms of chronic kidney disease. Mutations within PKD1 or PKD2 lead to innumerable fluid-filled cysts in the kidneys and in some instances, end-stage renal disease (ESRD). Affected individuals have a 50% chance of passing the mutation to each of their offspring. Assisted reproductive technology using preimplantation genetic diagnosis (PGD) allows these individuals to reduce this risk to 1% to 2%. We assess the disease burden of 8 individuals with ADPKD who have undergone genetic testing in preparation for PGD. Clinical features that predict high risk for progression to ESRD in patients with ADPKD include genotype, early onset of hypertension, a urologic event before age 35 years, and a large height-adjusted total kidney volume. Patients may have a family history of intracranial aneurysms or complications involving hepatic cysts, which may further influence the decision to pursue PGD. We also explore the cost, risks, and benefits of using PGD. All patients with ADPKD of childbearing potential, regardless of risk for progression to ESRD or risk for a significant disease burden, will likely benefit from genetic counseling. Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

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

lone AF, has a substantial genetic component. A number of genome-wide association studies (GWAS) have indicated that common genetic variants, more precisely the so called single-nucleotide polymorphisms (SNPs) are associated with AF. Presently more than 10 genomic regions have been identified using...

Eleven loci with new reproducible genetic associations with allergic disease risk

NARCIS (Netherlands)

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

2018-01-01

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

Serum chemistry reference values for the common genet (Genetta genetta): variations associated with Leishmania infantum infection.

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Millán, Javier; Chirife, Andrea D; Altet, Laura

2015-03-01

The role of wildlife in the epidemiology of leishmaniosis in under debate, and determining whether infection with Leishmania infantum causes illness in wild carnivores is important to determine its potential role as a reservoir. To provide for the first time serum biochemistry reference values for the common genet (Genetta genetta), and to determine variations associated with L. infantum infection. Twenty-five serum biochemistry parameters were determined in 22 wild-caught genets. Blood samples were analyzed for L. infantum DNA by means of real-time polymerase chain reaction (PCR). Two female genets were positive for L. infantum DNA but did not show any external clinical sign upon physical examination. Among other variations in the biochemistry values of these genets, one presented a higher concentration of gamma-globulins and cholesterol, whereas the other genet presented increased creatinine, bilirubin, and chloride levels when compared to uninfected females. Sex-related differences in some parameters were also reported. Infection with L. infantum may sometimes be accompanied by abnormal serum biochemistry in wild carnivores. Clinical disease may occur in L. infantum-infected wild carnivores. This has implications in the epidemiology of leishmaniosis. In addition, the data provided here would also be useful as reference values for researchers or rehabilitators working with the common genet.

The genetic basis of Parkinson's disease

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A. A. Tappakhov

2017-01-01

Full Text Available Parkinson's disease (PD is a multifactorial disease that develops in the presence of both genetic and environmental factors. In recent years, there has been sufficient information on the role of genetic predisposition in the development of not only familial cases, but also sporadic ones. A hereditary burden in PD may not be traced in cases of recessive inheritance with a low gene penetrance, as well as in a patient's death before the onset of the disease. Active introduction of molecular genetic methods, including next generation sequencing, can annually identify new gene mutations that underlie sporadic PD cases. This paper provides an overview of the current literature on the genetic aspects of PD with emphasis on the ethnic characteristics of the disease.

Advances in genetic detection of kidney disease

International Nuclear Information System (INIS)

Dosekun, Akinsan K.; Foringer, John R.; Kone, Bruce C.

2003-01-01

The Human Genome Project has provided a vast amount of molecular genetic information for the analysis of normal and diseased genes. This new information provides new opportunities for precise diagnosis, assessment of predisposition and risk factors and novel therapeutic strategies. At the same time, this constantly expanding knowledge base represents on e of the most difficult challenges in molecular medicine. For monogenic disease nearly 2000 human disease genes have thus for been identified. Most of these conditions are characterized by large mutational variation and even greater phenotypic variation. In nephrology, several genetic diseases have been elucidated that provide new insight into the structure, function and developmental biology of the glomerulus, tubules and urogenital tracts, as well as renal cell tumors. Great improvements in the diagnostic resolution of genetic diseases have been achieved, such that single base pair mutations can be readily detected. Because of accurate diagnosis and risk assessment, genetic testing may be valuable in improving disease management and preventive care when genotype-specific therapies are available. Moreover, such testing may identify de novo mutations and potentially aid in understanding the disease process. This review summarizes recent advances in the renal genetic database and methods for genetic testing of renal diseases. (author)

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

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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.

The humankind genome: from genetic diversity to the origin of human diseases.

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Belizário, Jose E

2013-12-01

Genome-wide association studies have failed to establish common variant risk for the majority of common human diseases. The underlying reasons for this failure are explained by recent studies of resequencing and comparison of over 1200 human genomes and 10 000 exomes, together with the delineation of DNA methylation patterns (epigenome) and full characterization of coding and noncoding RNAs (transcriptome) being transcribed. These studies have provided the most comprehensive catalogues of functional elements and genetic variants that are now available for global integrative analysis and experimental validation in prospective cohort studies. With these datasets, researchers will have unparalleled opportunities for the alignment, mining, and testing of hypotheses for the roles of specific genetic variants, including copy number variations, single nucleotide polymorphisms, and indels as the cause of specific phenotypes and diseases. Through the use of next-generation sequencing technologies for genotyping and standardized ontological annotation to systematically analyze the effects of genomic variation on humans and model organism phenotypes, we will be able to find candidate genes and new clues for disease's etiology and treatment. This article describes essential concepts in genetics and genomic technologies as well as the emerging computational framework to comprehensively search websites and platforms available for the analysis and interpretation of genomic data.

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...... of European ancestry. Initial association testing identified the SNP rs4418214, the C allele of which is known to tag the HLA-B*57:01 and B*27:05 alleles, as genome-wide significant (p = 3.6 × 10(-11)). However, restricting analysis to individuals with a known date of seroconversion suggested...... 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....

Quantitative genetics of disease traits.

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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. © 2015 Blackwell Verlag GmbH.

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

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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…

Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses.

Science.gov (United States)

Bertram, Lars; Tanzi, Rudolph E

2008-10-01

The genetic underpinnings of Alzheimer's disease (AD) remain largely elusive despite early successes in identifying three genes that cause early-onset familial AD (those that encode amyloid precursor protein (APP) and the presenilins (PSEN1 and PSEN2)), and one genetic risk factor for late-onset AD (the gene that encodes apolipoprotein E (APOE)). A large number of studies that aimed to help uncover the remaining disease-related loci have been published in recent decades, collectively proposing or refuting the involvement of over 500 different gene candidates. Systematic meta-analyses of these studies currently highlight more than 20 loci that have modest but significant effects on AD risk. This Review discusses the putative pathogenetic roles and common biochemical pathways of some of the most genetically and biologically compelling of these potential AD risk factors.

Role of genetic in periodontal disease

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Anand Narayanrao Wankhede

2017-01-01

Full Text Available Genetics is the study and understanding of the phenomena of heredity and variation. A large number of genes are associated with many systemic conditions. Periodontitis is inflammatory condition of periodontium. Periodontium consists of gingiva, periodontal ligament, cementum, and alveolar bone. It is considered being a multifactorial disease. Studies of animals and humans support the concept that a large number of genes' factor may be associated with periodontitis and clearly play a role in the predisposition and progression of periodontal diseases. It has been proven that genetic factors impair inflammatory and immune responses during periodontal diseases. Research on identifying specific genes causing periodontitis may improve and prevent the disease progression. The aim of this article is to focus on genetic risk factors and its influence for the various forms of periodontal disease.

G protein-coupled receptor mutations and human genetic disease.

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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

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

Science.gov (United States)

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

2009-01-01

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

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

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......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...... endophenotypes showed moderate to high heritability (0.31-0.69) and small cial environmental background...

Constraints on Biological Mechanism from Disease Comorbidity Using Electronic Medical Records and Database of Genetic Variants.

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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.

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

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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

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

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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. Copyright © 2015 Elsevier Inc. All rights reserved.

Current Evidence and Insights about Genetics in Thoracic Aorta Disease

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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. PMID:24453931

Genetics of animal health and disease in cattle

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Berry Donagh P

2011-03-01

Full Text Available Abstract There have been considerable recent advancements in animal breeding and genetics relevant to disease control in cattle, which can now be utilised as part of an overall programme for improved cattle health. This review summarises the contribution of genetic makeup to differences in resistance to many diseases affecting cattle. Significant genetic variation in susceptibility to disease does exist among cattle suggesting that genetic selection for improved resistance to disease will be fruitful. Deficiencies in accurately recorded data on individual animal susceptibility to disease are, however, currently hindering the inclusion of health and disease resistance traits in national breeding goals. Developments in 'omics' technologies, such as genomic selection, may help overcome some of the limitations of traditional breeding programmes and will be especially beneficial in breeding for lowly heritable disease traits that only manifest themselves following exposure to pathogens or environmental stressors in adulthood. However, access to large databases of phenotypes on health and disease will still be necessary. This review clearly shows that genetics make a significant contribution to the overall health and resistance to disease in cattle. Therefore, breeding programmes for improved animal health and disease resistance should be seen as an integral part of any overall national disease control strategy.

Genetics of Dyslipidemia and Ischemic Heart Disease.

Science.gov (United States)

Sharma, Kavita; Baliga, Ragavendra R

2017-05-01

Genetic dyslipidemias contribute to the prevalence of ischemic heart disease. The field of genetic dyslipidemias and their influence on atherosclerotic heart disease is rapidly developing and accumulating increasing evidence. The purpose of this review is to describe the current state of knowledge in regard to inherited atherogenic dyslipidemias. The disorders of familial hypercholesterolemia (FH) and elevated lipoprotein(a) will be detailed. Genetic technology has made rapid advancements, leading to new discoveries in inherited atherogenic dyslipidemias, which will be explored in this review, as well as a description of possible future developments. Increasing attention has come upon the genetic disorders of familial hypercholesterolemia and elevated lipoprotein(a). This review includes new knowledge of these disorders including description of these disorders, their method of diagnosis, their prevalence, their genetic underpinnings, and their effect on the development of cardiovascular disease. In addition, it discusses major advances in genetic technology, including the completion of the human genome sequence, next-generation sequencing, and genome-wide association studies. Also discussed are rare variant studies with specific genetic mechanisms involved in inherited dyslipidemias, such as in the proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme. The field of genetics of dyslipidemia and cardiovascular disease is rapidly growing, which will result in a bright future of novel mechanisms of action and new therapeutics.

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

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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.

Genetic Parameters of Common Wheat in Nepal

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Bal Krishna Joshi

2015-12-01

Full Text Available Knowledge on variation within traits and their genetics are prerequisites in crop improvement program. Thus, in present paper we aimed to estimate genetic and environmental indices of common wheat genotypes. For the purpose, eight quantitative traits were measured from 30 wheat genotypes, which were in randomized complete block design with 3 replicates. Components of variance and covariance were estimated along with heritability, genetic gain, realized heritability, coheritability and correlated response. Differences between phenotypic and genotypic variances in heading days, maturity days and plant height were not large. Grain yield and plant height showed the highest phenotypic (18.189% and genotypic (12.06% coefficient of variances, respectively. Phenotypic covariance was higher than genotypic and environmental covariance in most of the traits. The highest heritability and realized heritability were of heading days followed by maturity days. Genetic gain for plant height was the highest. Co-heritability of 1000-grain weight with tillers number was the highest. The highest correlated response was expressed by grain yield with tillers number. This study indicates the possibility of improving wheat genotypes through selection utilizing existing variation in these traits.

The Genetic Theory of Infectious Diseases: A Brief History and Selected Illustrations

Science.gov (United States)

Casanova, Jean-Laurent; Abel, Laurent

2016-01-01

Until the mid-nineteenth century, life expectancy at birth averaged 20 years worldwide, owing mostly to childhood fevers. The germ theory of diseases then gradually overcame the belief that diseases were intrinsic. However, around the turn of the twentieth century, asymptomatic infection was discovered to be much more common than clinical disease. Paradoxically, this observation barely challenged the newly developed notion that infectious diseases were fundamentally extrinsic. Moreover, interindividual variability in the course of infection was typically explained by the emerging immunological (or somatic) theory of infectious diseases, best illustrated by the impact of vaccination. This powerful explanation is, however, best applicable to reactivation and secondary infections, particularly in adults; it can less easily account for interindividual variability in the course of primary infection during childhood. Population and clinical geneticists soon proposed a complementary hypothesis, a germline genetic theory of infectious diseases. Over the past century, this idea has gained some support, particularly among clinicians and geneticists, but has also encountered resistance, particularly among microbiologists and immunologists. We present here the genetic theory of infectious diseases and briefly discuss its history and the challenges encountered during its emergence in the context of the apparently competing but actually complementary microbiological and immunological theories. We also illustrate its recent achievements by highlighting inborn errors of immunity underlying eight life-threatening infectious diseases of children and young adults. Finally, we consider the far-reaching biological and clinical implications of the ongoing human genetic dissection of severe infectious diseases. PMID:23724903

The genetic theory of infectious diseases: a brief history and selected illustrations.

Science.gov (United States)

Casanova, Jean-Laurent; Abel, Laurent

2013-01-01

Until the mid-nineteenth century, life expectancy at birth averaged 20 years worldwide, owing mostly to childhood fevers. The germ theory of diseases then gradually overcame the belief that diseases were intrinsic. However, around the turn of the twentieth century, asymptomatic infection was discovered to be much more common than clinical disease. Paradoxically, this observation barely challenged the newly developed notion that infectious diseases were fundamentally extrinsic. Moreover, interindividual variability in the course of infection was typically explained by the emerging immunological (or somatic) theory of infectious diseases, best illustrated by the impact of vaccination. This powerful explanation is, however, best applicable to reactivation and secondary infections, particularly in adults; it can less easily account for interindividual variability in the course of primary infection during childhood. Population and clinical geneticists soon proposed a complementary hypothesis, a germline genetic theory of infectious diseases. Over the past century, this idea has gained some support, particularly among clinicians and geneticists, but has also encountered resistance, particularly among microbiologists and immunologists. We present here the genetic theory of infectious diseases and briefly discuss its history and the challenges encountered during its emergence in the context of the apparently competing but actually complementary microbiological and immunological theories. We also illustrate its recent achievements by highlighting inborn errors of immunity underlying eight life-threatening infectious diseases of children and young adults. Finally, we consider the far-reaching biological and clinical implications of the ongoing human genetic dissection of severe infectious diseases.

Genetics Home Reference: Gaucher disease

Science.gov (United States)

... 500 to 1,000 people of Ashkenazi Jewish heritage. The other forms of Gaucher disease are uncommon and do not occur more frequently in people of Ashkenazi Jewish descent. Related Information What information about a genetic condition can statistics provide? Why are some genetic ...

Association Study of Common Genetic Variants and HIV-1 Acquisition in 6,300 Infected Cases and 7,200 Controls

Science.gov (United States)

Ripke, Stephan; van den Berg, Leonard; Buchbinder, Susan; Carrington, Mary; Cossarizza, Andrea; Dalmau, Judith; Deeks, Steven G.; Delaneau, Olivier; De Luca, Andrea; Goedert, James J.; Haas, David; Herbeck, Joshua T.; Kathiresan, Sekar; Kirk, Gregory D.; Lambotte, Olivier; Luo, Ma; Mallal, Simon; van Manen, Daniëlle; Martinez-Picado, Javier; Meyer, Laurence; Miro, José M.; Mullins, James I.; Obel, Niels; O'Brien, Stephen J.; Pereyra, Florencia; Plummer, Francis A.; Poli, Guido; Qi, Ying; Rucart, Pierre; Sandhu, Manj S.; Shea, Patrick R.; Schuitemaker, Hanneke; Theodorou, Ioannis; Vannberg, Fredrik; Veldink, Jan; Walker, Bruce D.; Weintrob, Amy; Winkler, Cheryl A.; Wolinsky, Steven; Telenti, Amalio; Goldstein, David B.; de Bakker, Paul I. W.; Zagury, Jean-François; Fellay, Jacques

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 in generally small samples. Under the auspices of the International Collaboration for the Genomics of HIV, we have combined the genome-wide single nucleotide polymorphism (SNP) data collected by 25 cohorts, studies, or institutions on HIV-1 infected individuals and compared them to carefully matched population-level data sets (a list of all collaborators appears in Note S1 in Text S1). After imputation using the 1,000 Genomes Project reference panel, we tested approximately 8 million common DNA variants (SNPs and indels) for association with HIV-1 acquisition in 6,334 infected patients and 7,247 population samples of European ancestry. Initial association testing identified the SNP rs4418214, the C allele of which is known to tag the HLA-B*57:01 and B*27:05 alleles, as genome-wide significant (p = 3.6×10−11). However, restricting analysis to individuals with a known date of seroconversion suggested 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. PMID:23935489

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

Directory of Open Access Journals (Sweden)

Paul J McLaren

Full Text Available 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 in generally small samples. Under the auspices of the International Collaboration for the Genomics of HIV, we have combined the genome-wide single nucleotide polymorphism (SNP data collected by 25 cohorts, studies, or institutions on HIV-1 infected individuals and compared them to carefully matched population-level data sets (a list of all collaborators appears in Note S1 in Text S1. After imputation using the 1,000 Genomes Project reference panel, we tested approximately 8 million common DNA variants (SNPs and indels for association with HIV-1 acquisition in 6,334 infected patients and 7,247 population samples of European ancestry. Initial association testing identified the SNP rs4418214, the C allele of which is known to tag the HLA-B*57:01 and B*27:05 alleles, as genome-wide significant (p = 3.6 × 10⁻¹¹. However, restricting analysis to individuals with a known date of seroconversion suggested 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.

The Pathogenesis of Nonalcoholic Fatty Liver Disease: Interplay between Diet, Gut Microbiota, and Genetic Background

Science.gov (United States)

Marsh, Sharon; Hu, Junbo; Feng, Wenke

2016-01-01

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world, and it comprises a spectrum of hepatic abnormalities from simple hepatic steatosis to steatohepatitis, fibrosis, cirrhosis, and liver cancer. While the pathogenesis of NAFLD remains incompletely understood, a multihit model has been proposed that accommodates causal factors from a variety of sources, including intestinal and adipose proinflammatory stimuli acting on the liver simultaneously. Prior cellular and molecular studies of patient and animal models have characterized several common pathogenic mechanisms of NAFLD, including proinflammation cytokines, lipotoxicity, oxidative stress, and endoplasmic reticulum stress. In recent years, gut microbiota has gained much attention, and dysbiosis is recognized as a crucial factor in NAFLD. Moreover, several genetic variants have been identified through genome-wide association studies, particularly rs738409 (Ile748Met) in PNPLA3 and rs58542926 (Glu167Lys) in TM6SF2, which are critical risk alleles of the disease. Although a high-fat diet and inactive lifestyles are typical risk factors for NAFLD, the interplay between diet, gut microbiota, and genetic background is believed to be more important in the development and progression of NAFLD. This review summarizes the common pathogenic mechanisms, the gut microbiota relevant mechanisms, and the major genetic variants leading to NAFLD and its progression. PMID:27247565

Genetics of Valvular Heart Disease

Science.gov (United States)

LaHaye, Stephanie; Lincoln, Joy

2015-01-01

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. PMID:24743897

Population Genetics and Natural Selection in Rheumatic Disease.

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Ramos, Paula S

2017-08-01

Human genetic diversity is the result of population genetic forces. This genetic variation influences disease risk and contributes to health disparities. Natural selection is an important influence on human genetic variation. Because immune and inflammatory function genes are enriched for signals of positive selection, the prevalence of rheumatic disease-risk alleles seen in different populations is partially the result of differing selective pressures (eg, due to pathogens). This review summarizes the genetic regions associated with susceptibility to different rheumatic diseases and concomitant evidence for natural selection, including known agents of selection exerting selective pressure in these regions. Copyright © 2017 Elsevier Inc. All rights reserved.

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.

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.

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.

Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease.

Science.gov (United States)

Johnson, Michael R; Shkura, Kirill; Langley, Sarah R; Delahaye-Duriez, Andree; Srivastava, Prashant; Hill, W David; Rackham, Owen J L; Davies, Gail; Harris, Sarah E; Moreno-Moral, Aida; Rotival, Maxime; Speed, Doug; Petrovski, Slavé; Katz, Anaïs; Hayward, Caroline; Porteous, David J; Smith, Blair H; Padmanabhan, Sandosh; Hocking, Lynne J; Starr, John M; Liewald, David C; Visconti, Alessia; Falchi, Mario; Bottolo, Leonardo; Rossetti, Tiziana; Danis, Bénédicte; Mazzuferi, Manuela; Foerch, Patrik; Grote, Alexander; Helmstaedter, Christoph; Becker, Albert J; Kaminski, Rafal M; Deary, Ian J; Petretto, Enrico

2016-02-01

Genetic determinants of cognition are poorly characterized, and their relationship to genes that confer risk for neurodevelopmental disease is unclear. Here we performed a systems-level analysis of genome-wide gene expression data to infer gene-regulatory networks conserved across species and brain regions. Two of these networks, M1 and M3, showed replicable enrichment for common genetic variants underlying healthy human cognitive abilities, including memory. Using exome sequence data from 6,871 trios, we found that M3 genes were also enriched for mutations ascertained from patients with neurodevelopmental disease generally, and intellectual disability and epileptic encephalopathy in particular. M3 consists of 150 genes whose expression is tightly developmentally regulated, but which are collectively poorly annotated for known functional pathways. These results illustrate how systems-level analyses can reveal previously unappreciated relationships between neurodevelopmental disease-associated genes in the developed human brain, and provide empirical support for a convergent gene-regulatory network influencing cognition and neurodevelopmental disease.

Studies on nonsense mediated decay reveal novel therapeutic options for genetic diseases.

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Bashyam, Murali D

2009-01-01

Scientific breakthroughs have often led to commercially viable patents mainly in the field of engineering. Commercialization in the field of medicine has been restricted mostly to machinery and engineering on the one hand and therapeutic drugs for common chronic ailments such as cough, cold, headache, etc, on the other. Sequencing of the human genome has attracted the attention of pharmaceutical companies and now biotechnology has become a goldmine for commercialization of products and processes. Recent advances in our understanding of basic biological processes have resulted in the opening of new avenues for treatment of human genetic diseases, especially single gene disorders. A significant proportion of human genetic disorders have been shown to be caused due to degradation of transcripts for specific genes through a process called nonsense mediated decay (NMD). The modulation of NMD provides a viable therapeutic option for treatment of several genetic disorders and therefore has been a good prospect for patenting and commercialization. In this review the molecular basis for NMD and attempts to treat genetic diseases which result from NMD are discussed.

NOTE - Characterization of genetic variability among common bean genotypes by morphological descriptors

Directory of Open Access Journals (Sweden)

Marilene Santos de Lima

2012-01-01

Full Text Available The purpose of this study was to characterize the genetic variability in 100 genotypes of the Active Germplasm Bank of common bean of the Federal University of Viçosa, by morphological descriptors, classify them in groups of genetic similarity and to identify the degree of relevance of descriptors of genetic divergence. The genotypes were evaluated based on 22 quantitative and qualitative morphological descriptors. The highyielding genotypes V 7936, Gold Gate, LM 95103904, 1829 S 349 Venezuela, and PF 9029975, CNFC 9454 andFe 732015, with upright growth, have potential for use as parents in common bean breeding programs. By genetic divergence analysis, the genotypes were clustered in eight groups of genetic dissimilarity. By methods of principal components, 9 of the 22 descriptors were eliminated, for being redundant or little variable, suggesting that 10-20 morphological descriptors can be used in studies of characterization of genetic variation.

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

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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.

A Genetic Variant Associated with Five Vascular Diseases Is a Distal Regulator of Endothelin-1 Gene Expression

NARCIS (Netherlands)

Gupta, Rajat M.; Hadaya, Joseph; Trehan, Aditi; Zekavat, Seyedeh M.; Roselli, Carolina; Klarin, Derek; Emdin, Connor A.; Hilvering, Catharina R.E.; Bianchi, Valerio; Mueller, Christian; Khera, Amit V.; Ryan, Russell J.H.; Engreitz, Jesse M.; Issner, Robbyn; Shoresh, Noam; Epstein, Charles B.; de Laat, Wouter; Brown, Jonathan D.; Schnabel, Renate B.; Bernstein, Bradley E.; Kathiresan, Sekar

2017-01-01

Genome-wide association studies (GWASs) implicate the PHACTR1 locus (6p24) in risk for five vascular diseases, including coronary artery disease, migraine headache, cervical artery dissection, fibromuscular dysplasia, and hypertension. Through genetic fine mapping, we prioritized rs9349379, a common

Genetic relationships among alfalfa gemplasms resistant to common ...

African Journals Online (AJOL)

Genetic relationships among 26 alfalfa cultivars, of which, 12 were of high resistance to common leaf spot (CLS), were assessed using sequence-related amplified polymorphism (SRAP) markers. 34 SRAP primer combinations were selected for fingerprinting of these cultivars and a total of 281 bands were observed, among ...

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); L.T. Strike (Lachlan); 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.J. 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 (Marcella); 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 (René); 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); 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.J. 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 (Cornelia); 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

Maternal-Zygotic Epistasis and the Evolution of Genetic Diseases

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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.

A Baseline Algorithm for Molecular Diagnosis of Genetic Eye Diseases: Ophthalmologist’s Perspective

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Hande Taylan Şekeroğlu

2016-12-01

Full Text Available To the Editor: Genetic eye diseases constitute a large and heterogeneous group. Individual diseases may cause multiple structural/functional anomalies and developmental features. Family history may be suggestive; however, it may also be challenging, particularly in late-onset conditions or in cases of variable expression. In the current era of genetic advances, diagnosis of a genetic eye disease is facilitated by well-established collaboration between ophthalmologists and geneticists, as increasingly more patients will be asking for genetic counseling and prenatal diagnosis in addition to ophthalmologic management. Molecular investigation of a genetic eye disease requires customized analysis and advanced technology in addition to the requisite detailed family history and accurate ophthalmological diagnosis. A common indication for genetic testing is the validation of a preliminary diagnosis made in clinical practice. The need to determine the prognostic implications of the genotype, assessment of the recurrence risk and in particular, the possibility of specific gene therapy in the near future encourages clinicians to pursue genetic research. We present here a baseline algorithm covering common genetic mechanisms in order to outline a basic molecular approach for ophthalmologists. The first step of the flow chart, a prudent clinical examination with complete description of the phenotype, is indispensible for making a precise and accurate preliminary diagnosis (Figure 1. If the phenotype is pathognomonic, Sanger sequencing is preferred for confirmation.1 A previously established genotype-phenotype correlation may add to the value, either by providing accurate prognostic information or by indicating which particular mutation to look for. One such example may be electroretinographic supranormal rod response, indicating KCNV2 mutation type cone dystrophy, which can be precisely detected by Sanger sequencing or qPCR.2 Conventional karyotyping reveals

Genetic Disease Foundation

Science.gov (United States)

... has used its fundraising efforts to help further research programs at Mount Sinai. Spotlight: Gaucher Gaucher Disease is the most common of the lipid storage diseases. Learn about its symptoms, how it ...

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

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.......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....

Genetic Modifiers of Sickle Cell Disease

Science.gov (United States)

Steinberg, Martin H.; Sebastiani, Paola

2015-01-01

Sickle cell anemia is associated with unusual clinical heterogeneity for a Mendelian disorder. Fetal hemoglobin concentration and coincident ∝ thalassemia, both which directly affect the sickle erythrocyte, are the major modulators of the phenotype of disease. Understanding the genetics underlying the heritable subphenotypes of sickle cell anemia would be prognostically useful, could inform personalized therapeutics, and might help the discovery of new “druggable” pathophysiologic targets. Genotype-phenotype association studies have been used to identify novel genetic modifiers. In the future, whole genome sequencing with its promise of discovering hitherto unsuspected variants could add to our understanding of the genetic modifiers of this disease. PMID:22641398

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

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.

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.

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.

An efficient and comprehensive strategy for genetic diagnostics of polycystic kidney disease.

Directory of Open Access Journals (Sweden)

Tobias Eisenberger

Full Text Available Renal cysts are clinically and genetically heterogeneous conditions. Autosomal dominant polycystic kidney disease (ADPKD is the most frequent life-threatening genetic disease and mainly caused by mutations in PKD1. The presence of six PKD1 pseudogenes and tremendous allelic heterogeneity make molecular genetic testing challenging requiring laborious locus-specific amplification. Increasing evidence suggests a major role for PKD1 in early and severe cases of ADPKD and some patients with a recessive form. Furthermore it is becoming obvious that clinical manifestations can be mimicked by mutations in a number of other genes with the necessity for broader genetic testing. We established and validated a sequence capture based NGS testing approach for all genes known for cystic and polycystic kidney disease including PKD1. Thereby, we demonstrate that the applied standard mapping algorithm specifically aligns reads to the PKD1 locus and overcomes the complication of unspecific capture of pseudogenes. Employing careful and experienced assessment of NGS data, the method is shown to be very specific and equally sensitive as established methods. An additional advantage over conventional Sanger sequencing is the detection of copy number variations (CNVs. Sophisticated bioinformatic read simulation increased the high analytical depth of the validation study and further demonstrated the strength of the approach. We further raise some awareness of limitations and pitfalls of common NGS workflows when applied in complex regions like PKD1 demonstrating that quality of NGS needs more than high coverage of the target region. By this, we propose a time- and cost-efficient diagnostic strategy for comprehensive molecular genetic testing of polycystic kidney disease which is highly automatable and will be of particular value when therapeutic options for PKD emerge and genetic testing is needed for larger numbers of patients.

An efficient and comprehensive strategy for genetic diagnostics of polycystic kidney disease.

Science.gov (United States)

Eisenberger, Tobias; Decker, Christian; Hiersche, Milan; Hamann, Ruben C; Decker, Eva; Neuber, Steffen; Frank, Valeska; Bolz, Hanno J; Fehrenbach, Henry; Pape, Lars; Toenshoff, Burkhard; Mache, Christoph; Latta, Kay; Bergmann, Carsten

2015-01-01

Renal cysts are clinically and genetically heterogeneous conditions. Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent life-threatening genetic disease and mainly caused by mutations in PKD1. The presence of six PKD1 pseudogenes and tremendous allelic heterogeneity make molecular genetic testing challenging requiring laborious locus-specific amplification. Increasing evidence suggests a major role for PKD1 in early and severe cases of ADPKD and some patients with a recessive form. Furthermore it is becoming obvious that clinical manifestations can be mimicked by mutations in a number of other genes with the necessity for broader genetic testing. We established and validated a sequence capture based NGS testing approach for all genes known for cystic and polycystic kidney disease including PKD1. Thereby, we demonstrate that the applied standard mapping algorithm specifically aligns reads to the PKD1 locus and overcomes the complication of unspecific capture of pseudogenes. Employing careful and experienced assessment of NGS data, the method is shown to be very specific and equally sensitive as established methods. An additional advantage over conventional Sanger sequencing is the detection of copy number variations (CNVs). Sophisticated bioinformatic read simulation increased the high analytical depth of the validation study and further demonstrated the strength of the approach. We further raise some awareness of limitations and pitfalls of common NGS workflows when applied in complex regions like PKD1 demonstrating that quality of NGS needs more than high coverage of the target region. By this, we propose a time- and cost-efficient diagnostic strategy for comprehensive molecular genetic testing of polycystic kidney disease which is highly automatable and will be of particular value when therapeutic options for PKD emerge and genetic testing is needed for larger numbers of patients.

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.

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

International Nuclear Information System (INIS)

Sung, Hyuna; Ahn, Sei-Hyun; Kang, Daehee; Jeon, Sujee; Lee, Kyoung-Mu; Han, Sohee; Song, Minkyo; Choi, Ji-Yeob; Park, Sue K; Yoo, Keun-Young; Noh, Dong-Young

2012-01-01

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. 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. 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). 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

Preimplantation genetic diagnosis of X-linked diseases examined by indirect linkage analysis.

Science.gov (United States)

Borgulova, I; Putzova, M; Soldatova, I; Krautova, L; Pecnova, L; Mika, J; Kren, R; Potuznikova, P; Stejskal, D

2015-01-01

Many centers of assisted reproduction in the Czech Republic offer preimplantation genetic diagnosis with fluorescent in situ hybridization (FISH) to couples requiring preimplantation genetic diagnosis (PGD) of X-linked diseases. However, this process results in discarding all male embryos and is not able to distinguish a carrier or healthy female embryo in X-linked recessive disorders. The main aim of this study was to summarize a six-year period of PGD of X-linked monogenic diseases using indirect linkage analysis. We wanted to accentuate the advantage indirect analysis of PGD using multiple displacement amplification (MDA) followed by short tandem repeat (STR) analysis. We present forty-six PGD cycles, including pre-case haplotyping (PGH) panel, for fifteen X-linked diseases. Embryo transfer was made thirty-eight times and gravidity was confirmed in thirteen female probands with a success rate of pregnancy calculated at 42 %. PGD procedure using MDA amplification followed by STR analysis provides help in identifying genetic defects within embryos prior to implantation. The reliability of the method was also supported by high pregnancy rate compared to other publications, which commonly achieved a 30-35 % success rate (Tab. 2, Fig. 1, Ref. 33).

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.

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

Science.gov (United States)

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

2014-01-01

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

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.

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.

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

Disease-Concordant Twins Empower Genetic Association Studies

DEFF Research Database (Denmark)

Tan, Qihua; Li, Weilong; Vandin, Fabio

2017-01-01

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...... 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...... 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...

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.

Personalized medicine and human genetic diversity.

Science.gov (United States)

Lu, Yi-Fan; Goldstein, David B; Angrist, Misha; Cavalleri, Gianpiero

2014-07-24

Human genetic diversity has long been studied both to understand how genetic variation influences risk of disease and infer aspects of human evolutionary history. In this article, we review historical and contemporary views of human genetic diversity, the rare and common mutations implicated in human disease susceptibility, and the relevance of genetic diversity to personalized medicine. First, we describe the development of thought about diversity through the 20th century and through more modern studies including genome-wide association studies (GWAS) and next-generation sequencing. We introduce several examples, such as sickle cell anemia and Tay-Sachs disease that are caused by rare mutations and are more frequent in certain geographical populations, and common treatment responses that are caused by common variants, such as hepatitis C infection. We conclude with comments about the continued relevance of human genetic diversity in medical genetics and personalized medicine more generally. Copyright © 2014 Cold Spring Harbor Laboratory Press; all rights reserved.

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.

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.

HLA DRB1*03 as a possible common etiology of schizophrenia, Graves' disease, and type 2 diabetes.

Science.gov (United States)

Sayeh, Aicha; Ben Cheikh, Cheker; Mardessi, Ali; Mrad, Meriem; Nsiri, Brahim; Oumaya, Abdelaziz; Fekih-Mrissa, Najiba

2017-01-01

Autoimmune diseases and schizophrenia share many common features. Association studies confirm a shared genetic association in the human leukocyte antigen (HLA) region between schizophrenia and most autoimmune diseases. To our knowledge, the simultaneous syndromes of Graves' disease (GD) and type 2 diabetes (T2D) in schizophrenia are rare in Tunisia. We report a case of a 42-year-old woman admitted to the department of psychiatry for an acute relapse of chronic schizophrenia. Her medical history revealed that she was followed for Graves' disease and for a type 2 diabetes mellitus. A low-resolution HLA typing was performed by polymerase chain reaction sequence-specific primer (PCR-SSP) techniques according to determine the patient's haplotype. Our study suggests that the HLA DRB1*03 allele may explain a common etiology underlying the co-morbidity of Graves' disease, type 2 diabetes, and schizophrenia in our patient.

Genetic testing in congenital heart disease: A clinical approach

Science.gov (United States)

Chaix, Marie A; Andelfinger, Gregor; Khairy, Paul

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 follow-up. 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. PMID:26981213

Genetics Home Reference: Pelizaeus-Merzbacher disease

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... condition worsens, affected children develop spasticity leading to joint deformities (contractures) that restrict movement. Individuals with connatal ... Topic: Leukodystrophies Health Topic: Neurologic Diseases Health Topic: Neuromuscular Disorders Genetic and Rare Diseases Information Center (1 ...

Clinical Perspectives of Genetic Analyses on Dyslipidemia and Coronary Artery Disease

Science.gov (United States)

Kawashiri, Masa-aki; Yamagishi, Masakazu

2017-01-01

We have learned that low-density lipoprotein (LDL) cholesterol is the cause of atherosclerosis from various aspects, including a single case with familial hypercholesterolemia, other cases with different types of Mendelian dyslipidemias, large-scale randomized controlled trials using LDL cholesterol lowering therapies, and Mendelian randomization studies using common as well as rare variants associated with LDL cholesterol levels. There is no doubt that determinations of genotypes in lipid-associated genes have contributed not only to the genetic diagnosis for Mendelian dyslipidemias but also to the discoveries of novel therapeutic targets. Furthermore, recent studies have shown that such genetic information could provide useful clues for the risk prediction as well as risk stratification in general and in particular population. We provide the current understanding of genetic analyses relating to plasma lipids and coronary artery disease. PMID:28250266

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

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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.

The landscape genetics of infectious disease emergence and spread.

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Biek, Roman; Real, Leslie A

2010-09-01

The spread of parasites is inherently a spatial process often embedded in physically complex landscapes. It is therefore not surprising that infectious disease researchers are increasingly taking a landscape genetics perspective to elucidate mechanisms underlying basic ecological processes driving infectious disease dynamics and to understand the linkage between spatially dependent population processes and the geographic distribution of genetic variation within both hosts and parasites. The increasing availability of genetic information on hosts and parasites when coupled to their ecological interactions can lead to insights for predicting patterns of disease emergence, spread and control. Here, we review research progress in this area based on four different motivations for the application of landscape genetics approaches: (i) assessing the spatial organization of genetic variation in parasites as a function of environmental variability, (ii) using host population genetic structure as a means to parameterize ecological dynamics that indirectly influence parasite populations, for example, gene flow and movement pathways across heterogeneous landscapes and the concurrent transport of infectious agents, (iii) elucidating the temporal and spatial scales of disease processes and (iv) reconstructing and understanding infectious disease invasion. Throughout this review, we emphasize that landscape genetic principles are relevant to infection dynamics across a range of scales from within host dynamics to global geographic patterns and that they can also be applied to unconventional 'landscapes' such as heterogeneous contact networks underlying the spread of human and livestock diseases. We conclude by discussing some general considerations and problems for inferring epidemiological processes from genetic data and try to identify possible future directions and applications for this rapidly expanding field.

Invited review: Opportunities for genetic improvement of metabolic diseases.

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Pryce, J E; Parker Gaddis, K L; Koeck, A; Bastin, C; Abdelsayed, M; Gengler, N; Miglior, F; Heringstad, B; Egger-Danner, C; Stock, K F; Bradley, A J; Cole, J B

2016-09-01

Metabolic disorders are disturbances to one or more of the metabolic processes in dairy cattle. Dysfunction of any of these processes is associated with the manifestation of metabolic diseases or disorders. In this review, data recording, incidences, genetic parameters, predictors, and status of genetic evaluations were examined for (1) ketosis, (2) displaced abomasum, (3) milk fever, and (4) tetany, as these are the most prevalent metabolic diseases where published genetic parameters are available. The reported incidences of clinical cases of metabolic disorders are generally low (less than 10% of cows are recorded as having a metabolic disease per herd per year or parity/lactation). Heritability estimates are also low and are typically less than 5%. Genetic correlations between metabolic traits are mainly positive, indicating that selection to improve one of these diseases is likely to have a positive effect on the others. Furthermore, there may also be opportunities to select for general disease resistance in terms of metabolic stability. Although there is inconsistency in published genetic correlation estimates between milk yield and metabolic traits, selection for milk yield may be expected to lead to a deterioration in metabolic disorders. Under-recording and difficulty in diagnosing subclinical cases are among the reasons why interest is growing in using easily measurable predictors of metabolic diseases, either recorded on-farm by using sensors and milk tests or off-farm using data collected from routine milk recording. Some countries have already initiated genetic evaluations of metabolic disease traits and currently most of these use clinical observations of disease. However, there are opportunities to use clinical diseases in addition to predictor traits and genomic information to strengthen genetic evaluations for metabolic health in the future. Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

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...

Preimplantation diagnosis of genetic diseases

Directory of Open Access Journals (Sweden)

Adiga S

2010-01-01

Full Text Available One of the landmarks in clinical genetics is prenatal diagnosis of genetic disorders. The recent advances in the field have made it possible to diagnose the genetic conditions in the embryos before implantation in a setting of in vitro fertilization. Polymerase chain reaction and fluorescence in situ hybridization are the two common techniques employed on a single or two cells obtained via embryo biopsy. The couple who seek in vitro fertilization may screen their embryos for aneuploidy and the couple at risk for a monogenic disorder but averse to abortion of the affected fetuses after prenatal diagnosis, are likely to be the best candidates to undergo this procedure. This article reviews the technique, indications, benefits, and limitations of pre-implantation genetic testing in clinical practice.

Exploration of genetic susceptibility factors for Parkinson's disease ...

Indian Academy of Sciences (India)

1Neurosciences Research Group, School of Medicine and Institute of Genetics, Universidad Nacional de Colombia, Bogotá ... factors for Parkinson's disease in a South American sample. J. Genet. 89, ... In the current work, we report the results of a system- ..... Synaptic dysfunction and oxidative stress in Alzheimer's disease:.

Genetic Variations and their Association with Diseases among ...

African Journals Online (AJOL)

genetics plays in disease, death and infections. The mode of study involved a combination of a retrospective study and the analysis of genetic variation among Kenyan ethnic populations using ABO blood group system. The results showed that there was association between allele frequencies of ABO system and disease ...

Elucidating novel dysfunctional pathways in Alzheimer's disease by integrating loci identified in genetic and epigenetic studies

Directory of Open Access Journals (Sweden)

Adam R. Smith

2016-06-01

Full Text Available Alzheimer's disease is a complex neurodegenerative disorder. A large number of genome-wide association studies have been performed, which have been supplemented more recently by the first epigenome-wide association studies, leading to the identification of a number of novel loci altered in disease. Twin studies have shown monozygotic twin discordance for Alzheimer's disease (Gatz et al., 2006, leading to the conclusion that a combination of genetic and epigenetic mechanisms is likely to be involved in disease etiology (Lunnon & Mill, 2013. This review focuses on identifying overlapping pathways between published genome-wide association studies and epigenome-wide association studies, highlighting dysfunctional synaptic, lipid metabolism, plasma membrane/cytoskeleton, mitochondrial, and immune cell activation pathways. Identifying common pathways altered in genetic and epigenetic studies will aid our understanding of disease mechanisms and identify potential novel targets for pharmacological intervention.

Genetics of liver disease: From pathophysiology to clinical practice.

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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. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Evaluating the Genetics of Common Variable Immunodeficiency: Monogenetic Model and Beyond

Directory of Open Access Journals (Sweden)

Guillem de Valles-Ibáñez

2018-05-01

Full Text Available Common variable immunodeficiency (CVID is the most frequent symptomatic primary immunodeficiency characterized by recurrent infections, hypogammaglobulinemia and poor response to vaccines. Its diagnosis is made based on clinical and immunological criteria, after exclusion of other diseases that can cause similar phenotypes. Currently, less than 20% of cases of CVID have a known underlying genetic cause. We have analyzed whole-exome sequencing and copy number variants data of 36 children and adolescents diagnosed with CVID and healthy relatives to estimate the proportion of monogenic cases. We have replicated an association of CVID to p.C104R in TNFRSF13B and reported the second case of homozygous patient to date. Our results also identify five causative genetic variants in LRBA, CTLA4, NFKB1, and PIK3R1, as well as other very likely causative variants in PRKCD, MAPK8, or DOCK8 among others. We experimentally validate the effect of the LRBA stop-gain mutation which abolishes protein production and downregulates the expression of CTLA4, and of the frameshift indel in CTLA4 producing expression downregulation of the protein. Our results indicate a monogenic origin of at least 15–24% of the CVID cases included in the study. The proportion of monogenic patients seems to be lower in CVID than in other PID that have also been analyzed by whole exome or targeted gene panels sequencing. Regardless of the exact proportion of CVID monogenic cases, other genetic models have to be considered for CVID. We propose that because of its prevalence and other features as intermediate penetrancies and phenotypic variation within families, CVID could fit with other more complex genetic scenarios. In particular, in this work, we explore the possibility of CVID being originated by an oligogenic model with the presence of heterozygous mutations in interacting proteins or by the accumulation of detrimental variants in particular immunological pathways, as well as

Genetics of Infectious and Inflammatory Diseases: Overlapping Discoveries from Association and Exome-Sequencing Studies.

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Langlais, David; Fodil, Nassima; Gros, Philippe

2017-04-26

Genome technologies have defined a complex genetic architecture in major infectious, inflammatory, and autoimmune disorders. High density marker arrays and Immunochips have powered genome-wide association studies (GWAS) that have mapped nearly 450 genetic risk loci in 22 major inflammatory diseases, including a core of common genes that play a central role in pathological inflammation. Whole-exome and whole-genome sequencing have identified more than 265 genes in which mutations cause primary immunodeficiencies and rare forms of severe inflammatory bowel disease. Combined analysis of inflammatory disease GWAS and primary immunodeficiencies point to shared proteins and pathways that are required for immune cell development and protection against infections and are also associated with pathological inflammation. Finally, sequencing of chromatin immunoprecipitates containing specific transcription factors, with parallel RNA sequencing, has charted epigenetic regulation of gene expression by proinflammatory transcription factors in immune cells, providing complementary information to characterize morbid genes at infectious and inflammatory disease loci.

Common Genetic Variation and Haplotypes of the Anion Exchanger SLC4A2 in Primary Biliary Cirrhosis

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Juran, Brian D.; Atkinson, Elizabeth J.; Larson, Joseph J.; Schlicht, Erik M.; Lazaridis, Konstantinos N.

2010-01-01

Objectives Deficiencies of the anion exchanger SLC4A2 are thought to play a pathogenic role in primary biliary cirrhosis (PBC), evidenced by decreased expression and activity in PBC patients and development of disease features in SLC4A2 knockout mice. We hypothesized that genetic variation in SLC4A2 might influence this pathogenic contribution. Thus, we aimed to perform a comprehensive assessment of SLC4A2 genetic variation in PBC using a linkage disequilibrium (LD)-based haplotype-tagging approach. Methods Twelve single nucleotide polymorphisms (SNPs) across SLC4A2 were genotyped in 409 PBC patients and 300 controls and evaluated for association with disease, as well as with prior orthotopic liver transplant and antimitochondrial antibody (AMA) status among the PBC patients, both individually and as inferred haplotypes, using logistic regression. Results All SNPs were in Hardy–Weinberg equilibrium. No associations with disease or liver transplantation were detected, but two variants, rs2303929 and rs3793336, were associated with negativity for antimitochondrial antibodies among the PBC patients. Conclusions The common genetic variation of SLC4A2 does not directly affect the risk of PBC or its clinical outcome. Whether the deficiency of SLC4A2 expression and activity observed earlier in PBC patients is an acquired epiphenomenon of underlying disease or is because of heritable factors in unappreciated regulatory regions remains uncertain. Of note, two SLC4A2 variants appear to influence AMA status among PBC patients. The mechanisms behind this finding are unclear. PMID:19491853

Trends in population-based studies of human genetics in infectious diseases.

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Rowell, Jessica L; Dowling, Nicole F; Yu, Wei; Yesupriya, Ajay; Zhang, Lyna; Gwinn, Marta

2012-01-01

Pathogen genetics is already a mainstay of public health investigation and control efforts; now advances in technology make it possible to investigate the role of human genetic variation in the epidemiology of infectious diseases. To describe trends in this field, we analyzed articles that were published from 2001 through 2010 and indexed by the HuGE Navigator, a curated online database of PubMed abstracts in human genome epidemiology. We extracted the principal findings from all meta-analyses and genome-wide association studies (GWAS) with an infectious disease-related outcome. Finally, we compared the representation of diseases in HuGE Navigator with their contributions to morbidity worldwide. We identified 3,730 articles on infectious diseases, including 27 meta-analyses and 23 GWAS. The number published each year increased from 148 in 2001 to 543 in 2010 but remained a small fraction (about 7%) of all studies in human genome epidemiology. Most articles were by authors from developed countries, but the percentage by authors from resource-limited countries increased from 9% to 25% during the period studied. The most commonly studied diseases were HIV/AIDS, tuberculosis, hepatitis B infection, hepatitis C infection, sepsis, and malaria. As genomic research methods become more affordable and accessible, population-based research on infectious diseases will be able to examine the role of variation in human as well as pathogen genomes. This approach offers new opportunities for understanding infectious disease susceptibility, severity, treatment, control, and prevention.

Genetics Home Reference: non-alcoholic fatty liver disease

Science.gov (United States)

... individual is considered to have a fatty liver (hepatic steatosis) if the liver contains more than 5 to ... Resources Genetic Testing (2 links) Genetic Testing Registry: Fatty liver disease, nonalcoholic 1 Genetic Testing Registry: Fatty liver ...

Genetic factors and molecular mechanisms in dry eye disease.

Science.gov (United States)

Lee, Ling; Garrett, Qian; Flanagan, Judith; Chakrabarti, Subhabrata; Papas, Eric

2018-04-01

Dry eye disease (DED) is a complex condition with a multifactorial etiology that can be difficult to manage successfully. While external factors are modifiable, treatment success is limited if genetic factors contribute to the disease. The purpose of this review is to compile research describing normal and abnormal ocular surface function on a molecular level, appraise genetic studies involving DED or DED-associated diseases, and introduce the basic methods used for conducting genetic epidemiology studies. Copyright © 2018 Elsevier Inc. All rights reserved.

Psoriasis Patients Are Enriched for Genetic Variants That Protect against HIV-1 Disease

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Chen, Haoyan; Hayashi, Genki; Lai, Olivia Y.; Dilthey, Alexander; Kuebler, Peter J.; Wong, Tami V.; Martin, Maureen P.; Fernandez Vina, Marcelo A.; McVean, Gil; Wabl, Matthias; Leslie, Kieron S.; Maurer, Toby; Martin, Jeffrey N.; Deeks, Steven G.; Carrington, Mary; Bowcock, Anne M.; Nixon, Douglas F.; Liao, Wilson

2012-01-01

An important paradigm in evolutionary genetics is that of a delicate balance between genetic variants that favorably boost host control of infection but which may unfavorably increase susceptibility to autoimmune disease. Here, we investigated whether patients with psoriasis, a common immune-mediated disease of the skin, are enriched for genetic variants that limit the ability of HIV-1 virus to replicate after infection. We analyzed the HLA class I and class II alleles of 1,727 Caucasian psoriasis cases and 3,581 controls and found that psoriasis patients are significantly more likely than controls to have gene variants that are protective against HIV-1 disease. This includes several HLA class I alleles associated with HIV-1 control; amino acid residues at HLA-B positions 67, 70, and 97 that mediate HIV-1 peptide binding; and the deletion polymorphism rs67384697 associated with high surface expression of HLA-C. We also found that the compound genotype KIR3DS1 plus HLA-B Bw4-80I, which respectively encode a natural killer cell activating receptor and its putative ligand, significantly increased psoriasis susceptibility. This compound genotype has also been associated with delay of progression to AIDS. Together, our results suggest that genetic variants that contribute to anti-viral immunity may predispose to the development of psoriasis. PMID:22577363

Gene-Environment Interplay in Common Complex Diseases: Forging an Integrative Model—Recommendations From an NIH Workshop

Science.gov (United States)

Bookman, Ebony B.; McAllister, Kimberly; Gillanders, Elizabeth; Wanke, Kay; Balshaw, David; Rutter, Joni; Reedy, Jill; Shaughnessy, Daniel; Agurs-Collins, Tanya; Paltoo, Dina; Atienza, Audie; Bierut, Laura; Kraft, Peter; Fallin, M. Daniele; Perera, Frederica; Turkheimer, Eric; Boardman, Jason; Marazita, Mary L.; Rappaport, Stephen M.; Boerwinkle, Eric; Suomi, Stephen J.; Caporaso, Neil E.; Hertz-Picciotto, Irva; Jacobson, Kristen C.; Lowe, William L.; Goldman, Lynn R.; Duggal, Priya; Gunnar, Megan R.; Manolio, Teri A.; Green, Eric D.; Olster, Deborah H.; Birnbaum, Linda S.

2011-01-01

Although it is recognized that many common complex diseases are a result of multiple genetic and environmental risk factors, studies of gene-environment interaction remain a challenge and have had limited success to date. Given the current state-of-the-science, NIH sought input on ways to accelerate investigations of gene-environment interplay in health and disease by inviting experts from a variety of disciplines to give advice about the future direction of gene-environment interaction studies. Participants of the NIH Gene-Environment Interplay Workshop agreed that there is a need for continued emphasis on studies of the interplay between genetic and environmental factors in disease and that studies need to be designed around a multifaceted approach to reflect differences in diseases, exposure attributes, and pertinent stages of human development. The participants indicated that both targeted and agnostic approaches have strengths and weaknesses for evaluating main effects of genetic and environmental factors and their interactions. The unique perspectives represented at the workshop allowed the exploration of diverse study designs and analytical strategies, and conveyed the need for an interdisciplinary approach including data sharing, and data harmonization to fully explore gene-environment interactions. Further, participants also emphasized the continued need for high-quality measures of environmental exposures and new genomic technologies in ongoing and new studies. PMID:21308768

Functional modules, mutational load and human genetic disease.

Science.gov (United States)

Zaghloul, Norann A; Katsanis, Nicholas

2010-04-01

The ability to generate a massive amount of sequencing and genotyping data is transforming the study of human genetic disorders. Driven by such innovation, it is likely that whole exome and whole-genome resequencing will replace regionally focused approaches for gene discovery and clinical testing in the next few years. However, this opportunity brings a significant interpretative challenge to assigning function and phenotypic variance to common and rare alleles. Understanding the effect of individual mutations in the context of the remaining genomic variation represents a major challenge to our interpretation of disease. Here, we discuss the challenges of assigning mutation functionality and, drawing from the examples of ciliopathies as well as cohesinopathies and channelopathies, discuss possibilities for the functional modularization of the human genome. Functional modularization in addition to the development of physiologically relevant assays to test allele functionality will accelerate our understanding of disease architecture and enable the use of genome-wide sequence data for disease diagnosis and phenotypic prediction in individuals. Copyright 2010 Elsevier Ltd. All rights reserved.

Genetic susceptibility to Grave's disease.

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Li, Hong; Chen, Qiuying

2013-06-01

The variety of clinical presentations of eye changes in patients with Graves' disease (GD) suggests that complex interactions between genetic, environmental, endogenous and local factors influence the severity of Graves' ophthalmopathy (GO). It is thought that the development of GO might be influenced by genetic factors and environmental factors, such as cigarette smoking. At present, however, the role of genetic factors in the development of GO is not known. On the basis of studies with candidate genes and other genetic approaches, several susceptibility loci in GO have been proposed, including immunological genes, human leukocyte antigen (HLA), cytotoxic T-lymphocyte antigen-4 (CTLA-4), regulatory T-cell genes and thyroid-specific genes. This review gives a brief overview of the current range of major susceptibility genes found for GD.

Shared genetics in coeliac disease and other immune-mediated diseases

NARCIS (Netherlands)

Gutierrez-Achury, J.; Coutinho de Almeida, R.; Wijmenga, C.

Gutierrez-Achury J, Coutinho de Almeida R, Wijmenga C (University Medical Centre Groningen and University of Groningen, Groningen, the Netherlands; University of Brasilia School of Health Sciences, Brasilia, DF, Brazil). Shared genetics in coeliac disease and other immune-mediated diseases

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.

The genetics of Alzheimer disease: back to the future.

Science.gov (United States)

Bertram, Lars; Lill, Christina M; Tanzi, Rudolph E

2010-10-21

Three decades of genetic research in Alzheimer disease (AD) have substantially broadened our understanding of the pathogenetic mechanisms leading to neurodegeneration and dementia. Positional cloning led to the identification of rare, disease-causing mutations in APP, PSEN1, and PSEN2 causing early-onset familial AD, followed by the discovery of APOE as the single most important risk factor for late-onset AD. Recent genome-wide association approaches have delivered several additional AD susceptibility loci that are common in the general population, but exert only very small risk effects. As a result, a large proportion of the heritability of AD continues to remain unexplained by the currently known disease genes. It seems likely that much of this "missing heritability" may be accounted for by rare sequence variants, which, owing to recent advances in high-throughput sequencing technologies, can now be assessed in unprecedented detail. Copyright © 2010 Elsevier Inc. All rights reserved.

Multi-taxa integrated landscape genetics for zoonotic infectious diseases: deciphering variables influencing disease emergence.

Science.gov (United States)

Leo, Sarah S T; Gonzalez, Andrew; Millien, Virginie

2016-05-01

Zoonotic disease transmission systems involve sets of species interacting with each other and their environment. This complexity impedes development of disease monitoring and control programs that require reliable identification of spatial and biotic variables and mechanisms facilitating disease emergence. To overcome this difficulty, we propose a framework that simultaneously examines all species involved in disease emergence by integrating concepts and methods from population genetics, landscape ecology, and spatial statistics. Multi-taxa integrated landscape genetics (MTILG) can reveal how interspecific interactions and landscape variables influence disease emergence patterns. We test the potential of our MTILG-based framework by modelling the emergence of a disease system across multiple species dispersal, interspecific interaction, and landscape scenarios. Our simulations showed that both interspecific-dependent dispersal patterns and landscape characteristics significantly influenced disease spread. Using our framework, we were able to detect statistically similar inter-population genetic differences and highly correlated spatial genetic patterns that imply species-dependent dispersal. Additionally, species that were assigned coupled-dispersal patterns were affected to the same degree by similar landscape variables. This study underlines the importance of an integrated approach to investigating emergence of disease systems. MTILG is a robust approach for such studies and can identify potential avenues for targeted disease management strategies.

The development and treatment of Alzheimer’s disease: Some genetic aspects

Directory of Open Access Journals (Sweden)

I. S. Preobrazhenskaya

2014-01-01

Full Text Available The paper gives an update on the occurrence and development of Alzheimer’s disease (AD, a condition manifesting itself as a steady reduction in memory. AD is common in the modern population. The reason for its higher incidence rate is the specific features of the current information sphere. Genetic factors that both directly lead to the development of AD and indirectly influence its occurrence are also imperative. At the present time, the genetic bank of mutations associated with the development of AD contains information on more than 300 different mutations. Genetic predetermination of this disease has a negative impact on prognosis and prospects for patient treatment.Patients and methods. The distribution of hereditary forms of AD in a Russian population was analyzed at the Clinic of Nervous System Diseases, I.M. Sechenov First Moscow State Medical University. The investigation enrolled 46 patients (13 men and 33 women who met the international criteria for AD; all had its proven hereditary history. The patients' mean age was 73.7±8.3 years in the men and 73.4±8.5 in the women; the mean disease duration was 29.6±12.4 and 28.0±18.8 months, respectively. The incidence of AD was estimated depending on age, comorbidity, degree of cognitive impairments, and pattern of the disease. Its history was rated using a questionnaire. No genome mapping was carried out.Results and discussion. The patients were divided into two groups: 1 presenile AD (age at its onset less than 65 years; n=8 and 2 senile AD (age at its onset more than 65 years; n=38. There was a preponderance of patients with mild dementia in both groups; however, in the patients with senile AD, the latter was diagnosed at the stage of moderate cognitive impairments in 7.9% of cases. Comorbidity was mild in all the patients. Depression and behavioral disorders were noted in half of the patients with AD; at the same time, behavioral and emotional disorders were significantly

Genetics Home Reference: uromodulin-associated kidney disease

Science.gov (United States)

... disease Related Information How are genetic conditions and genes named? Additional Information & Resources MedlinePlus (3 links) Health Topic: Gout Health Topic: Kidney Diseases Health Topic: Kidney Failure ...

Genetics of celiac disease

NARCIS (Netherlands)

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

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

Genetics Home Reference: Danon disease

Science.gov (United States)

... are compartments in the cell that digest and recycle materials. The role the LAMP-2 protein plays ... Page Boucek D, Jirikowic J, Taylor M. Natural history of Danon disease. Genet Med. 2011 Jun;13( ...

Genetics Home Reference: Crohn disease

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... JH. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012 Nov 1; ... Health & Human Services National Institutes of Health National Library of Medicine Lister Hill National Center for Biomedical ...

Frequency and distribution of 152 genetic disease variants in over 100,000 mixed breed and purebred dogs.

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Jonas Donner

2018-04-01

Full Text Available Knowledge on the genetic epidemiology of disorders in the dog population has implications for both veterinary medicine and sustainable breeding. Limited data on frequencies of genetic disease variants across breeds exists, and the disease heritage of mixed breed dogs remains poorly explored to date. Advances in genetic screening technologies now enable comprehensive investigations of the canine disease heritage, and generate health-related big data that can be turned into action. We pursued population screening of genetic variants implicated in Mendelian disorders in the largest canine study sample examined to date by examining over 83,000 mixed breed and 18,000 purebred dogs representing 330 breeds for 152 known variants using a custom-designed beadchip microarray. We further announce the creation of MyBreedData (www.mybreeddata.com, an online updated inherited disorder prevalence resource with its foundation in the generated data. We identified the most prevalent, and rare, disease susceptibility variants across the general dog population while providing the first extensive snapshot of the mixed breed disease heritage. Approximately two in five dogs carried at least one copy of a tested disease variant. Most disease variants are shared by both mixed breeds and purebreds, while breed- or line-specificity of others is strongly suggested. Mixed breed dogs were more likely to carry a common recessive disease, whereas purebreds were more likely to be genetically affected with one, providing DNA-based evidence for hybrid vigor. We discovered genetic presence of 22 disease variants in at least one additional breed in which they were previously undescribed. Some mutations likely manifest similarly independently of breed background; however, we emphasize the need for follow up investigations in each case and provide a suggested validation protocol for broader consideration. In conclusion, our study provides unique insight into genetic epidemiology of

Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD.

Directory of Open Access Journals (Sweden)

Wei Sun

2016-08-01

Full Text Available 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

Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD

Science.gov (United States)

Drummond, M. Bradley; Hawkins, Gregory A.; Yang, Jenny; Chen, Ting-huei; Quibrera, Pedro Miguel; Anderson, Wayne; Barr, R. Graham; 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.; 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.

2016-01-01

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

The OncoArray Consortium: a Network for Understanding the Genetic Architecture of Common Cancers

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Amos, Christopher I.; Dennis, Joe; Wang, Zhaoming; Byun, Jinyoung; Schumacher, Fredrick R.; Gayther, Simon A.; Casey, Graham; Hunter, David J.; Sellers, Thomas A.; Gruber, Stephen B.; Dunning, Alison M.; Michailidou, Kyriaki; Fachal, Laura; Doheny, Kimberly; Spurdle, Amanda B.; Li, Yafang; Xiao, Xiangjun; Romm, Jane; Pugh, Elizabeth; Coetzee, Gerhard A.; Hazelett, Dennis J.; Bojesen, Stig E.; Caga-Anan, Charlisse; Haiman, Christopher A.; Kamal, Ahsan; Luccarini, Craig; Tessier, Daniel; Vincent, Daniel; Bacot, François; Van Den Berg, David J.; Nelson, Stefanie; Demetriades, Stephen; Goldgar, David E.; Couch, Fergus J.; Forman, Judith L.; Giles, Graham G.; Conti, David V.; Bickeböller, Heike; Risch, Angela; Waldenberger, Melanie; Brüske, Irene; Hicks, Belynda D.; Ling, Hua; McGuffog, Lesley; Lee, Andrew; Kuchenbaecker, Karoline B.; Soucy, Penny; Manz, Judith; Cunningham, Julie M.; Butterbach, Katja; Kote-Jarai, Zsofia; Kraft, Peter; FitzGerald, Liesel M.; Lindström, Sara; Adams, Marcia; McKay, James D.; Phelan, Catherine M.; Benlloch, Sara; Kelemen, Linda E.; Brennan, Paul; Riggan, Marjorie; O’Mara, Tracy A.; Shen, Hongbin; Shi, Yongyong; Thompson, Deborah J.; Goodman, Marc T.; Nielsen, Sune F.; Berchuck, Andrew; Laboissiere, Sylvie; Schmit, Stephanie L.; Shelford, Tameka; Edlund, Christopher K.; Taylor, Jack A.; Field, John K.; Park, Sue K.; Offit, Kenneth; Thomassen, Mads; Schmutzler, Rita; Ottini, Laura; Hung, Rayjean J.; Marchini, Jonathan; Al Olama, Ali Amin; Peters, Ulrike; Eeles, Rosalind A.; Seldin, Michael F.; Gillanders, Elizabeth; Seminara, Daniela; Antoniou, Antonis C.; Pharoah, Paul D.; Chenevix-Trench, Georgia; Chanock, Stephen J.; Simard, Jacques; Easton, Douglas F.

2016-01-01

Background Common cancers develop through a multistep process often including inherited susceptibility. Collaboration among multiple institutions, and funding from multiple sources, has allowed the development of an inexpensive genotyping microarray, the OncoArray. The array includes a genome-wide backbone, comprising 230,000 SNPs tagging most common genetic variants, together with dense mapping of known susceptibility regions, rare variants from sequencing experiments, pharmacogenetic markers and cancer related traits. Methods The OncoArray can be genotyped using a novel technology developed by Illumina to facilitate efficient genotyping. The consortium developed standard approaches for selecting SNPs for study, for quality control of markers and for ancestry analysis. The array was genotyped at selected sites and with prespecified replicate samples to permit evaluation of genotyping accuracy among centers and by ethnic background. Results The OncoArray consortium genotyped 447,705 samples. A total of 494,763 SNPs passed quality control steps with a sample success rate of 97% of the samples. Participating sites performed ancestry analysis using a common set of markers and a scoring algorithm based on principal components analysis. Conclusions Results from these analyses will enable researchers to identify new susceptibility loci, perform fine mapping of new or known loci associated with either single or multiple cancers, assess the degree of overlap in cancer causation and pleiotropic effects of loci that have been identified for disease-specific risk, and jointly model genetic, environmental and lifestyle related exposures. Impact Ongoing analyses will shed light on etiology and risk assessment for many types of cancer. PMID:27697780

[Preimplantation genetic diagnosis and monogenic inherited eye diseases].

Science.gov (United States)

Hlavatá, L; Ďuďáková, Ľ; Trková, M; Soldátová, I; Skalická, P; Kousal, B; Lišková, P

Preimplantation genetic diagnosis (PGD) is an established application of genetic testing in the context of in vitro fertilization. PGD is an alternative method to prenatal diagnosis which aims to prevent the transmission of an inherited disorder to the progeny by implanting only embryos that do not carry genetic predisposition for a particular disease. The aim of this study is to provide an overview of eye disorders for which PGD has been carried out. The European literature search focused on best practices, ethical issues, risks and results of PGD for inherited eye disorders. PGD is performed for a number of ocular disorders; a prerequisite for its application is however, the knowledge of a disease-causing mutation(s). The main advantage of this method is that the couple is not exposed to a decision of whether or not to undergo an abortion. Qualified counselling must be provided prior to the PGD in order to completely understand the risk of disability in any child conceived, consequences of disease manifestation, and advantages as well as limitations of this method. In the group of non-syndromic eye diseases and diseases in which ocular findings dominate, PGD has been performed in European countries for aniridia, choroideremia, congenital fibrosis of extraocular muscles, Leber congenital amaurosis, ocular albinism, retinitis pigmentosa, X-linked retinoschisis, Stargardt disease, blepharophimosis-ptosis-inverse epicanthus syndrome and retinoblastoma. Sexing for X-linked or mitochondrial diseases has been carried out for blue cone monochromatism, choroideremia, familial exudative vitreoretinopathy, Leber hereditary optic neuropathy, macular dystrophy (not further specified), Norrie disease, X-linked congenital stationary night blindness, X-linked retinoschisis and nystagmus (not further specified). In recent years, there has been an increase in potential to use PGD. The spectrum of diseases for this method has widened to include severe inherited eye diseases

[Genetic diagnostics of cancer diseases].

Science.gov (United States)

Cobilanschi, Joana

2013-11-27

Cancer is caused by genetic alterations, but only 10% of the cancer diseases are inherited. The probability for an individual or a family of having inherited cancer, individual consequences of the respective results of genetic testing, as well as its costs and reimbursement by the health insurance must be addressed by expert genetic counseling which at-risk requires special expertise. Identification of a germline mutation which may predispose to a variety of different cancer types allows determination of an individual's specific life time risk in symptomatic as well as in a-symptomatic family members. Identification of the underlying defective gene in heritable cancer disorders also enables optimized preventive and novel therapeutic approaches specifically targeting the underlying molecular pathomechanisms.

Genetic and familial predisposition to rotator cuff disease: a systematic review.

Science.gov (United States)

Dabija, Dominique I; Gao, Chan; Edwards, Todd L; Kuhn, John E; Jain, Nitin B

2017-06-01

Rotator cuff disease is a common disorder leading to shoulder pain and loss of function. Its etiology in atraumatic cases is uncertain and is likely to extend beyond repetitive microtrauma or overuse. Our objective was to determine whether there is a genetic or familial predisposition to rotator cuff disease. A literature search of PubMed and Embase databases identified 251 citations. After review of the titles, abstracts, and full articles, 7 met our inclusion and exclusion criteria. Four studies assessed familial predisposition to rotator cuff disease. One of these demonstrated that siblings of an individual with a rotator cuff tear were more likely to develop a full-thickness tear and more likely to be symptomatic. A 5-year follow-up showed that the relative risks were increased for the siblings to have a full-thickness tear, for a tear to progress in size, and for being symptomatic. Another study demonstrated that a significantly higher number of individuals with tears had family members with a history of tears or surgery than those without tears did. The other 3 studies investigated whether a genetic predisposition to rotator cuff disease exists and found significant association of haplotypes in DEFB1, FGFR1, FGF3, ESRRB, and FGF10 and 2 single-nucleotide polymorphisms within SAP30BP and SASH1. Prior studies provide preliminary evidence for genetic and familial predisposition to rotator cuff disease. However, there is a lack of large genome-wide studies that can provide more definitive information and guide early detection of individuals at risk, prophylactic rehabilitation, and potential gene therapies and regenerative medicine interventions. Copyright © 2016 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.

Common and Rare Genetic Variants Associated With Alzheimer's Disease.

Science.gov (United States)

Marei, Hany E; Althani, Asmaa; Suhonen, Jaana; El Zowalaty, Mohamed E; Albanna, Mohammad A; Cenciarelli, Carlo; Wang, Tengfei; Caceci, Thomas

2016-07-01

Alzheimer's disease (AD) is one of the most devastating disorders. Despite the continuing increase of its incidence among aging populations, no effective cure has been developed mainly due to difficulties in early diagnosis of the disease before damaging of the brain, and the failure to explore its complex underlying molecular mechanisms. Recent technological advances in genome-wide association studies (GWAS) and high throughput next generation whole genome, and exome sequencing had deciphered many of AD-related loci, and discovered single nucleotide polymorphisms (SNPs) that are associated with altered AD molecular pathways. Highlighting altered molecular pathways linked to AD pathogenesis is crucial to identify novel diagnostic and therapeutic AD targets. © 2015 Wiley Periodicals, Inc.

Genetically Determined Height and Coronary Artery Disease

NARCIS (Netherlands)

Nelson, Christopher P.; Hamby, Stephen E.; Saleheen, Danish; Hopewell, Jenna C.; Zeng, Lingyao; Assimes, Themistocles L.; Kanoni, Stavroula; Willenborg, Christina; Burgess, Stephen; Amouyel, Phillipe; Anand, Sonia; Blankenberg, Stefan; Boehm, Bernhard O.; Clarke, Robert J.; Collins, Rory; Dedoussis, George; Farrall, Martin; Franks, Paul W.; Groop, Leif; Hall, Alistair S.; Hamsten, Anders; Hengstenberg, Christian; Hovingh, G. Kees; Ingelsson, Erik; Kathiresan, Sekar; Kee, Frank; König, Inke R.; Kooner, Jaspal; Lehtimäki, Terho; März, Winifred; McPherson, Ruth; Metspalu, Andres; Nieminen, Markku S.; O'Donnell, Christopher J.; Palmer, Colin N. A.; Peters, Annette; Perola, Markus; Reilly, Muredach P.; Ripatti, Samuli; Roberts, Robert; Salomaa, Veikko; Shah, Svati H.; Schreiber, Stefan; Siegbahn, Agneta; Thorsteinsdottir, Unnur; Veronesi, Giovani; Wareham, Nicholas; Willer, Cristen J.; Zalloua, Pierre A.; Erdmann, Jeanette

2015-01-01

BACKGROUND The nature and underlying mechanisms of an inverse association between adult height and the risk of coronary artery disease (CAD) are unclear. METHODS We used a genetic approach to investigate the association between height and CAD, using 180 height-associated genetic variants. We tested

Current Views on Genetics and Epigenetics of Cholesterol Gallstone Disease

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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.

Is Autism a Member of a Family of Diseases Resulting from Genetic/Cultural Mismatches? Implications for Treatment and Prevention

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Staci D. Bilbo

2012-01-01

Full Text Available Several lines of evidence support the view that autism is a typical member of a large family of immune-related, noninfectious, chronic diseases associated with postindustrial society. This family of diseases includes a wide range of inflammatory, allergic, and autoimmune diseases and results from consequences of genetic/culture mismatches which profoundly destabilize the immune system. Principle among these consequences is depletion of important components, particularly helminths, from the ecosystem of the human body, the human biome. Autism shares a wide range of features in common with this family of diseases, including the contribution of genetics/epigenetics, the identification of disease-inducing triggers, the apparent role of immunity in pathogenesis, high prevalence, complex etiologies and manifestations, and potentially some aspects of epidemiology. Fortunately, using available resources and technology, modern medicine has the potential to effectively reconstitute the human biome, thus treating or even avoiding altogether the consequences of genetic/cultural mismatches which underpin this entire family of disease. Thus, if indeed autism is an epidemic of postindustrial society associated with immune hypersensitivity, we can expect that the disease is readily preventable.

Common Genetic Components of Obesity Traits and Serum Leptin

DEFF Research Database (Denmark)

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

2008-01-01

To estimate common and distinct genetic influences on a panel of obesity-related traits and serum leptin level in adults. In a cross-sectional study of 625 Danish, adult, healthy, monozygotic, and same-sex dizygotic twin pairs of both genders, we carried out detailed anthropometry (height, weight...... components, which suggests that it is important to distinguish between the different phenotypes in the search for genes involved in the development of obesity.Obesity (2008) doi:10.1038/oby.2008.440........ For leptin vs. the various measures of overall and local fatness the correlations ranged from 0.54 to 0.74 in men and from 0.48 to 0.75 in women. All correlations were significantly different genetic...

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

NARCIS (Netherlands)

C.M. van Duijn (Cornelia)

1992-01-01

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

Genetic variation of common walnut (Juglans regia in Piedmont, Northwestern Italy

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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.

Genetics of Human and Canine Dilated Cardiomyopathy.

Science.gov (United States)

Simpson, Siobhan; Edwards, Jennifer; Ferguson-Mignan, Thomas F N; Cobb, Malcolm; Mongan, Nigel P; Rutland, Catrin S

2015-01-01

Cardiovascular disease is a leading cause of death in both humans and dogs. Dilated cardiomyopathy (DCM) accounts for a large number of these cases, reported to be the third most common form of cardiac disease in humans and the second most common in dogs. In human studies of DCM there are more than 50 genetic loci associated with the disease. Despite canine DCM having similar disease progression to human DCM studies into the genetic basis of canine DCM lag far behind those of human DCM. In this review the aetiology, epidemiology, and clinical characteristics of canine DCM are examined, along with highlighting possible different subtypes of canine DCM and their potential relevance to human DCM. Finally the current position of genetic research into canine and human DCM, including the genetic loci, is identified and the reasons many studies may have failed to find a genetic association with canine DCM are reviewed.

Eye and rare genetic diseases: Case series and literature review ...

African Journals Online (AJOL)

Genetic diseases are generally characterised by a multi visceral pathogenesis. Although orphan, these diseases interest many disciplines due to their clinical expression. Eye is sometimes part of the clinical polymorphism of some rare genetic diseases. Ocular signs are in some cases leading to the diagnosis of these ...

Host genetic risk factors for West Nile virus infection and disease progression.

Directory of Open Access Journals (Sweden)

Abigail W Bigham

Full Text Available West Nile virus (WNV, a category B pathogen endemic in parts of Africa, Asia and Europe, emerged in North America in 1999, and spread rapidly across the continental U.S. Outcomes of infection with WNV range from asymptomatic to severe neuroinvasive disease manifested as encephalitis, paralysis, and/or death. Neuroinvasive WNV disease occurs in less than one percent of cases, and although host genetic factors are thought to influence risk for symptomatic disease, the identity of these factors remains largely unknown. We tested 360 common haplotype tagging and/or functional SNPs in 86 genes that encode key regulators of immune function in 753 individuals infected with WNV including: 422 symptomatic WNV cases and 331 cases with asymptomatic infections. After applying a Bonferroni correction for multiple tests and controlling for population stratification, SNPs in IRF3 (OR 0.54, p = 0.035 and MX1, (OR 0.19, p = 0.014 were associated with symptomatic WNV infection and a single SNP in OAS1 (OR 9.79, p = 0.003 was associated with increased risk for West Nile encephalitis and paralysis (WNE/P. Together, these results suggest that genetic variation in the interferon response pathway is associated with both risk for symptomatic WNV infection and WNV disease progression.

Genetics of Human and Canine Dilated Cardiomyopathy

OpenAIRE

Siobhan Simpson; Jennifer Edwards; Thomas F. N. Ferguson-Mignan; Malcolm Cobb; Nigel P. Mongan; Catrin S. Rutland

2015-01-01

Cardiovascular disease is a leading cause of death in both humans and dogs. Dilated cardiomyopathy (DCM) accounts for a large number of these cases, reported to be the third most common form of cardiac disease in humans and the second most common in dogs. In human studies of DCM there are more than 50 genetic loci associated with the disease. Despite canine DCM having similar disease progression to human DCM studies into the genetic basis of canine DCM lag far behind those of human DCM. In th...

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.

The genetics of Ménière’s disease

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Chiarella G

2015-01-01

Full Text Available Giuseppe Chiarella,1 C Petrolo,1 E Cassandro2 1Department of Experimental and Clinical Medicine, Audiology and Phoniatrics Unit, Magna Graecia University of Catanzaro, Catanzaro, Italy; 2Department of Medicine and Surgery, University of Salerno, Salerno, Italy Abstract: Our understanding of the genetic basis of Ménière’s disease (MD is still limited. Although the familial clustering and the geographical and racial differences in incidence strongly suggest a certain role for genetic factors in the development of MD, no convincing evidence for an association with any gene exists, at present. In this review, starting from rational bases for a genetic approach to MD, we explored the numerous reports published in literature and summarize the recent advances in understanding of the genetic fundaments of the disease. Keywords: Mènière’s disease, gene, vertigo, etiology, pathogenesis

How much can a large population study on genes, environments, their interactions and common diseases contribute to the health of the American people?

Science.gov (United States)

Chaufan, Claudia

2007-10-01

I offer a critical perspective on a large-scale population study on gene-environment interactions and common diseases proposed by the US Secretary of Health and Human Services' Advisory Committee on Genetics, Health, and Society (SACGHS). I argue that for scientific and policy reasons this and similar studies have little to add to current knowledge about how to prevent, treat, or decrease inequalities in common diseases, all of which are major claims of the proposal. I use diabetes as an exemplar of the diseases that the study purports to illuminate. I conclude that the question is not whether the study will meet expectations or whether the current emphasis on a genetic paradigm is real or imagined, desirable or not. Rather, the question is why, given the flaws of the science underwriting the study, its assumptions remain unchallenged. Future research should investigate the reasons for this immunity from criticism and for the popularity of this and similar projects among laypersons as well as among intellectuals.

The beginnings of Alzheimer’s disease: A review on inflammatory, mitochondrial, genetic and epigenetic pathways

Directory of Open Access Journals (Sweden)

Perna Simone

2016-01-01

Full Text Available Alzheimer’s Disease (AD is the most common cause of sporadic dementia, as it affects 60% of cognitive impaired patients; it commonly affects middle and late life, and it is considered an age-related disease. Early-onset familial AD is associated with mutations of the genes encoding amyloid precursor protein (APP, presenilin 1 (PS-1, or PS-2, resulting in the overproduction of amyloid beta-protein. Epidemiological and case-control studies have led to the identification of several risk factors for sporadic AD. The most concrete genetic risk factor for AD is the epsilon4 allele of apolipoprotein E gene (APOE. In addition, several genes such as CTNNA3, GAB2, PVRL2, TOMM40, and APOC1 are known to be the risk factors that contribute to AD pathogenesis. A direct role of interaction between genetic and environmental determinants has been proposed in an epigenetic dynamic for environmental factors operating during the preconceptual, fetal and infant phases of life. Also the the association between mtDNA inherited variants and multifactorial diseases and AD has been investigated by a number of studies that, however, didn’t reach a general consensus on the correlation between mtDNA haplogroups and AD.

Genetics of Human and Canine Dilated Cardiomyopathy

Directory of Open Access Journals (Sweden)

Siobhan Simpson

2015-01-01

Full Text Available Cardiovascular disease is a leading cause of death in both humans and dogs. Dilated cardiomyopathy (DCM accounts for a large number of these cases, reported to be the third most common form of cardiac disease in humans and the second most common in dogs. In human studies of DCM there are more than 50 genetic loci associated with the disease. Despite canine DCM having similar disease progression to human DCM studies into the genetic basis of canine DCM lag far behind those of human DCM. In this review the aetiology, epidemiology, and clinical characteristics of canine DCM are examined, along with highlighting possible different subtypes of canine DCM and their potential relevance to human DCM. Finally the current position of genetic research into canine and human DCM, including the genetic loci, is identified and the reasons many studies may have failed to find a genetic association with canine DCM are reviewed.

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.

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...

Preimplantation Genetic Diagnosis for Stargardt Disease

Science.gov (United States)

Sohrab, Mahsa A.; Allikmets, Rando; Guarnaccia, Michael M.; Smith, R. Theodore

2010-01-01

Purpose To report the first use of in vitro fertilization (IVF) and preimplantation genetic diagnosis to achieve an unaffected pregnancy in an autosomal-recessive retinal dystrophy. Design Case report. Methods An affected male with Stargardt disease and his carrier wife underwent IVF. Embryos obtained by intracytoplasmic sperm injection underwent single-cell DNA testing via polymerase chain reaction and restriction enzyme analysis to detect the presence of ABCA4 mutant alleles. Embryos were diagnosed as being either affected by or carriers for Stargardt disease. A single carrier embryo was implanted. Results Chorionic villus sampling performed during the first trimester verified that the fetus possessed only one mutant paternal allele and one normal maternal allele, thus making her an unaffected carrier of the disease. A healthy, live-born female was delivered. Conclusion IVF and preimplantation genetic diagnosis can assist couples with an affected spouse and a carrier spouse with recessive retinal dystrophies to have an unaffected child. PMID:20149343

Biomarkers and Genetics in Peripheral Artery Disease.

Science.gov (United States)

Hazarika, Surovi; Annex, Brian H

2017-01-01

Peripheral artery disease (PAD) is highly prevalent and there is considerable diversity in the initial clinical manifestation and disease progression among individuals. Currently, there is no ideal biomarker to screen for PAD, to risk stratify patients with PAD, or to monitor therapeutic response to revascularization procedures. Advances in human genetics have markedly enhanced the ability to develop novel diagnostic and therapeutic approaches across a host of human diseases, but such developments in the field of PAD are lagging. In this article, we will discuss the epidemiology, traditional risk factors for, and clinical presentations of PAD. We will discuss the possible role of genetic factors and gene-environment interactions in the development and/or progression of PAD. We will further explore future avenues through which genetic advances can be used to better our understanding of the pathophysiology of PAD and potentially find newer therapeutic targets. We will discuss the potential role of biomarkers in identifying patients at risk for PAD and for risk stratifying patients with PAD, and novel approaches to identification of reliable biomarkers in PAD. The exponential growth of genetic tools and newer technologies provides opportunities to investigate and identify newer pathways in the development and progression of PAD, and thereby in the identification of newer biomarkers and therapies. © 2016 American Association for Clinical Chemistry.

Genotype-phenotype correlations in a mountain population community with high prevalence of Wilson's disease: genetic and clinical homogeneity.

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Relu Cocoş

Full Text Available Wilson's disease is an autosomal recessive disorder caused by more than 500 mutations in ATP7B gene presenting considerably clinical manifestations heterogeneity even in patients with a particular mutation. Previous findings suggested a potential role of additional genetic modifiers and environment factors on phenotypic expression among the affected patients. We conducted clinical and genetic investigations to perform genotype-phenotype correlation in two large families living in a socio-culturally isolated community with the highest prevalence of Wilson's disease ever reported of 1 ∶ 1130. Sequencing of ATP7B gene in seven affected individuals and 43 family members identified a common compound heterozygous genotype, H1069Q/M769H-fs, in five symptomatic and two asymptomatic patients and detected the presence of two out of seven identified single nucleotide polymorphisms in all affected patients. Symptomatic patients had similar clinical phenotype and age at onset (18 ± 1 years showing dysarthria and dysphagia as common clinical features at the time of diagnosis. Moreover, all symptomatic patients presented Kayser-Fleischer rings and lack of dystonia accompanied by unfavourable clinical outcomes. Our findings add value for understanding of genotype-phenotype correlations in Wilson's disease based on a multifamily study in an isolated population with high extent of genetic and environmental homogeneity as opposed to majority of reports. We observed an equal influence of presumed other genetic modifiers and environmental factors on clinical presentation and age at onset of Wilson's disease in patients with a particular genotype. These data provide valuable inferences that could be applied for predicting clinical management in asymptomatic patients in such communities.

The Collaborative Cross Resource for Systems Genetics Research of Infectious Diseases.

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Maurizio, Paul L; Ferris, Martin T

2017-01-01

An increasing body of evidence highlights the role of host genetic variation in driving susceptibility to severe disease following pathogen infection. In order to fully appreciate the importance of host genetics on infection susceptibility and resulting disease, genetically variable experimental model systems should be employed. These systems allow for the identification, characterization, and mechanistic dissection of genetic variants that cause differential disease responses. Herein we discuss application of the Collaborative Cross (CC) panel of recombinant inbred strains to study viral pathogenesis, focusing on practical considerations for experimental design, assessment and analysis of disease responses within the CC, as well as some of the resources developed for the CC. Although the focus of this chapter is on viral pathogenesis, many of the methods presented within are applicable to studies of other pathogens, as well as to case-control designs in genetically diverse populations.

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

Science.gov (United States)

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

2016-01-09

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

Prospect of Induced Pluripotent Stem Cell Genetic Repair to Cure Genetic Diseases

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Jeanne Adiwinata Pawitan

2012-01-01

Full Text Available In genetic diseases, where the cells are already damaged, the damaged cells can be replaced by new normal cells, which can be differentiated from iPSC. To avoid immune rejection, iPSC from the patient’s own cell can be developed. However, iPSC from the patients’s cell harbors the same genetic aberration. Therefore, before differentiating the iPSCs into required cells, genetic repair should be done. This review discusses the various technologies to repair the genetic aberration in patient-derived iPSC, or to prevent the genetic aberration to cause further damage in the iPSC-derived cells, such as Zn finger and TALE nuclease genetic editing, RNA interference technology, exon skipping, and gene transfer method. In addition, the challenges in using the iPSC and the strategies to manage the hurdles are addressed.

Parkinson's disease: piecing together a genetic jigsaw.

NARCIS (Netherlands)

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

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

Genetics of bipolar disorder

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Kerner B

2014-02-01

Full Text Available Berit Kerner Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA Abstract: Bipolar disorder is a common, complex genetic disorder, but the mode of transmission remains to be discovered. Many researchers assume that common genomic variants carry some risk for manifesting the disease. The research community has celebrated the first genome-wide significant associations between common single nucleotide polymorphisms (SNPs and bipolar disorder. Currently, attempts are under way to translate these findings into clinical practice, genetic counseling, and predictive testing. However, some experts remain cautious. After all, common variants explain only a very small percentage of the genetic risk, and functional consequences of the discovered SNPs are inconclusive. Furthermore, the associated SNPs are not disease specific, and the majority of individuals with a “risk” allele are healthy. On the other hand, population-based genome-wide studies in psychiatric disorders have rediscovered rare structural variants and mutations in genes, which were previously known to cause genetic syndromes and monogenic Mendelian disorders. In many Mendelian syndromes, psychiatric symptoms are prevalent. Although these conditions do not fit the classic description of any specific psychiatric disorder, they often show nonspecific psychiatric symptoms that cross diagnostic boundaries, including intellectual disability, behavioral abnormalities, mood disorders, anxiety disorders, attention deficit, impulse control deficit, and psychosis. Although testing for chromosomal disorders and monogenic Mendelian disorders is well established, testing for common variants is still controversial. The standard concept of genetic testing includes at least three broad criteria that need to be fulfilled before new genetic tests should be introduced: analytical validity, clinical validity, and clinical utility. These criteria are

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 important investigation ... result from the same streptococcal infection. .... musculoskeletal system. ... Prediction of histopathology from clinical.

Common dental and periodontal diseases: evaluation and management.

Science.gov (United States)

Laudenbach, Joel M; Simon, Ziv

2014-11-01

Physicians may encounter patients with dental and periodontal diseases in the context of outpatient medical practice. It is important for physicians to be aware of common dental and periodontal conditions and be able to assess for the presence and severity of these diseases. This article reviews common dental and periodontal conditions, their cardinal signs and symptoms, outpatient-setting assessment techniques, as well as common methods of treatment. Physicians detecting gross abnormalities on clinical examination should refer the patient to a dentist for further evaluation and management. Copyright © 2014 Elsevier Inc. All rights reserved.

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...

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.

Human genetics of infectious diseases: between proof of principle and paradigm.

Science.gov (United States)

Alcaïs, Alexandre; Abel, Laurent; Casanova, Jean-Laurent

2009-09-01

The observation that only a fraction of individuals infected by infectious agents develop clinical disease raises fundamental questions about the actual pathogenesis of infectious diseases. Epidemiological and experimental evidence is accumulating to suggest that human genetics plays a major role in this process. As we discuss here, human predisposition to infectious diseases seems to cover a continuous spectrum from monogenic to polygenic inheritance. Although many studies have provided proof of principle that infectious diseases may result from various types of inborn errors of immunity, the genetic determinism of most infectious diseases in most patients remains unclear. However, in the future, studies in human genetics are likely to establish a new paradigm for infectious diseases.

RARE DISEASES AND GENETIC DISCRIMINATION

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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

Genetic analysis of infectious diseases: Estimating gene effects for susceptibility and infectivity

NARCIS (Netherlands)

Anche, M.T.; Bijma, P.; Jong, de M.C.M.

2015-01-01

Background: Genetic selection of livestock against infectious diseases can complement existing interventions to control infectious diseases. Most genetic approaches that aim at reducing disease prevalence assume that individual disease status (infected/not-infected) is solely a function of its

Defining the genetic connection linking amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD).

Science.gov (United States)

Lattante, Serena; Ciura, Sorana; Rouleau, Guy A; Kabashi, Edor

2015-05-01

Several genetic causes have been recently described for neurological diseases, increasing our knowledge of the common pathological mechanisms involved in these disorders. Mutation analysis has shown common causative factors for two major neurodegenerative disorders, ALS and FTD. Shared pathological and genetic markers as well as common neurological signs between these diseases have given rise to the notion of an ALS/FTD spectrum. This overlap among genetic factors causing ALS/FTD and the coincidence of mutated alleles (including causative, risk and modifier variants) have given rise to the notion of an oligogenic model of disease. In this review we summarize major advances in the elucidation of novel genetic factors in these diseases which have led to a better understanding of the common pathogenic factors leading to neurodegeneration. Copyright © 2015 Elsevier Ltd. All rights reserved.

The Human Phenotype Ontology: Semantic Unification of Common and Rare Disease

Science.gov (United States)

Groza, Tudor; Köhler, Sebastian; Moldenhauer, Dawid; Vasilevsky, Nicole; Baynam, Gareth; Zemojtel, Tomasz; Schriml, Lynn Marie; Kibbe, Warren Alden; Schofield, Paul N.; Beck, Tim; Vasant, Drashtti; Brookes, Anthony J.; Zankl, Andreas; Washington, Nicole L.; Mungall, Christopher J.; Lewis, Suzanna E.; Haendel, Melissa A.; Parkinson, Helen; Robinson, Peter N.

2015-01-01

The Human Phenotype Ontology (HPO) is widely used in the rare disease community for differential diagnostics, phenotype-driven analysis of next-generation sequence-variation data, and translational research, but a comparable resource has not been available for common disease. Here, we have developed a concept-recognition procedure that analyzes the frequencies of HPO disease annotations as identified in over five million PubMed abstracts by employing an iterative procedure to optimize precision and recall of the identified terms. We derived disease models for 3,145 common human diseases comprising a total of 132,006 HPO annotations. The HPO now comprises over 250,000 phenotypic annotations for over 10,000 rare and common diseases and can be used for examining the phenotypic overlap among common diseases that share risk alleles, as well as between Mendelian diseases and common diseases linked by genomic location. The annotations, as well as the HPO itself, are freely available. PMID:26119816

Genetic Testing for Respiratory Disease: Are We There Yet?

Directory of Open Access Journals (Sweden)

Peter D Paré

2012-01-01

Full Text Available The human genome project promised a revolution in health care – the development of ‘personalized medicine’, where knowledge of an individual’s genetic code enables the prediction of risk for specific diseases and the potential to alter that risk based on preventive measures and lifestyle modification. The present brief review provides a report card on the progress toward that goal with respect to respiratory disease. Should generalized population screening for genetic risk factors for respiratory disease be instituted? Or not?

[Genetic counseling and testing for families with Alzheimer's disease].

Science.gov (United States)

Kowalska, Anna

2004-01-01

With the identification of the genes responsible for autosomal dominant early-onset familial Alzheimer's disease (FAD genes), there is a considerable interest in the application of this genetic information in medical practice through genetic testing and counseling. Pathogenic mutations in the PSEN1 and PSEN2 genes encoding presenilin-1 and -2, and the APP gene encoding amyloid b precursor protein, account for 18-50% of familial EOAD cases with autosomal dominant pattern of inheritance. A clinical algorithm of genetic testing and counseling proposed for families with AD has been presented here. A screening for mutations in the APP, PSEN1, and PSEN2 genes is available to individuals with AD symptoms and at-risk children or siblings of patients with early-onset disease determined by a known mutation. In an early-onset family, a known mutation in an affected patient puts the siblings and children at a 50% risk of inheriting the same mutation. The goal of genetic testing is to identify at-risk individuals in order to facilitate early and effective treatments in the symptomatic person based on an individual's genotype and strategies to delay the onset of disease in the presymptomatic mutation carriers. However, there are several arguments against the use of genetic testing both presymptomatically (unpredictable psychological consequences of information about a genetic defect for family members) and as a diagnostic tool for the differential diagnosis of dementia in general practice (a risk of errors in an interpretation of mutation penetrance and its secondary effects on family members, especially for novel mutations; the possibility of coexistence of another form of dementia at the presence of a mutation). Currently, APOE genotyping for presymptomatic individuals with a family history of late-onset disease is not recommended. The APOE4 allele may only confer greater risk for disease, but its presence is not conclusive for the development of AD.

Genetics of allergy and bronchial hyperresponsiveness

NARCIS (Netherlands)

Howard, TD; Wiesch, DG; Koppelman, GH; Postma, DS; Meyers, DA; Bleecker, ER

Allergy and asthma are closely related complex diseases caused by a combination of both genetic and environmental influences. Two common genetic approaches, candidate gene studies and genome-wide screens, have been used to localize and evaluate potential genetic factors that confer susceptibility or

Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval

DEFF Research Database (Denmark)

Lin, Honghuang; van Setten, Jessica; Smith, Albert V

2018-01-01

BACKGROUND: Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequ...

Low-frequency and common genetic variation in ischemic stroke: The METASTROKE collaboration.

Science.gov (United States)

Malik, Rainer; Traylor, Matthew; Pulit, Sara L; Bevan, Steve; Hopewell, Jemma C; Holliday, Elizabeth G; Zhao, Wei; Abrantes, Patricia; Amouyel, Philippe; Attia, John R; Battey, Thomas W K; Berger, Klaus; Boncoraglio, Giorgio B; Chauhan, Ganesh; Cheng, Yu-Ching; Chen, Wei-Min; Clarke, Robert; Cotlarciuc, Ioana; Debette, Stephanie; Falcone, Guido J; Ferro, Jose M; Gamble, Dale M; Ilinca, Andreea; Kittner, Steven J; Kourkoulis, Christina E; Lemmens, Robin; Levi, Christopher R; Lichtner, Peter; Lindgren, Arne; Liu, Jingmin; Meschia, James F; Mitchell, Braxton D; Oliveira, Sofia A; Pera, Joana; Reiner, Alex P; Rothwell, Peter M; Sharma, Pankaj; Slowik, Agnieszka; Sudlow, Cathie L M; Tatlisumak, Turgut; Thijs, Vincent; Vicente, Astrid M; Woo, Daniel; Seshadri, Sudha; Saleheen, Danish; Rosand, Jonathan; Markus, Hugh S; Worrall, Bradford B; Dichgans, Martin

2016-03-29

To investigate the influence of common and low-frequency genetic variants on the risk of ischemic stroke (all IS) and etiologic stroke subtypes. We meta-analyzed 12 individual genome-wide association studies comprising 10,307 cases and 19,326 controls imputed to the 1000 Genomes (1 KG) phase I reference panel. We selected variants showing the highest degree of association (p frequencies for all IS and stroke subtypes. We showed genome-wide significance for 4 loci: ABO for all IS, HDAC9 for large vessel disease (LVD), and both PITX2 and ZFHX3 for cardioembolic stroke (CE). We further refined the association peaks for ABO and PITX2. Analyzing different allele frequency bins, we showed significant enrichment in low-frequency variants (allele frequency frequency variants (allele frequency 10% and 30%) for CE (all p low-frequency and rare variants. Larger sample sizes are needed to identify the variants associated with all IS and stroke subtypes. © 2016 American Academy of Neurology.

Genetics of Autosomal Recessive Polycystic Kidney Disease and Its Differential Diagnoses

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Carsten Bergmann

2018-02-01

Full Text Available Autosomal recessive polycystic kidney disease (ARPKD is a hepatorenal fibrocystic disorder that is characterized by enlarged kidneys with progressive loss of renal function and biliary duct dilatation and congenital hepatic fibrosis that leads to portal hypertension in some patients. Mutations in the PKHD1 gene are the primary cause of ARPKD; however, the disease is genetically not as homogeneous as long thought and mutations in several other cystogenes can phenocopy ARPKD. The family history usually is negative, both for recessive, but also often for dominant disease genes due to de novo arisen mutations or recessive inheritance of variants in genes that usually follow dominant patterns such as the main ADPKD genes PKD1 and PKD2. Considerable progress has been made in the understanding of polycystic kidney disease (PKD. A reduced dosage of disease proteins leads to the disruption of signaling pathways underlying key mechanisms involved in cellular homeostasis, which may help to explain the accelerated and severe clinical progression of disease course in some PKD patients. A comprehensive knowledge of disease-causing genes is essential for counseling and to avoid genetic misdiagnosis, which is particularly important in the prenatal setting (e.g., preimplantation genetic diagnosis/PGD. For ARPKD, there is a strong demand for early and reliable prenatal diagnosis, which is only feasible by molecular genetic analysis. A clear genetic diagnosis is helpful for many families and improves the clinical management of patients. Unnecessary and invasive measures can be avoided and renal and extrarenal comorbidities early be detected in the clinical course. The increasing number of genes that have to be considered benefit from the advances of next-generation sequencing (NGS which allows simultaneous analysis of a large group of genes in a single test at relatively low cost and has become the mainstay for genetic diagnosis. The broad phenotypic and genetic

Protocol for stage 2 of the GaP study (genetic testing acceptability for Paget's disease of bone: A questionnaire study to investigate whether relatives of people with Paget's disease would accept genetic testing and preventive treatment if they were available

Directory of Open Access Journals (Sweden)

McCallum Marilyn

2008-05-01

Full Text Available Abstract Background Paget's disease of bone (PDB disrupts normal bone architecture and causes pain, deformity, deafness, osteoarthritis, and fractures. Genetic factors play a role in PDB and genetic tests are now conducted for research purposes. It is thus timely to investigate the potential for a clinical programme of genetic testing and preventative treatment for people who have a family history of PDB. This study examines the beliefs of relatives of people with PDB. It focuses particularly on illness and treatment representations as predictors of the acceptability and uptake of potential clinical programmes. Illness representations are examined using Leventhal's Common Sense Self-Regulation Model while cognitions about treatment behaviours (acceptance of testing and treatment uptake are conceptualised within the Theory of Planned Behaviour. Methods/Design A postal questionnaire of non-affected relatives of people with Paget's disease. The sample will include relatives of Paget's patients with a family history of Paget's disease and relatives of Paget's patients without a family history of Paget's disease. The questionnaire will explore whether a range of factors relate to acceptability of a programme of genetic testing and preventive treatment in relatives of Paget's disease sufferers. The questionnaire will include several measures: illness representations (as measured by the Brief Illness Perceptions Questionnaire; treatment representations (as measured by Theory of Planned Behaviour-based question items, informed by a prior interview elicitation study; descriptive and demographic details; and questions exploring family environment and beliefs of other important people. Data will also be collected from family members who have been diagnosed with Paget's disease to describe the disease presentation and its distribution within a family. Discussion The answers to these measures will inform the feasibility of a programme of genetic testing and

Common carotid artery disease in Takayasu's arteritis

International Nuclear Information System (INIS)

Hamdan, Nabil; Calderon, Luis I; Castro, Pablo and others

2004-01-01

Takayasu's arteritis is a disease of unknown etiology with main involvement of the common carotid 5 artery and its branches. we report the case of a 69 years old female patient with Tokays arteritis with 2 bilateral involvements of the common carotid arteries, treated with percutaneous angioplasty and Stent implantation

Animal models for human genetic diseases

African Journals Online (AJOL)

Sharif Sons

The study of human genetic diseases can be greatly aided by animal models because of their similarity .... and gene targeting in embryonic stem cells) has been a powerful tool in .... endonucleases that are designed to make a doublestrand.

Impact of gender and genetics on emotion processing in Parkinson's disease - A multimodal study

Directory of Open Access Journals (Sweden)

Julia Heller

Full Text Available Background: Parkinson's disease (PD has been suggested to affect males and females differently. Neuropsychiatric symptoms are common and disabling in PD. However, previous studies focusing on emotion recognition in PD have neglected the confounder of gender and lack evidence on the underlying endocrinal and genetic mechanisms. Moreover, while there are many imaging studies on emotion processing in PD, gender-related analyses of neural data are scarce. We therefore aimed at exploring the interplay of the named factors on emotion recognition and processing in PD. Methods: 51 non-demented PD patients (26 male and 44 age- and gender-matched healthy controls (HC; 25 male were examined clinically and neuropsychologically including an emotion recognition task (Ekman 60faces test. A subsample of 25 patients and 31 HC underwent task-based functional magnetic resonance imaging (fMRI comprised of videos of emotional facial expressions. To examine the impact of hormones and genetics on emotion processing, blood samples were taken for endocrinal (testosterone, estradiol, progesterone and genetic testing (5-HTTLPR, Val158Met COMT polymorphisms. Results: No group or gender differences emerged regarding cognitive abilities. Male but not female PD patients exhibited confined impairments in recognizing the emotion anger accompanied by diminished neural response to facial expressions (e.g. in the putamen and insula. Endocrinologically, fear recognition was positively correlated with estrogen levels in female patients, while on the genetic level we found an effect of Val158Met COMT genotype on the recognition of fear in PD patients. Conclusions: Our study provides evidence that impaired emotion processing in PD specifically affects male patients, and that hormones and genetics contribute to emotion recognition performance. Further research on the underlying neural, endocrinological and genetic mechanisms of specific symptoms in PD is of clinical relevance, as it

Exploration of genetic susceptibility factors for Parkinson's disease

Indian Academy of Sciences (India)

Home; Journals; Journal of Genetics; Volume 89; Issue 2. Exploration of genetic susceptibility factors for Parkinson's disease in a South American sample. Bruno A. Benitez Diego A. Forero Gonzalo H. Arboleda Luis A. Granados Juan J. Yunis William Fernandez Humberto Arboleda. Research Note Volume 89 Issue 2 ...

A strategy to discover genes that carry multi-allelic or mono-allelic risk for common diseases: A cohort allelic sums test (CAST)

International Nuclear Information System (INIS)

Morgenthaler, Stephan; Thilly, William G.

2007-01-01

A method is described to discover if a gene carries one or more allelic mutations that confer risk for any specified common disease. The method does not depend upon genetic linkage of risk-conferring mutations to high frequency genetic markers such as single nucleotide polymorphisms. Instead, the sums of allelic mutation frequencies in case and control cohorts are determined and a statistical test is applied to discover if the difference in these sums is greater than would be expected by chance. A statistical model is presented that defines the ability of such tests to detect significant gene-disease relationships as a function of case and control cohort sizes and key confounding variables: zygosity and genicity, environmental risk factors, errors in diagnosis, limits to mutant detection, linkage of neutral and risk-conferring mutations, ethnic diversity in the general population and the expectation that among all exonic mutants in the human genome greater than 90% will be neutral with regard to any effect on disease risk. Means to test the null hypothesis for, and determine the statistical power of, each test are provided. For this 'cohort allelic sums test' or 'CAST', the statistical model and test are provided as an Excel (TM) program, CASTAT (C) at http://epidemiology.mit.edu. Based on genetics, technology and statistics, a strategy of enumerating the mutant alleles carried in the exons and splice sites of the estimated ∼25,000 human genes in case cohort samples of 10,000 persons for each of 100 common diseases is proposed and evaluated: A wide range of possible conditions of multi-allelic or mono-allelic and monogenic, multigenic or polygenic (including epistatic) risk are found to be detectable using the statistical criteria of 1 or 10 ''false positive'' gene associations per 25,000 gene-disease pair-wise trials and a statistical power of >0.8. Using estimates of the distribution of both neutral and gene-inactivating nondeleterious mutations in humans and

The genetics of Alzheimer's disease

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Bagyinszky E

2014-04-01

Full Text Available Eva Bagyinszky,1 Young Chul Youn,2 Seong Soo A An,1,* SangYun Kim3,*1Department of BioNano Technology Gachon University, Gyeonggi-do, 2Department of Neurology, Chung-Ang University College of Medicine, Seoul, 3Department of Neurology, Seoul National University Budang Hospital, Gyeonggi-do, South Korea*These authors contributed equally to this workAbstract: Alzheimer's disease (AD is a complex and heterogeneous neurodegenerative disorder, classified as either early onset (under 65 years of age, or late onset (over 65 years of age. Three main genes are involved in early onset AD: amyloid precursor protein (APP, presenilin 1 (PSEN1, and presenilin 2 (PSEN2. The apolipoprotein E (APOE E4 allele has been found to be a main risk factor for late-onset Alzheimer's disease. Additionally, genome-wide association studies (GWASs have identified several genes that might be potential risk factors for AD, including clusterin (CLU, complement receptor 1 (CR1, phosphatidylinositol binding clathrin assembly protein (PICALM, and sortilin-related receptor (SORL1. Recent studies have discovered additional novel genes that might be involved in late-onset AD, such as triggering receptor expressed on myeloid cells 2 (TREM2 and cluster of differentiation 33 (CD33. Identification of new AD-related genes is important for better understanding of the pathomechanisms leading to neurodegeneration. Since the differential diagnoses of neurodegenerative disorders are difficult, especially in the early stages, genetic testing is essential for diagnostic processes. Next-generation sequencing studies have been successfully used for detecting mutations, monitoring the epigenetic changes, and analyzing transcriptomes. These studies may be a promising approach toward understanding the complete genetic mechanisms of diverse genetic disorders such as AD.Keywords: dementia, amyloid precursor protein, presenilin 1, presenilin 2, APOE, mutation, diagnosis, genetic testing

Population structure analysis using rare and common functional variants

Directory of Open Access Journals (Sweden)

Ding Lili

2011-11-01

Full Text Available Abstract Next-generation sequencing technologies now make it possible to genotype and measure hundreds of thousands of rare genetic variations in individuals across the genome. Characterization of high-density genetic variation facilitates control of population genetic structure on a finer scale before large-scale genotyping in disease genetics studies. Population structure is a well-known, prevalent, and important factor in common variant genetic studies, but its relevance in rare variants is unclear. We perform an extensive population structure analysis using common and rare functional variants from the Genetic Analysis Workshop 17 mini-exome sequence. The analysis based on common functional variants required 388 principal components to account for 90% of the variation in population structure. However, an analysis based on rare variants required 532 significant principal components to account for similar levels of variation. Using rare variants, we detected fine-scale substructure beyond the population structure identified using common functional variants. Our results show that the level of population structure embedded in rare variant data is different from the level embedded in common variant data and that correcting for population structure is only as good as the level one wishes to correct.

Efficient prion disease transmission through common environmental materials.

Science.gov (United States)

Pritzkow, Sandra; Morales, Rodrigo; Lyon, Adam; Concha-Marambio, Luis; Urayama, Akihiko; Soto, Claudio

2018-03-02

Prion diseases are a group of fatal neurodegenerative diseases associated with a protein-based infectious agent, termed prion. Compelling evidence suggests that natural transmission of prion diseases is mediated by environmental contamination with infectious prions. We hypothesized that several natural and man-made materials, commonly found in the environments of wild and captive animals, can bind prions and may act as vectors for disease transmission. To test our hypothesis, we exposed surfaces composed of various common environmental materials ( i.e. wood, rocks, plastic, glass, cement, stainless steel, aluminum, and brass) to hamster-adapted 263K scrapie prions and studied their attachment and retention of infectivity in vitro and in vivo Our results indicated that these surfaces, with the sole exception of brass, efficiently bind, retain, and release prions. Prion replication was studied in vitro using the protein misfolding cyclic amplification technology, and infectivity of surface-bound prions was analyzed by intracerebrally challenging hamsters with contaminated implants. Our results revealed that virtually all prion-contaminated materials transmitted the disease at high rates. To investigate a more natural form of exposure to environmental contamination, we simply housed animals with large contaminated spheres made of the different materials under study. Strikingly, most of the hamsters developed classical clinical signs of prion disease and typical disease-associated brain changes. Our findings suggest that prion contamination of surfaces commonly present in the environment can be a source of disease transmission, thus expanding our understanding of the mechanisms for prion spreading in nature. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

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.

A database of annotated promoters of genes associated with common respiratory and related diseases

KAUST Repository

Chowdhary, Rajesh; Tan, Sinlam; Pavesi, Giulio; Jin, Gg; Dong, Difeng; Mathur, Sameer K.; Burkart, Arthur; Narang, Vipin; Glurich, Ingrid E.; Raby, Benjamin A.; Weiss, Scott T.; Limsoon, Wong; Liu, Jun; Bajic, Vladimir B.

2012-01-01

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.

Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake

NARCIS (Netherlands)

T. Tanaka (Toshiko); J.S. Ngwa; F.J.A. van Rooij (Frank); M.C. Zillikens (Carola); M.K. Wojczynski (Mary ); A.C. Frazier-Wood (Alexis); D.K. Houston (Denise); S. Kanoni (Stavroula); R.N. Lemaitre (Rozenn ); J. Luan; V. Mikkilä (Vera); F. Renström (Frida); E. Sonestedt (Emily); J.H. Zhao (Jing Hua); A.Y. Chu (Audrey); L. Qi (Lu); D.I. Chasman (Daniel); M.C. De Oliveira Otto (Marcia); E.J. Dhurandhar (Emily); M.F. Feitosa (Mary Furlan); I. Johansson (Ingegerd); K-T. Khaw (Kay-Tee); K. Lohman (Kurt); A. Manichaikul (Ani); N.M. McKeown (Nicola ); D. Mozaffarian (Dariush); A.B. Singleton (Andrew); K. Stirrups (Kathy); J. Viikari (Jorma); Z. Ye (Zheng); S. Bandinelli (Stefania); I.E. Barroso (Inês); P. Deloukas (Panagiotis); N.G. Forouhi (Nita); A. Hofman (Albert); Y. Liu (YongMei); L.-P. Lyytikäinen (Leo-Pekka); K.E. North (Kari); M. Dimitriou (Maria); G. Hallmans (Göran); M. Kähönen (Mika); C. Langenberg (Claudia); J.M. Ordovas (Jose); A.G. Uitterlinden (André); F.B. Hu (Frank); I.-P. Kalafati (Ioanna-Panagiota); O. Raitakari (Olli); O.H. Franco (Oscar); A. Johnson (Anthony); V. Emilsson (Valur); J.A. Schrack (Jennifer); R.D. Semba; D.S. Siscovick (David); D.K. Arnett (Donna); I.B. Borecki (Ingrid); P.W. Franks (Paul); S.B. Kritchevsky (Stephen); R.J.F. Loos (Ruth); M. Orho-Melander (Marju); J.I. Rotter (Jerome); N.J. Wareham (Nick); J.C.M. Witteman (Jacqueline); L. Ferrucci (Luigi); G.V. Dedoussis (George); L.A. Cupples (Adrienne); J.A. Nettleton (Jennifer )

2013-01-01

textabstractBackground: Macronutrient intake varies substantially between individuals, and there is evidence that this variation is partly accounted for by genetic variants. Objective: The objective of the study was to identify common genetic variants that are associated with macronutrient intake.

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. © 2014 John Wiley & Sons Ltd.

The genetics of chronic obstructive pulmonary disease

Directory of Open Access Journals (Sweden)

Silverman Edwin K

2001-01-01

Full Text Available Abstract Chronic obstructive pulmonary disease (COPD is a significant cause of global morbidity and mortality. Previous studies have shown that COPD aggregates in families, suggesting a genetic predisposition to airflow obstruction. Many candidate genes have been assessed, but the data are often conflicting. We review the genetic factors that predispose smokers to COPD and highlight the future role of genomic scans in identifying novel susceptibility genes.

Genetic engineering in nonhuman primates for human disease modeling.

Science.gov (United States)

Sato, Kenya; Sasaki, Erika

2018-02-01

Nonhuman primate (NHP) experimental models have contributed greatly to human health research by assessing the safety and efficacy of newly developed drugs, due to their physiological and anatomical similarities to humans. To generate NHP disease models, drug-inducible methods, and surgical treatment methods have been employed. Recent developments in genetic and developmental engineering in NHPs offer new options for producing genetically modified disease models. Moreover, in recent years, genome-editing technology has emerged to further promote this trend and the generation of disease model NHPs has entered a new era. In this review, we summarize the generation of conventional disease model NHPs and discuss new solutions to the problem of mosaicism in genome-editing technology.

Indirect Genetic Effects and the Spread of Infectious Disease: Are We Capturing the Full Heritable Variation Underlying Disease Prevalence?

Science.gov (United States)

Lipschutz-Powell, Debby; Woolliams, John A.; Bijma, Piter; Doeschl-Wilson, Andrea B.

2012-01-01

Reducing disease prevalence through selection for host resistance offers a desirable alternative to chemical treatment. Selection for host resistance has proven difficult, however, due to low heritability estimates. These low estimates may be caused by a failure to capture all the relevant genetic variance in disease resistance, as genetic analysis currently is not taylored to estimate genetic variation in infectivity. Host infectivity is the propensity of transmitting infection upon contact with a susceptible individual, and can be regarded as an indirect effect to disease status. It may be caused by a combination of physiological and behavioural traits. Though genetic variation in infectivity is difficult to measure directly, Indirect Genetic Effect (IGE) models, also referred to as associative effects or social interaction models, allow the estimation of this variance from more readily available binary disease data (infected/non-infected). We therefore generated binary disease data from simulated populations with known amounts of variation in susceptibility and infectivity to test the adequacy of traditional and IGE models. Our results show that a conventional model fails to capture the genetic variation in infectivity inherent in populations with simulated infectivity. An IGE model, on the other hand, does capture some of the variation in infectivity. Comparison with expected genetic variance suggests that there is scope for further methodological improvement, and that potential responses to selection may be greater than values presented here. Nonetheless, selection using an index of estimated direct and indirect breeding values was shown to have a greater genetic selection differential and reduced future disease risk than traditional selection for resistance only. These findings suggest that if genetic variation in infectivity substantially contributes to disease transmission, then breeding designs which explicitly incorporate IGEs might help reduce disease

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,

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,

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…

International Cooperation to Enable the Diagnosis of All Rare Genetic Diseases.

Science.gov (United States)

Boycott, Kym M; Rath, Ana; Chong, Jessica X; Hartley, Taila; Alkuraya, Fowzan S; Baynam, Gareth; Brookes, Anthony J; Brudno, Michael; Carracedo, Angel; den Dunnen, Johan T; Dyke, Stephanie O M; Estivill, Xavier; Goldblatt, Jack; Gonthier, Catherine; Groft, Stephen C; Gut, Ivo; Hamosh, Ada; Hieter, Philip; Höhn, Sophie; Hurles, Matthew E; Kaufmann, Petra; Knoppers, Bartha M; Krischer, Jeffrey P; Macek, Milan; Matthijs, Gert; Olry, Annie; Parker, Samantha; Paschall, Justin; Philippakis, Anthony A; Rehm, Heidi L; Robinson, Peter N; Sham, Pak-Chung; Stefanov, Rumen; Taruscio, Domenica; Unni, Divya; Vanstone, Megan R; Zhang, Feng; Brunner, Han; Bamshad, Michael J; Lochmüller, Hanns

2017-05-04

Provision of a molecularly confirmed diagnosis in a timely manner for children and adults with rare genetic diseases shortens their "diagnostic odyssey," improves disease management, and fosters genetic counseling with respect to recurrence risks while assuring reproductive choices. In a general clinical genetics setting, the current diagnostic rate is approximately 50%, but for those who do not receive a molecular diagnosis after the initial genetics evaluation, that rate is much lower. Diagnostic success for these more challenging affected individuals depends to a large extent on progress in the discovery of genes associated with, and mechanisms underlying, rare diseases. Thus, continued research is required for moving toward a more complete catalog of disease-related genes and variants. The International Rare Diseases Research Consortium (IRDiRC) was established in 2011 to bring together researchers and organizations invested in rare disease research to develop a means of achieving molecular diagnosis for all rare diseases. Here, we review the current and future bottlenecks to gene discovery and suggest strategies for enabling progress in this regard. Each successful discovery will define potential diagnostic, preventive, and therapeutic opportunities for the corresponding rare disease, enabling precision medicine for this patient population. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Genetic characteristics of inflammatory bowel disease in a Japanese population.

Science.gov (United States)

Fuyuno, Yuta; Yamazaki, Keiko; Takahashi, Atsushi; Esaki, Motohiro; Kawaguchi, Takaaki; Takazoe, Masakazu; Matsumoto, Takayuki; Matsui, Toshiyuki; Tanaka, Hiroki; Motoya, Satoshi; Suzuki, Yasuo; Kiyohara, Yutaka; Kitazono, Takanari; Kubo, Michiaki

2016-07-01

Crohn's disease (CD) and ulcerative colitis (UC) are two major forms of inflammatory bowel disease (IBD). Meta-analyses of genome-wide association studies (GWAS) have identified 163 susceptibility loci for IBD among European populations; however, there is limited information for IBD susceptibility in a Japanese population. We performed a GWAS using imputed genotypes of 743 IBD patients (372 with CD and 371 with UC) and 3321 controls. Using 100 tag single-nucleotide polymorphisms (SNPs) (P Japanese and European populations. In the IBD GWAS, two East Asia-specific IBD susceptibility loci were identified in the Japanese population: ATG16L2-FCHSD2 and SLC25A15-ELF1-WBP4. Among 163 reported SNPs in European IBD patients, significant associations were confirmed in 18 (8 CD-specific, 4 UC-specific, and 6 IBD-shared). In Japanese CD patients, genes in the Th17-IL23 pathway showed stronger genetic effects, whereas the association of genes in the autophagy pathway was limited. The association of genes in the epithelial barrier and the Th17-IL23R pathways were similar in the Japanese and European UC populations. We confirmed two IBD susceptibility loci as common for CD and UC, and East Asian-specific. The genetic architecture in UC appeared to be similar between Europeans and East Asians, but may have some differences in CD.

Genetics of Atrial Fibrillation and Possible Implications for Ischemic Stroke

Directory of Open Access Journals (Sweden)

Robin Lemmens

2011-01-01

Full Text Available Atrial fibrillation is the most common cardiac arrhythmia mainly caused by valvular, ischemic, hypertensive, and myopathic heart disease. Atrial fibrillation can occur in families suggesting a genetic background especially in younger subjects. Additionally recent studies have identified common genetic variants to be associated with atrial fibrillation in the general population. This cardiac arrhythmia has important public health implications because of its main complications: congestive heart failure and ischemic stroke. Since atrial fibrillation can result in ischemic stroke, one might assume that genetic determinants of this cardiac arrhythmia are also implicated in cerebrovascular disease. Ischemic stroke is a multifactorial, complex disease where multiple environmental and genetic factors interact. Whether genetic variants associated with a risk factor for ischemic stroke also increase the risk of a particular vascular endpoint still needs to be confirmed in many cases. Here we review the current knowledge on the genetic background of atrial fibrillation and the consequences for cerebrovascular disease.

[Coronary heart disease: epidemiologic-genetic aspects].

Science.gov (United States)

Epstein, F H

1985-01-01

Coronary heart disease and the risk factors which predispose to it aggregate in families. How much of this clustering of disease is "explained" by the familial resemblance in predisposing factors? The published reports which bear on this question fall into six distinct study designs: prospective studies, persons at high or low risk or persons with and without a positive family history as points of departure, case-control studies, studies of patients who had a coronary angiogram and studies in different ethnic groups. The findings of the 16 investigations reviewed suggest that there are as yet unidentified factors - genetic, environmental or both - which are responsible for familial clustering of coronary heart disease, apart from the three main risk factors (serum lipids, blood pressure, smoking) and diabetes. Future research must put greater emphasis on studies of families rather than individuals and on closer collaboration between epidemiologists and geneticists, in order to fill these gaps in knowledge. It is likely that the individual predisposition to coronary heart disease is due in part to genetic influences which remain to be discovered in the course of such studies. They would help in identifying susceptible person in the population with greater precision than is now possible. The "high-risk strategy" of coronary heart disease prevention will become more efficient as more specific and sensitive tests of disease prediction are developed. In the meantime, preventive programmes must be put into action on the basis of what is already known, on the level of both the high-risk and the community-wide mass strategy.

Genetics of nonsyndromic obesity.

Science.gov (United States)

Lee, Yung Seng

2013-12-01

Common obesity is widely regarded as a complex, multifactorial trait influenced by the 'obesogenic' environment, sedentary behavior, and genetic susceptibility contributed by common and rare genetic variants. This review describes the recent advances in understanding the role of genetics in obesity. New susceptibility loci and genetic variants are being uncovered, but the collective effect is relatively small and could not explain most of the BMI heritability. Yet-to-be identified common and rare variants, epistasis, and heritable epigenetic changes may account for part of the 'missing heritability'. Evidence is emerging about the role of epigenetics in determining obesity susceptibility, mediating developmental plasticity, which confers obesity risk from early life experiences. Genetic prediction scores derived from selected genetic variants, and also differential DNA methylation levels and methylation scores, have been shown to correlate with measures of obesity and response to weight loss intervention. Genetic variants, which confer susceptibility to obesity-related morbidities like nonalcoholic fatty liver disease, were also discovered recently. We can expect discovery of more rare genetic variants with the advent of whole exome and genome sequencing, and also greater understanding of epigenetic mechanisms by which environment influences genetic expression and which mediate the gene-environment interaction.

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.

Quality of life, fatigue and mental health in patients with the m.3243A > G mutation and its correlates with genetic characteristics and disease manifestation

NARCIS (Netherlands)

Verhaak, Christianne; de Laat, Paul; Koene, Saskia; Tibosch, Marijke; Rodenburg, Richard; de Groot, Imelda; Knoop, Hans; Janssen, Mirian; Smeitink, Jan

2016-01-01

Background: Mitochondrial disorders belong to the most prevalent inherited metabolic diseases with the m.3243A > G mutation reflecting being one of the most common mutations in mitochondrial DNA. Previous studies showed little relationship between mitochondrial genetics and disease manifestation.

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.

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...

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

NARCIS (Netherlands)

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

2015-01-01

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

Comprehensive genetic study of fatty acids helps explain the role of noncoding inflammatory bowel disease associated SNPs and fatty acid metabolism in disease pathogenesis.

Science.gov (United States)

Jezernik, Gregor; Potočnik, Uroš

2018-03-01

Fatty acids and their derivatives play an important role in inflammation. Diet and genetics influence fatty acid profiles. Abnormalities of fatty acid profiles have been observed in inflammatory bowel diseases (IBD), a group of complex diseases defined by chronic gastrointestinal inflammation. IBD associated fatty acid profile abnormalities were observed independently of nutritional status or disease activity, suggesting a common genetic background. However, no study so far has attempted to look for overlap between IBD loci and fatty acid associated loci or investigate the genetics of fatty acid profiles in IBD. To this end, we conducted a comprehensive genetic study of fatty acid profiles in IBD using iCHIP, a custom microarray platform designed for deep sequencing of immune-mediated disease associated loci. This study identifies 10 loci associated with fatty acid profiles in IBD. The most significant associations were a locus near CBS (p = 7.62 × 10 -8 ) and a locus in LRRK2 (p = 1.4 × 10 -7 ). Of note, this study replicates the FADS gene cluster locus, previously associated with both fatty acid profiles and IBD pathogenesis. Furthermore, we identify 18 carbon chain trans-fatty acids (p = 1.12 × 10 -3 ), total trans-fatty acids (p = 4.49 × 10 -3 ), palmitic acid (p = 5.85 × 10 -3 ) and arachidonic acid (p = 8.58 × 10 -3 ) as significantly associated with IBD pathogenesis. Copyright © 2018 Elsevier Ltd. All rights reserved.

Congenital and Genetic Disease in Domestic Animals

Science.gov (United States)

Mulvihill, John J.

1972-01-01

Reviews observations on domestic animals that have led to the identification of environmental teratogens, and have provided insight into the pathogenesis of congenital defects and genetic diseases in man." (Author/AL)

Evaluation of common diseases in laboratory animals | Oguwike ...

African Journals Online (AJOL)

, diet or faulty functioning of a process. Laboratory animals are prone to some of these diseases. This study was undertaken to evaluate common diseases found in laboratory animals in our environment. 200 animals consisting of rats, mice, ...

Molecular Genetic Studies of Some Eye Diseases Affecting the ...

Indian Academy of Sciences (India)

First page Back Continue Last page Overview Graphics. Molecular Genetic Studies of Some Eye Diseases Affecting the Indian Population. Single gene disorders. Complex eye diseases. Genotype-phenotype correlation. Molecular diagnostics.

Glioblastomas with oligodendroglial component - common origin of the different histological parts and genetic subclassification.

Science.gov (United States)

Klink, Barbara; Schlingelhof, Ben; Klink, Martin; Stout-Weider, Karen; Patt, Stephan; Schrock, Evelin

2010-01-01

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. The oligodendroglial and the "classic" glioblastoma parts of 13 GBMO were analyzed separately by interphase fluorescence in situ hybridization (FISH) on paraffin sections using a custom probe set (regions 1p, 1q, 7q, 10q, 17p, 19q, cen18, 21q) and by comparative genomic hybridization (CGH) of microdissected paraffin embedded tumor tissue. We identified four distinct genetic subtypes in 13 GBMOs: an "astrocytic" subtype (9/13) characterized by +7/-10; an "oligodendroglial" subtype with -1p/-19q (1/13); an "intermediate" subtype showing +7/-1p (1/13), and an "other" subtype having none of the former aberrations typical for gliomas (2/13). The different histological tumor parts of GBMO revealed common genetic changes in all tumors and showed additional aberrations specific for each part. Our findings demonstrate the monoclonal origin of GBMO followed by the development of the astrocytic and oligodendroglial components. The diagnostic determination of the genetic signatures may allow for a better prognostication of the patients.

Application of computational methods in genetic study of inflammatory bowel disease.

Science.gov (United States)

Li, Jin; Wei, Zhi; Hakonarson, Hakon

2016-01-21

Genetic factors play an important role in the etiology of inflammatory bowel disease (IBD). The launch of genome-wide association study (GWAS) represents a landmark in the genetic study of human complex disease. Concurrently, computational methods have undergone rapid development during the past a few years, which led to the identification of numerous disease susceptibility loci. IBD is one of the successful examples of GWAS and related analyses. A total of 163 genetic loci and multiple signaling pathways have been identified to be associated with IBD. Pleiotropic effects were found for many of these loci; and risk prediction models were built based on a broad spectrum of genetic variants. Important gene-gene, gene-environment interactions and key contributions of gut microbiome are being discovered. Here we will review the different types of analyses that have been applied to IBD genetic study, discuss the computational methods for each type of analysis, and summarize the discoveries made in IBD research with the application of these methods.

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.

Genetics of allergy and allergic sensitization

DEFF Research Database (Denmark)

Bønnelykke, Klaus; Sparks, Rachel; Waage, Johannes

2015-01-01

information about shared genetics between allergy, related phenotypes and autoimmunity. Studies of monogenic diseases have elucidated critical cellular pathways and protein functions responsible for allergy. These complementary approaches imply genetic mechanisms involved in Th2 immunity, T......Our understanding of the specific genetic lesions in allergy has improved in recent years due to identification of common risk variants from genome-wide association studies (GWAS) and studies of rare, monogenic diseases. Large-scale GWAS have identified novel susceptibility loci and provided...

The effect of genetic bottlenecks and inbreeding on the incidence of two major autoimmune diseases in standard poodles, sebaceous adenitis and Addison's disease.

Science.gov (United States)

Pedersen, Niels C; Brucker, Lynn; Tessier, Natalie Green; Liu, Hongwei; Penedo, Maria Cecilia T; Hughes, Shayne; Oberbauer, Anita; Sacks, Ben

2015-01-01

likely to develop SA or AD as dogs with common haplotypes. Miniature/Standard Poodle crosses being used for outcrossing were more genetically diverse than Standard Poodles and genetically distinguishable across the genome and in the DLA class I and II region. Ancestral genetic polymorphisms responsible for SA and AD entered Standard Poodles through separate lineages, AD earlier and SA later, and were increasingly fixed by a period of close linebreeding that was related to popular bloodlines from the mid-twentieth century. This event has become known as the midcentury bottleneck or MCB. Sustained positive selection resulted in a marked imbalance in genetic diversity across the genome and in the DLA class I and II region. Both SA and AD were concentrated among the most inbred dogs, with genetic outliers being relatively disease free. No specific genetic markers other than those reflecting the degree of inbreeding were consistently associated with either disease. Standard Poodles as a whole remain genetically diverse, but steps should be taken to rebalance diversity using genetic outliers and if necessary, outcrosses to phenotypically similar but genetically distinct breeds.

Vitamin K-dependent proteins GAS6 and Protein S and TAM receptors in patients of systemic lupus erythematosus: correlation with common genetic variants and disease activity.

Science.gov (United States)

Recarte-Pelz, Pedro; Tàssies, Dolors; Espinosa, Gerard; Hurtado, Begoña; Sala, Núria; Cervera, Ricard; Reverter, Joan Carles; de Frutos, Pablo García

2013-03-12

Growth arrest-specific gene 6 protein (GAS6) and protein S (ProS) are vitamin K-dependent proteins present in plasma with important regulatory functions in systems of response and repair to damage. They interact with receptor tyrosine kinases of the Tyro3, Axl and MerTK receptor tyrosine kinase (TAM) family, involved in apoptotic cell clearance (efferocytosis) and regulation of the innate immunity. TAM-deficient mice show spontaneous lupus-like symptoms. Here we tested the genetic profile and plasma levels of components of the system in patients with systemic lupus erythematosus (SLE), and compare them with a control healthy population. Fifty SLE patients and 50 healthy controls with matched age, gender and from the same geographic area were compared. Genetic analysis was performed in GAS6 and the TAM receptor genes on SNPs previously identified. The concentrations of GAS6, total and free ProS, and the soluble forms of the three TAM receptors (sAxl, sMerTK and sTyro3) were measured in plasma from these samples. Plasma concentrations of GAS6 were higher and, total and free ProS were lower in the SLE patients compared to controls, even when patients on oral anticoagulant treatment were discarded. Those parameters correlated with SLE disease activity index (SLEDAI) score, GAS6 being higher in the most severe cases, while free and total ProS were lower. All 3 soluble receptors increased its concentration in plasma of lupus patients. The present study highlights that the GAS6/ProS-TAM system correlates in several ways with disease activity in SLE. We show here that this correlation is affected by common polymorphisms in the genes of the system. These findings underscore the importance of mechanism of regulatory control of innate immunity in the pathology of SLE.

Genetic influences on the development of fibrosis in Crohn’s Disease

Directory of Open Access Journals (Sweden)

Bram eVerstockt

2016-05-01

Full Text Available Fibrostenotic strictures are an important complication in patients with Crohn’s Disease, very often necessitating surgery. This fibrotic process develops in a genetically susceptible individual, and is influenced by an interplay with environmental, immunological and disease-related factors. A deeper understanding of the genetic factors driving this fibrostenotic process might help to unravel the pathogenesis, and ultimately lead to development of new, anti-fibrotic therapy. Here we review the genetic factors that have been associated with the development of fibrosis in patients with Crohn’s disease, as well as their potential pathophysiological mechanism(s. We also hypothesize on clinical implications if any, and future research directions.

Adults' perceptions of genetic counseling and genetic testing.

Science.gov (United States)

Houfek, Julia Fisco; Soltis-Vaughan, Brigette S; Atwood, Jan R; Reiser, Gwendolyn M; Schaefer, G Bradley

2015-02-01

This study described the perceptions of genetic counseling and testing of adults (N = 116) attending a genetic education program. Understanding perceptions of genetic counseling, including the importance of counseling topics, will contribute to patient-focused care as clinical genetic applications for common, complex disorders evolve. Participants completed a survey addressing: the importance of genetic counseling topics, benefits and negative effects of genetic testing, and sharing test results. Topics addressing practical information about genetic conditions were rated most important; topics involving conceptual genetic/genomic principles were rated least important. The most frequently identified benefit and negative effect of testing were prevention/early detection/treatment and psychological distress. Participants perceived that they were more likely to share test results with first-degree than other relatives. Findings suggest providing patients with practical information about genetic testing and genetic contributions to disease, while also determining whether their self-care abilities would be enhanced by teaching genetic/genomic principles. Copyright © 2014 Elsevier Inc. All rights reserved.

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

Directory of Open Access Journals (Sweden)

Carayol Jerome

2010-02-01

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

Celiac Disease Genetics : Past, Present and Future Challenges

NARCIS (Netherlands)

Wijmenga, Cisca; Gutierrez Achury, Javier

In the past few years there has been enormous progress in unraveling the genetic basis of celiac disease (CD). Apart from the well-known association to HLA, there are currently 40 genomic loci associated to CD. Most of these loci show pleiotropic effects across many autoimmune diseases and highlight

Genetics Home Reference: REN-related kidney disease

Science.gov (United States)

... 2 Related Information How are genetic conditions and genes named? Additional Information & Resources MedlinePlus (5 links) Encyclopedia: Hyperkalemia Encyclopedia: Renin Health Topic: Anemia Health Topic: Gout Health Topic: Kidney Diseases Additional NIH Resources (2 ...

Common variants at five new loci associated with early-onset inflammatory bowel disease.

Science.gov (United States)

Imielinski, Marcin; Baldassano, Robert N; Griffiths, Anne; Russell, Richard K; Annese, Vito; Dubinsky, Marla; Kugathasan, Subra; Bradfield, Jonathan P; Walters, Thomas D; Sleiman, Patrick; Kim, Cecilia E; Muise, Aleixo; Wang, Kai; Glessner, Joseph T; Saeed, Shehzad; Zhang, Haitao; Frackelton, Edward C; Hou, Cuiping; Flory, James H; Otieno, George; Chiavacci, Rosetta M; Grundmeier, Robert; Castro, Massimo; Latiano, Anna; Dallapiccola, Bruno; Stempak, Joanne; Abrams, Debra J; Taylor, Kent; McGovern, Dermot; Silber, Gary; Wrobel, Iwona; Quiros, Antonio; Barrett, Jeffrey C; Hansoul, Sarah; Nicolae, Dan L; Cho, Judy H; Duerr, Richard H; Rioux, John D; Brant, Steven R; Silverberg, Mark S; Taylor, Kent D; Barmuda, M Michael; Bitton, Alain; Dassopoulos, Themistocles; Datta, Lisa Wu; Green, Todd; Griffiths, Anne M; Kistner, Emily O; Murtha, Michael T; Regueiro, Miguel D; Rotter, Jerome I; Schumm, L Philip; Steinhart, A Hillary; Targan, Stephen R; Xavier, Ramnik J; Libioulle, Cécile; Sandor, Cynthia; Lathrop, Mark; Belaiche, Jacques; Dewit, Olivier; Gut, Ivo; Heath, Simon; Laukens, Debby; Mni, Myriam; Rutgeerts, Paul; Van Gossum, André; Zelenika, Diana; Franchimont, Denis; Hugot, J P; de Vos, Martine; Vermeire, Severine; Louis, Edouard; Cardon, Lon R; Anderson, Carl A; Drummond, Hazel; Nimmo, Elaine; Ahmad, Tariq; Prescott, Natalie J; Onnie, Clive M; Fisher, Sheila A; Marchini, Jonathan; Ghori, Jilur; Bumpstead, Suzannah; Gwillam, Rhian; Tremelling, Mark; Delukas, Panos; Mansfield, John; Jewell, Derek; Satsangi, Jack; Mathew, Christopher G; Parkes, Miles; Georges, Michel; Daly, Mark J; Heyman, Melvin B; Ferry, George D; Kirschner, Barbara; Lee, Jessica; Essers, Jonah; Grand, Richard; Stephens, Michael; Levine, Arie; Piccoli, David; Van Limbergen, John; Cucchiara, Salvatore; Monos, Dimitri S; Guthery, Stephen L; Denson, Lee; Wilson, David C; Grant, Straun F A; Daly, Mark; Silverberg, Mark S; Satsangi, Jack; Hakonarson, Hakon

2009-12-01

The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis are common causes of morbidity in children and young adults in the western world. Here we report the results of a genome-wide association study in early-onset IBD involving 3,426 affected individuals and 11,963 genetically matched controls recruited through international collaborations in Europe and North America, thereby extending the results from a previous study of 1,011 individuals with early-onset IBD. We have identified five new regions associated with early-onset IBD susceptibility, including 16p11 near the cytokine gene IL27 (rs8049439, P = 2.41 x 10(-9)), 22q12 (rs2412973, P = 1.55 x 10(-9)), 10q22 (rs1250550, P = 5.63 x 10(-9)), 2q37 (rs4676410, P = 3.64 x 10(-8)) and 19q13.11 (rs10500264, P = 4.26 x 10(-10)). Our scan also detected associations at 23 of 32 loci previously implicated in adult-onset Crohn's disease and at 8 of 17 loci implicated in adult-onset ulcerative colitis, highlighting the close pathogenetic relationship between early- and adult-onset IBD.

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.

Genetics of Parkinson’s Disease - A Clinical Perspective

Directory of Open Access Journals (Sweden)

Sang-Myung Cheon

2012-10-01

Full Text Available Discovering genes following Medelian inheritance, such as autosomal dominant-synuclein and leucine-rich repeat kinase 2 gene, or autosomal recessive Parkin, P-TEN-induced putative kinase 1 gene and Daisuke-Junko 1 gene, has provided great insights into the pathogenesis of Parkinson’s disease (PD. Genes found to be associated with PD through investigating genetic polymorphisms or via the whole genome association studies suggest that such genes could also contribute to an increased risk of PD in the general population. Some environmental factors have been found to be associated with genetic factors in at-risk patients, further implicating the role of gene-environment interactions in sporadic PD. There may be confusion for clinicians facing rapid progresses of genetic understanding in PD. After a brief review of PD genetics, we will discuss the insight of new genetic discoveries to clinicians, the implications of ethnic differences in PD genetics and the role of genetic testing for general clinicians managing PD patients.

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

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....

Genetic Influences on the Development of Fibrosis in Crohn's Disease

OpenAIRE

Verstockt, Bram; Cleynen, Isabelle

2016-01-01

Fibrostenotic strictures are an important complication in patients with Crohn’s disease (CD), very often necessitating surgery. This fibrotic process develops in a genetically susceptible individual and is influenced by an interplay with environmental, immunological, and disease-related factors. A deeper understanding of the genetic factors driving this fibrostenotic process might help to unravel the pathogenesis, and ultimately lead to development of new, anti-fibrotic therapy. Here, we revi...

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

Glioblastomas with Oligodendroglial Component ? Common Origin of the Different Histological Parts and Genetic Subclassification

OpenAIRE

Klink, Barbara; Schlingelhof, Ben; Klink, Martin; Stout-Weider, Karen; Patt, Stephan; Schrock, Evelin

2010-01-01

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. Methods: The oligodendroglial and the ?classic? glioblastoma parts of 13 GBMO were analyzed separately by interphase flu...

A genetic-epidemiologic study of Alzheimer’s disease

NARCIS (Netherlands)

A. Arias-Vásquez (Alejandro)

2006-01-01

textabstractAlzheimer's disease (AD) is the most frequent cause of dementia and thus is a major public-health problem. Age and genetic predisposition to the disease are the most important risk factors. In 2001 more than 24 million people in the western world had dementia. This number is expected to

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.

Childhood separation anxiety disorder and adult onset panic attacks share a common genetic diathesis.

Science.gov (United States)

Roberson-Nay, Roxann; Eaves, Lindon J; Hettema, John M; Kendler, Kenneth S; Silberg, Judy L

2012-04-01

Childhood separation anxiety disorder (SAD) is hypothesized to share etiologic roots with panic disorder. The aim of this study was to estimate the genetic and environmental sources of covariance between childhood SAD and adult onset panic attacks (AOPA), with the primary goal to determine whether these two phenotypes share a common genetic diathesis. Participants included parents and their monozygotic or dizygotic twins (n = 1,437 twin pairs) participating in the Virginia Twin Study of Adolescent Behavioral Development and those twins who later completed the Young Adult Follow-Up (YAFU). The Child and Adolescent Psychiatric Assessment was completed at three waves during childhood/adolescence followed by the Structured Clinical Interview for DSM-III-R at the YAFU. Two separate, bivariate Cholesky models were fit to childhood diagnoses of SAD and overanxious disorder (OAD), respectively, and their relation with AOPA; a trivariate Cholesky model also examined the collective influence of childhood SAD and OAD on AOPA. In the best-fitting bivariate model, the covariation between SAD and AOPA was accounted for by genetic and unique environmental factors only, with the genetic factor associated with childhood SAD explaining significant variance in AOPA. Environmental risk factors were not significantly shared between SAD and AOPA. By contrast, the genetic factor associated with childhood OAD did not contribute significantly to AOPA. Results of the trivariate Cholesky reaffirmed outcomes of bivariate models. These data indicate that childhood SAD and AOPA share a common genetic diathesis that is not observed for childhood OAD, strongly supporting the hypothesis of a specific genetic etiologic link between the two phenotypes. © 2012 Wiley Periodicals, Inc.

The importance of genetics in the diagnosis of animal diseases - A ...

African Journals Online (AJOL)

The use of recombinant DNA techniques in conjunction with conventional genetic methods have led to a rapid increase in knowledge of the genetic map. Many animal genes have been mapped to chromosomes. A detailed genetic map has become of great value in the diagnosis of genetic diseases and in the development ...

Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease

NARCIS (Netherlands)

van der Harst, Pim; Verweij, Niek

2018-01-01

Rationale: Coronary artery disease (CAD) is a complex phenotype driven by genetic and environmental factors. Ninety-seven genetic risk loci have been identified to date, but the identification of additional susceptibility loci might be important to enhance our understanding of the genetic

Identification of a shared genetic susceptibility locus for coronary heart disease and periodontitis.

Directory of Open Access Journals (Sweden)

Arne S Schaefer

2009-02-01

Full Text Available Recent studies indicate a mutual epidemiological relationship between coronary heart disease (CHD and periodontitis. Both diseases are associated with similar risk factors and are characterized by a chronic inflammatory process. In a candidate-gene association study, we identify an association of a genetic susceptibility locus shared by both diseases. We confirm the known association of two neighboring linkage disequilibrium regions on human chromosome 9p21.3 with CHD and show the additional strong association of these loci with the risk of aggressive periodontitis. For the lead SNP of the main associated linkage disequilibrium region, rs1333048, the odds ratio of the autosomal-recessive mode of inheritance is 1.99 (95% confidence interval 1.33-2.94; P = 6.9 x 10(-4 for generalized aggressive periodontitis, and 1.72 (1.06-2.76; P = 2.6 x 10(-2 for localized aggressive periodontitis. The two associated linkage disequilibrium regions map to the sequence of the large antisense noncoding RNA ANRIL, which partly overlaps regulatory and coding sequences of CDKN2A/CDKN2B. A closely located diabetes-associated variant was independent of the CHD and periodontitis risk haplotypes. Our study demonstrates that CHD and periodontitis are genetically related by at least one susceptibility locus, which is possibly involved in ANRIL activity and independent of diabetes associated risk variants within this region. Elucidation of the interplay of ANRIL transcript variants and their involvement in increased susceptibility to the interactive diseases CHD and periodontitis promises new insight into the underlying shared pathogenic mechanisms of these complex common diseases.

Energy metabolism disorders in rare and common diseases. Toward bioenergetic modulation therapy and the training of a new generation of European scientists.

Science.gov (United States)

Rossignol, Rodrigue

2015-06-01

Energy metabolism alterations are found in a large number of rare and common diseases of genetic or environmental origin. The number of patients that could benefit from bioenergetic modulation therapy (BIOMET) is therefore very important and includes individuals with pathologies as diverse as mitochondrial diseases, acute coronary syndrome, chronic kidney disease, asthma or even cancer. Although, the alteration of energy metabolism is disease specific and sometimes patient specific, the strategies for BIOMET could be common and target a series of bioenergetic regulatory mechanisms discussed in this article. An excellent training of scientists in the field of energy metabolism, related human diseases and drug discovery is also crucial to form a young generation of MDs, PHDs and Pharma or CRO-group leaders who will discover novel personalized bioenergetic medicines, through pharmacology, genetics, nutrition or adapted exercise training. The Mitochondrial European Educational Training (MEET) consortium was created to pursue this goal, and we dedicated here a special issue of Organelle in Focus (OiF) to highlight their objectives. A total of 10 OiFs articles constitute this Directed Issue on Mitochondrial Medicine. As part of this editorial article, we asked timely questions to the PR. Jan W. Smeitink, professor of Mitochondrial Medicine and CEO of Khondrion, a mitochondrial medicine company. He shared with us his objectives and strategies for the study of mitochondrial diseases and the identification of future treatments. This article is part of a Directed Issue entitled: Energy Metabolism Disorders and Therapies. Copyright © 2015 Elsevier Ltd. All rights reserved.

The Relationship Between the Genetic and Environmental Influences on Common Externalizing Psychopathology and Mental Wellbeing

Science.gov (United States)

Kendler, Kenneth S.; Myers, John M.; Keyes, Corey L. M.

2012-01-01

To determine the relationship between the genetic and environmental risk factors for externalizing psychopathology and mental wellbeing, we examined detailed measures of emotional, social and psychological wellbeing, and a history of alcohol-related problems and smoking behavior in the last year in 1,386 individual twins from same-sex pairs from the MIDUS national US sample assessed in 1995. Cholesky decomposition analyses were performed with the Mx program. The best fit model contained one highly heritable common externalizing psychopathology factor for both substance use/abuse measures, and one strongly heritable common factor for the three wellbeing measures. Genetic and environmental risk factors for externalizing psychopathology were both negatively associated with levels of mental wellbeing and accounted for, respectively, 7% and 21% of its genetic and environmental influences. Adding internalizing psychopathology assessed in the last year to the model, genetic risk factors unique for externalizing psychopathology were now positively related to levels of mental wellbeing, although accounting for only 5% of the genetic variance. Environmental risk factors unique to externalizing psychopathology continued to be negatively associated with mental wellbeing, accounting for 26% of the environmental variance. When both internalizing psychopathology and externalizing psychopathology are associated with mental wellbeing, the strongest risk factors for low mental wellbeing are genetic factors that impact on both internalizing psychopathology and externalizing psychopathology, and environmental factors unique to externalizing psychopathology. In this model, genetic risk factors for externalizing psychopathology predict, albeit weakly, higher levels of mental wellbeing. PMID:22506307

Environment-Gene interaction in common complex diseases: New approaches

Directory of Open Access Journals (Sweden)

William A. Toscano, Jr.

2014-10-01

Full Text Available Approximately 100,000 different environmental chemicals that are in use as high production volume chemicals confront us in our daily lives. Many of the chemicals we encounter are persistent and have long half-lives in the environment and our bodies. These compounds are referred to as Persistent Organic Pollutants, or POPS. The total environment however is broader than just toxic pollutants. It includes social capital, social economic status, and other factors that are not commonly considered in traditional approaches to studying environment-human interactions. The mechanism of action of environmental agents in altering the human phenotype from health to disease is more complex than once thought. The focus in public health has shifted away from the study of single-gene rare diseases and has given way to the study of multifactorial complex diseases that are common in the population. To understand common complex diseases, we need teams of scientists from different fields working together with common aims. We review some approaches for studying the action of the environment by discussing use-inspired research, and transdisciplinary research approaches. The Genomic era has yielded new tools for study of gene-environment interactions, including genomics, epigenomics, and systems biology. We use environmentally-driven diabetes mellitus type two as an example of environmental epigenomics and disease. The aim of this review is to start the conversation of how the application of advances in biomedical science can be used to advance public health.

[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.

Genetic dysbiosis: the role of microbial insults in chronic inflammatory diseases

Directory of Open Access Journals (Sweden)

Luigi Nibali

2014-02-01

Full Text Available Thousands of bacterial phylotypes colonise the human body and the host response to this bacterial challenge greatly influences our state of health or disease. The concept of infectogenomics highlights the importance of host genetic factors in determining the composition of human microbial biofilms and the response to this microbial challenge. We hereby introduce the term ‘genetic dysbiosis’ to highlight the role of human genetic variants affecting microbial recognition and host response in creating an environment conducive to changes in the normal microbiota. Such changes can, in turn, predispose to, and influence, diseases such as: cancer, inflammatory bowel disease, rheumatoid arthritis, psoriasis, bacterial vaginosis and periodontitis. This review presents the state of the evidence on host genetic factors affecting dysbiosis and microbial misrecognition (i.e. an aberrant response to the normal microbiota and highlights the need for further research in this area.

Genetics Modulate Gray Matter Variation Beyond Disease Burden in Prodromal Huntington’s Disease

Directory of Open Access Journals (Sweden)

Jingyu Liu

2018-03-01

Full Text Available Huntington’s disease (HD is a neurodegenerative disorder caused by an expansion mutation of the cytosine–adenine–guanine (CAG trinucleotide in the HTT gene. Decline in cognitive and motor functioning during the prodromal phase has been reported, and understanding genetic influences on prodromal disease progression beyond CAG will benefit intervention therapies. From a prodromal HD cohort (N = 715, we extracted gray matter (GM components through independent component analysis and tested them for associations with cognitive and motor functioning that cannot be accounted for by CAG-induced disease burden (cumulative effects of CAG expansion and age. Furthermore, we examined genetic associations (at the genomic, HD pathway, and candidate region levels with the GM components that were related to functional decline. After accounting for disease burden, GM in a component containing cuneus, lingual, and middle occipital regions was positively associated with attention and working memory performance, and the effect size was about a tenth of that of disease burden. Prodromal participants with at least one dystonia sign also had significantly lower GM volume in a bilateral inferior parietal component than participants without dystonia, after controlling for the disease burden. Two single-nucleotide polymorphisms (SNPs: rs71358386 in NCOR1 and rs71358386 in ADORA2B in the HD pathway were significantly associated with GM volume in the cuneus component, with minor alleles being linked to reduced GM volume. Additionally, homozygous minor allele carriers of SNPs in a candidate region of ch15q13.3 had significantly higher GM volume in the inferior parietal component, and one minor allele copy was associated with a total motor score decrease of 0.14 U. Our findings depict an early genetical GM reduction in prodromal HD that occurs irrespective of disease burden and affects regions important for cognitive and motor functioning.

The influence of genetic variability and proinflammatory status on the development of bone disease in patients with Gaucher disease.

Directory of Open Access Journals (Sweden)

Javier Gervas-Arruga

Full Text Available Gaucher disease, the most common lysosomal storage disorder, is caused by β-glucocerebrosidase deficiency. Bone complications are the major cause of morbidity in patients with type 1 Gaucher disease (GD1. Genetic components strongly influence bone remodelling. In addition, chronic inflammation produced by Gaucher cells induces the production of several cytokines, which leads to direct changes in the bone remodelling process and can also affect the process indirectly through other immune cells. In this study, we analysed the association between bone mineral density (BMD, bone marrow burden score, and relevant genetic polymorphisms related to bone metabolism, as well as profiles of proinflammatory cytokines in a GD1 cohort. This study included 83 patients distributed according to bone status. BMD was measured with DXA and broadband ultrasound attenuation; bone marrow involvement was evaluated using MRI. We also analysed 26 SNPs located in 14 genes related to bone metabolism. To assess proinflammatory status, we analysed IL-4, IL-6, IL-7, IL-10, IL-13, MIP-1α, MIP-1β, and TNFα in plasma samples from 71 control participants and GD1 patients. SNP genotype proportions and BMD differed significantly between ESRI c.453-397T>C and VDR c.1024+283G>A variants. We also observed significant associations between GD1 genotypes and bone affectation. When patients were stratified by spleen status, we observed significant correlations between non-/splenectomized groups and Spanish MRI (S-MRI score. Across genotype proportions of non-/splenectomized patients and S-MRI, we observed significant differences in ESRI c.453-397T>C, VDR c.-83-25988G>A, and TNFRSF11B c.9C>G polymorphisms. We observed different significant proinflammatory profiles between control participants, treatment-naïve patients, and patients on enzyme replacement therapy (ERT; between non-/splenectomized patients (between untreated and ERT-treated patients and among those with differing GBA

The Moroccan Genetic Disease Database (MGDD): a database for DNA variations related to inherited disorders and disease susceptibility.

Science.gov (United States)

Charoute, Hicham; Nahili, Halima; Abidi, Omar; Gabi, Khalid; Rouba, Hassan; Fakiri, Malika; Barakat, Abdelhamid

2014-03-01

National and ethnic mutation databases provide comprehensive information about genetic variations reported in a population or an ethnic group. In this paper, we present the Moroccan Genetic Disease Database (MGDD), a catalogue of genetic data related to diseases identified in the Moroccan population. We used the PubMed, Web of Science and Google Scholar databases to identify available articles published until April 2013. The Database is designed and implemented on a three-tier model using Mysql relational database and the PHP programming language. To date, the database contains 425 mutations and 208 polymorphisms found in 301 genes and 259 diseases. Most Mendelian diseases in the Moroccan population follow autosomal recessive mode of inheritance (74.17%) and affect endocrine, nutritional and metabolic physiology. The MGDD database provides reference information for researchers, clinicians and health professionals through a user-friendly Web interface. Its content should be useful to improve researches in human molecular genetics, disease diagnoses and design of association studies. MGDD can be publicly accessed at http://mgdd.pasteur.ma.

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.

[Analysis of 14 individuals who requested predictive genetic testing for hereditary neuromuscular diseases].

Science.gov (United States)

Yoshida, Kunihiro; Tamai, Mariko; Kubota, Takeo; Kawame, Hiroshi; Amano, Naoji; Ikeda, Shu-ichi; Fukushima, Yoshimitsu

2002-02-01

Predictive genetic testing for hereditary neuromuscular diseases is a delicate issue for individuals at risk and their families, as well as for medical staff because these diseases are often late-onset and intractable. Therefore careful pre- and post-test genetic counseling and psychosocial support should be provided along with such genetic testing. The Division of Clinical and Molecular Genetics was established at our hospital in May 1996 to provide skilled professional genetic counseling. Since its establishment, 14 individuals have visited our clinic to request predictive genetic testing for hereditary neuromuscular diseases (4 for myotonic dystrophy, 6 for spinocerebellar ataxia, 3 for Huntington's disease, and 1 for Alzheimer's disease). The main reasons for considering testing were to remove uncertainty about the genetic status and to plan for the future. Nine of 14 individuals requested testing for making decisions about a forthcoming marriage or pregnancy (family planning). Other reasons raised by the individuals included career or financial planning, planning for their own health care, and knowing the risk for their children. At the first genetic counseling session, all of the individuals expressed hopes of not being a gene carrier and of escaping from fear of disease, and seemed not to be mentally well prepared for an increased-risk result. To date, 7 of the 14 individuals have received genetic testing and only one, who underwent predictive genetic testing for spinocerebellar ataxia, was given an increased-risk result. The seven individuals including the one with an increased-risk result, have coped well with their new knowledge about their genetic status after the testing results were disclosed. None of them has expressed regret. In pre-test genetic counseling sessions, we consider it quite important not only to determine the psychological status of the individual, but also to make the individual try to anticipate the changes in his/her life upon

Mouth and fin deformities in common carp: is there a genetic basis?

Czech Academy of Sciences Publication Activity Database

Kocour, Martin; Linhart, Otomar; Vandeputte, M.

2006-01-01

Roč. 37, 4 (2006), s. 419-422 ISSN 1355-557X R&D Projects: GA MZe(CZ) QF4117 Grant - others:BARRANDE 03218RF; BARRANDE 07508SA Institutional research plan: CEZ:AV0Z50450515 Keywords : common carp Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.051, year: 2006

Animal models for human genetic diseases | Sharif | African Journal ...

African Journals Online (AJOL)

The study of human genetic diseases can be greatly aided by animal models because of their similarity to humans in terms of genetics. In addition to understand diverse aspects of basic biology, model organisms are extensively used in applied research in agriculture, industry, and also in medicine, where they are used to ...

Pomegranate seed oil nanoemulsions for the prevention and treatment of neurodegenerative diseases: the case of genetic CJD.

Science.gov (United States)

Mizrahi, Michal; Friedman-Levi, Yael; Larush, Liraz; Frid, Kati; Binyamin, Orli; Dori, Dvir; Fainstein, Nina; Ovadia, Haim; Ben-Hur, Tamir; Magdassi, Shlomo; Gabizon, Ruth

2014-08-01

Neurodegenerative diseases generate the accumulation of specific misfolded proteins, such as PrP(Sc) prions or A-beta in Alzheimer's diseases, and share common pathological features, like neuronal death and oxidative damage. To test whether reduced oxidation alters disease manifestation, we treated TgMHu2ME199K mice, modeling for genetic prion disease, with Nano-PSO, a nanodroplet formulation of pomegranate seed oil (PSO). PSO comprises large concentrations of a unique polyunsaturated fatty acid, Punicic acid, among the strongest natural antioxidants. Nano-PSO significantly delayed disease presentation when administered to asymptomatic TgMHu2ME199K mice and postponed disease aggravation in already sick mice. Analysis of brain samples revealed that Nano-PSO treatment did not decrease PrP(Sc) accumulation, but rather reduced lipid oxidation and neuronal loss, indicating a strong neuroprotective effect. We propose that Nano-PSO and alike formulations may be both beneficial and safe enough to be administered for long years to subjects at risk or to those already affected by neurodegenerative conditions. This team of authors report that a nanoformulation of pomegranade seed oil, containing high levels of a strong antioxidant, can delay disease onset in a mouse model of genetic prion diseases, and the formulation also indicates a direct neuroprotective effect. Copyright © 2014 Elsevier Inc. All rights reserved.

Hope and major strides for genetic diseases of the eye

Indian Academy of Sciences (India)

2009-12-31

Dec 31, 2009 ... genetic etiology of inherited eye diseases and their underly- ing pathophysiology in the ... recent advances in the field of ophthalmic genetics. There have been .... sible or unlikely to be developed in the near future. Many of.

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 t...

Impact of genetic variations in C-C chemokine receptors and ligands on infectious diseases.

Science.gov (United States)

Qidwai, Tabish; Khan, M Y

2016-10-01

Chemokine receptors and ligands are crucial for extensive immune response against infectious diseases such as malaria, leishmaniasis, HIV and tuberculosis and a wide variety of other diseases. Role of chemokines are evidenced in the activation and regulation of immune cell migration which is important for immune response against diseases. Outcome of disease is determined by complex interaction among pathogen, host genetic variability and surrounding milieu. Variation in expression or function of chemokines caused by genetic polymorphisms could be associated with attenuated immune responses. Exploration of chemokine genetic polymorphisms in therapeutic response, gene regulation and disease outcome is important. Infectious agents in human host alter the expression of chemokines via epigenetic alterations and thus contribute to disease pathogenesis. Although some fragmentary data are available on chemokine genetic variations and their contribution in diseases, no unequivocal conclusion has been arrived as yet. We therefore, aim to investigate the association of CCR5-CCL5 and CCR2-CCL2 genetic polymorphisms with different infectious diseases, transcriptional regulation of gene, disease severity and response to therapy. Furthermore, the role of epigenetics in genes related to chemokines and infectious disease are also discussed. Copyright © 2016 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

Pleiotropic Meta-Analyses of Longitudinal Studies Discover Novel Genetic Variants Associated with Age-Related Diseases

Directory of Open Access Journals (Sweden)

Liang He

2016-10-01

Full Text Available Age-related diseases may result from shared biological mechanisms in intrinsic processes of aging. Genetic effects on age-related diseases are often modulated by environmental factors due to their little contribution to fitness or are mediated through certain endophenotypes. Identification of genetic variants with pleiotropic effects on both common complex diseases and endophenotypes may reveal potential conflicting evolutionary pressures and deliver new insights into shared genetic contribution to healthspan and lifespan. Here, we performed pleiotropic meta-analyses of genetic variants using five NIH-funded datasets by integrating univariate summary statistics for age-related diseases and endophenotypes. We investigated three groups of traits: (1 endophenotypes such as blood glucose, blood pressure, lipids, hematocrit, and body mass index, (2 time-to-event outcomes such as the age-at-onset of diabetes mellitus (DM, cancer, cardiovascular diseases (CVDs and neurodegenerative diseases (NDs, and (3 both combined. In addition to replicating previous findings, we identify seven novel genome-wide significant loci (< 5e-08, out of which five are low-frequency variants. Specifically, from Group 2, we find rs7632505 on 3q21.1 in SEMA5B, rs460976 on 21q22.3 (1 kb from TMPRSS2 and rs12420422 on 11q24.1 predominantly associated with a variety of CVDs, rs4905014 in ITPK1 associated with stroke and heart failure, rs7081476 on 10p12.1 in ANKRD26 associated with multiple diseases including DM, CVDs, and NDs. From Group 3, we find rs8082812 on 18p11.22 and rs1869717 on 4q31.3 associated with both endophenotypes and CVDs. Our follow-up analyses show that rs7632505, rs4905014, and rs8082812 have age-dependent effects on coronary heart disease or stroke. Functional annotation suggests that most of these SNPs are within regulatory regions or DNase clusters and in linkage disequilibrium with expression quantitative trait loci, implying their potential regulatory

Pediatric chronic pancreatitis is associated with genetic risk factors and substantial disease burden.

Science.gov (United States)

Schwarzenberg, Sarah Jane; Bellin, Melena; Husain, Sohail Z; Ahuja, Monika; Barth, Bradley; Davis, Heather; Durie, Peter R; Fishman, Douglas S; Freedman, Steven D; Gariepy, Cheryl E; Giefer, Matthew J; Gonska, Tanja; Heyman, Melvin B; Himes, Ryan; Kumar, Soma; Morinville, Veronique D; Lowe, Mark E; Nuehring, Neil E; Ooi, Chee Y; Pohl, John F; Troendle, David; Werlin, Steven L; Wilschanski, Michael; Yen, Elizabeth; Uc, Aliye

2015-04-01

To determine the clinical presentation, diagnostic variables, risk factors, and disease burden in children with chronic pancreatitis. We performed a cross-sectional study of data from the International Study Group of Pediatric Pancreatitis: In Search for a Cure, a registry of children with acute recurrent pancreatitis and chronic pancreatitis. Between-group differences were compared using Wilcoxon rank-sum test. Among 170 subjects in the registry, 76 (45%) had chronic pancreatitis; 57% were female, 80% were white; median age at diagnosis was 9.9 years. Pancreatitis-predisposing genetic mutations were identified in 51 (67%) and obstructive risk factors in 25 (33%). Toxic/metabolic and autoimmune factors were uncommon. Imaging demonstrated ductal abnormalities and pancreatic atrophy more commonly than calcifications. Fifty-nine (77%) reported abdominal pain within the past year; pain was reported as constant and receiving narcotics in 28%. Children with chronic pancreatitis reported a median of 3 emergency department visits and 2 hospitalizations in the last year. Forty-seven subjects (70%) missed 1 day of school in the past month as the result of chronic pancreatitis; 26 (34%) missed 3 or more days. Children reporting constant pain were more likely to miss school (P = .002), visit the emergency department (P = .01), and experience hospitalizations (P = .03) compared with children with episodic pain. Thirty-three children (43%) underwent therapeutic endoscopic retrograde pancreatography; one or more pancreatic surgeries were performed in 30 (39%). Chronic pancreatitis occurs at a young age with distinct clinical features. Genetic and obstructive risk factors are common, and disease burden is substantial. Copyright © 2015 Elsevier Inc. All rights reserved.

Genetic influences on incidence and case-fatality of infectious disease

DEFF Research Database (Denmark)

Petersen, Liselotte; Andersen, Per Kragh; Sørensen, Thorkild I A

2010-01-01

Family, twin and adoption studies suggest that genetic susceptibility contributes to familial aggregation of infectious diseases or to death from infections. We estimated genetic and shared environmental influences separately on the risk of acquiring an infection (incidence) and on dying from...

The Impact of Evolutionary Driving Forces on Human Complex Diseases: A Population Genetics Approach

Directory of Open Access Journals (Sweden)

Amr T. M. Saeb

2016-01-01

Full Text Available Investigating the molecular evolution of human genome has paved the way to understand genetic adaptation of humans to the environmental changes and corresponding complex diseases. In this review, we discussed the historical origin of genetic diversity among human populations, the evolutionary driving forces that can affect genetic diversity among populations, and the effects of human movement into new environments and gene flow on population genetic diversity. Furthermore, we presented the role of natural selection on genetic diversity and complex diseases. Then we reviewed the disadvantageous consequences of historical selection events in modern time and their relation to the development of complex diseases. In addition, we discussed the effect of consanguinity on the incidence of complex diseases in human populations. Finally, we presented the latest information about the role of ancient genes acquired from interbreeding with ancient hominids in the development of complex diseases.

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

Energy Technology Data Exchange (ETDEWEB)

Duster, T.

1998-11-01

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

Conservation and genetic characterisation of common bean landraces from Cilento region (southern Italy): high differentiation in spite of low genetic diversity.

Science.gov (United States)

De Luca, Daniele; Cennamo, Paola; Del Guacchio, Emanuele; Di Novella, Riccardo; Caputo, Paolo

2018-02-01

Since its introduction from Central-South America to Italy almost 500 years ago, the common bean (Phaseolus vulgaris L.) was largely cultivated across the peninsula in hundreds of different landraces. However, globalisation and technological modernisation of agricultural practices in the last decades promoted the cultivation of few varieties at the expense of traditional and local agro-ecotypes, which have been confined to local markets or have completely disappeared. The aim of this study was to evaluate the genetic diversity and differentiation in 12 common bean landraces once largely cultivated in the Cilento region (Campania region, southern Italy), and now the object of a recovery program to save them from extinction. The analysis conducted using 13 nuclear microsatellite loci in 140 individuals revealed a high degree of homozygosity within each landrace and a strong genetic differentiation that was reflected in the success in assigning individuals to the source landrace. On the contrary, internal transcribed spacers 1 and 2, analysed in one individual per landrace, were highly similar among common bean landraces but allowed the identification of a cowpea variety (Vigna unguiculata Walp.), a crop largely cultivated in the Old World before the arrival of common bean from Americas. In conclusion, our study highlighted that conservation of landraces is important not only for the cultural and socio-economic value that they have for local communities, but also because the time and conditions in which they have been selected have led to that genetic distinctiveness that is at the basis of many potential agronomical applications and dietary benefits.

Genetics Home Reference: chronic granulomatous disease

Science.gov (United States)

... Other common areas of infection in people with chronic granulomatous disease include the skin, liver , and lymph nodes . Inflammation can occur in ... Other common areas of inflammation in people with chronic granulomatous ... and skin. Additionally, granulomas within the gastrointestinal tract can lead ...

Reduced serum myostatin concentrations associated with genetic muscle disease progression.

Science.gov (United States)

Burch, Peter M; Pogoryelova, Oksana; Palandra, Joe; Goldstein, Richard; Bennett, Donald; Fitz, Lori; Guglieri, Michela; Bettolo, Chiara Marini; Straub, Volker; Evangelista, Teresinha; Neubert, Hendrik; Lochmüller, Hanns; Morris, Carl

2017-03-01

Myostatin is a highly conserved protein secreted primarily from skeletal muscle that can potently suppress muscle growth. This ability to regulate skeletal muscle mass has sparked intense interest in the development of anti-myostatin therapies for a wide array of muscle disorders including sarcopenia, cachexia and genetic neuromuscular diseases. While a number of studies have examined the circulating myostatin concentrations in healthy and sarcopenic populations, very little data are available from inherited muscle disease patients. Here, we have measured the myostatin concentration in serum from seven genetic neuromuscular disorder patient populations using immunoaffinity LC-MS/MS. Average serum concentrations of myostatin in all seven muscle disease patient groups were significantly less than those measured in healthy controls. Furthermore, circulating myostatin concentrations correlated with clinical measures of disease progression for five of the muscle disease patient populations. These findings greatly expand the understanding of myostatin in neuromuscular disease and suggest its potential utility as a biomarker of disease progression.

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

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Yiming Hu

2017-06-01

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

Genetic Contributors to Intergenerational CAG Repeat Instability in Huntington's Disease Knock-In Mice.

Science.gov (United States)

Neto, João Luís; Lee, Jong-Min; Afridi, Ali; Gillis, Tammy; Guide, Jolene R; Dempsey, Stephani; Lager, Brenda; Alonso, Isabel; Wheeler, Vanessa C; Pinto, Ricardo Mouro

2017-02-01

Huntington's disease (HD) is a neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in exon 1 of the HTT gene. Longer repeat sizes are associated with increased disease penetrance and earlier ages of onset. Intergenerationally unstable transmissions are common in HD families, partly underlying the genetic anticipation seen in this disorder. HD CAG knock-in mouse models also exhibit a propensity for intergenerational repeat size changes. In this work, we examine intergenerational instability of the CAG repeat in over 20,000 transmissions in the largest HD knock-in mouse model breeding datasets reported to date. We confirmed previous observations that parental sex drives the relative ratio of expansions and contractions. The large datasets further allowed us to distinguish effects of paternal CAG repeat length on the magnitude and frequency of expansions and contractions, as well as the identification of large repeat size jumps in the knock-in models. Distinct degrees of intergenerational instability were observed between knock-in mice of six background strains, indicating the occurrence of trans-acting genetic modifiers. We also found that lines harboring a neomycin resistance cassette upstream of Htt showed reduced expansion frequency, indicative of a contributing role for sequences in cis, with the expanded repeat as modifiers of intergenerational instability. These results provide a basis for further understanding of the mechanisms underlying intergenerational repeat instability. Copyright © 2017 by the Genetics Society of America.

Genetic basis of atrial fibrillation

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Oscar Campuzano

2016-12-01

Full Text Available Atrial fibrillation is the most common sustained arrhythmia and remains as one of main challenges in current clinical practice. The disease may be induced secondary to other diseases such as hypertension, valvular heart disease, and heart failure, conferring an increased risk of stroke and sudden death. Epidemiological studies have provided evidence that genetic factors play an important role and up to 30% of clinically diagnosed patients may have a family history of atrial fibrillation. To date, several rare variants have been identified in a wide range of genes associated with ionic channels, calcium handling protein, fibrosis, conduction and inflammation. Important advances in clinical, genetic and molecular basis have been performed over the last decade, improving diagnosis and treatment. However, the genetics of atrial fibrillation is complex and pathophysiological data remains still unraveling. A better understanding of the genetic basis will induce accurate risk stratification and personalized clinical treatment. In this review, we have focused on current genetics basis of atrial fibrillation.

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

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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.

Estimating the contribution of genetic variants to difference in incidence of disease between population groups

Science.gov (United States)

Moonesinghe, Ramal; Ioannidis, John PA; Flanders, W Dana; Yang, Quanhe; Truman, Benedict I; Khoury, Muin J

2012-01-01

Genome-wide association studies have identified multiple genetic susceptibility variants to several complex human diseases. However, risk-genotype frequency at loci showing robust associations might differ substantially among different populations. In this paper, we present methods to assess the contribution of genetic variants to the difference in the incidence of disease between different population groups for different scenarios. We derive expressions for the contribution of a single genetic variant, multiple genetic variants, and the contribution of the joint effect of a genetic variant and an environmental factor to the difference in the incidence of disease. The contribution of genetic variants to the difference in incidence increases with increasing difference in risk-genotype frequency, but declines with increasing difference in incidence between the two populations. The contribution of genetic variants also increases with increasing relative risk and the contribution of joint effect of genetic and environmental factors increases with increasing relative risk of the gene–environmental interaction. The contribution of genetic variants to the difference in incidence between two populations can be expressed as a function of the population attributable risks of the genetic variants in the two populations. The contribution of a group of genetic variants to the disparity in incidence of disease could change considerably by adding one more genetic variant to the group. Any estimate of genetic contribution to the disparity in incidence of disease between two populations at this stage seems to be an elusive goal. PMID:22333905

Estimating the contribution of genetic variants to difference in incidence of disease between population groups.

Science.gov (United States)

Moonesinghe, Ramal; Ioannidis, John P A; Flanders, W Dana; Yang, Quanhe; Truman, Benedict I; Khoury, Muin J

2012-08-01

Genome-wide association studies have identified multiple genetic susceptibility variants to several complex human diseases. However, risk-genotype frequency at loci showing robust associations might differ substantially among different populations. In this paper, we present methods to assess the contribution of genetic variants to the difference in the incidence of disease between different population groups for different scenarios. We derive expressions for the contribution of a single genetic variant, multiple genetic variants, and the contribution of the joint effect of a genetic variant and an environmental factor to the difference in the incidence of disease. The contribution of genetic variants to the difference in incidence increases with increasing difference in risk-genotype frequency, but declines with increasing difference in incidence between the two populations. The contribution of genetic variants also increases with increasing relative risk and the contribution of joint effect of genetic and environmental factors increases with increasing relative risk of the gene-environmental interaction. The contribution of genetic variants to the difference in incidence between two populations can be expressed as a function of the population attributable risks of the genetic variants in the two populations. The contribution of a group of genetic variants to the disparity in incidence of disease could change considerably by adding one more genetic variant to the group. Any estimate of genetic contribution to the disparity in incidence of disease between two populations at this stage seems to be an elusive goal.

Somatic USP8 Gene Mutations Are a Common Cause of Pediatric Cushing Disease.

Science.gov (United States)

Faucz, Fabio R; Tirosh, Amit; Tatsi, Christina; Berthon, Annabel; Hernández-Ramírez, Laura C; Settas, Nikolaos; Angelousi, Anna; Correa, Ricardo; Papadakis, Georgios Z; Chittiboina, Prashant; Quezado, Martha; Pankratz, Nathan; Lane, John; Dimopoulos, Aggeliki; Mills, James L; Lodish, Maya; Stratakis, Constantine A

2017-08-01

Somatic mutations in the ubiquitin-specific protease 8 (USP8) gene have been recently identified as the most common genetic alteration in patients with Cushing disease (CD). However, the frequency of these mutations in the pediatric population has not been extensively assessed. We investigated the status of the USP8 gene at the somatic level in a cohort of pediatric patients with corticotroph adenomas. The USP8 gene was fully sequenced in both germline and tumor DNA samples from 42 pediatric patients with CD. Clinical, biochemical, and imaging data were compared between patients with and without somatic USP8 mutations. Five different USP8 mutations (three missense, one frameshift, and one in-frame deletion) were identified in 13 patients (31%), all of them located in exon 14 at the previously described mutational hotspot, affecting the 14-3-3 binding motif of the protein. Patients with somatic mutations were older at disease presentation [mean 5.1 ± 2.1 standard deviation (SD) vs 13.1 ± 3.6 years, P = 0.03]. Levels of urinary free cortisol, midnight serum cortisol, and adrenocorticotropic hormone, as well as tumor size and frequency of invasion of the cavernous sinus, were not significantly different between the two groups. However, patients harboring somatic USP8 mutations had a higher likelihood of recurrence compared with patients without mutations (46.2% vs 10.3%, P = 0.009). Somatic USP8 gene mutations are a common cause of pediatric CD. Patients harboring a somatic mutation had a higher likelihood of tumor recurrence, highlighting the potential importance of this molecular defect for the disease prognosis and the development of targeted therapeutic options. Copyright © 2017 Endocrine Society

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

Directory of Open Access Journals (Sweden)

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.

Genetics, mental illness, and complex disease: development and distribution of an interactive CD-ROM for genetic counselors. Final report for period 15 August 2000 - 31 December 2002

Energy Technology Data Exchange (ETDEWEB)

McInerney, Joseph D.

2003-03-31

"Genetics and Major Psychiatric Disorders: A Program for Genetic Counselors" provides an introduction to psychiatric genetics, with a focus on the genetics of common complex disease, for genetics professionals. The program is available as a CD-ROM and an online educational resource. The on-line version requires a direct internet connection. Each educational module begins with an interactive case study that raises significant issues addressed in each module. In addition, case studies provided throughout the educational materials support teaching of major concepts. Incorporated throughout the content are expert video clips, video clips from individuals affected by psychiatric illness, and optional "learn more" materials that offer greater depth about a particular topic. The structure of the CD-ROM permits self-navigation, but we have suggested a sequence that allows materials to build upon each other. At any point in the materials, users may pause and look up terms in the glossary or review the DSM-IV criteria for selected psychiatric disorders. A detailed site map is available for those who choose to self navigate through the content.

Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases

DEFF Research Database (Denmark)

Ferrari, Raffaele; Wang, Yunpeng; Vandrovcova, Jana

2017-01-01

BACKGROUND: Clinical, pathological and genetic overlap between sporadic frontotemporal dementia (FTD), Alzheimer's disease (AD) and Parkinson's disease (PD) has been suggested; however, the relationship between these disorders is still not well understood. Here we evaluated genetic overlap between...

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...

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...

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.J. van der Lee (Sven); A.A.E. Vinkhuyzen (Anna A.); N. Amin (Najaf); D. Conley (Dalton); J. Derringer; C.M. van Duijn (Cornelia); 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

Fatal Prion Disease in a Mouse Model of Genetic E200K Creutzfeldt-Jakob Disease

Science.gov (United States)

Friedman-Levi, Yael; Meiner, Zeev; Canello, Tamar; Frid, Kati; Kovacs, Gabor G.; Budka, Herbert; Avrahami, Dana; Gabizon, Ruth

2011-01-01

Genetic prion diseases are late onset fatal neurodegenerative disorders linked to pathogenic mutations in the prion protein-encoding gene, PRNP. The most prevalent of these is the substitution of Glutamate for Lysine at codon 200 (E200K), causing genetic Creutzfeldt-Jakob disease (gCJD) in several clusters, including Jews of Libyan origin. Investigating the pathogenesis of genetic CJD, as well as developing prophylactic treatments for young asymptomatic carriers of this and other PrP mutations, may well depend upon the availability of appropriate animal models in which long term treatments can be evaluated for efficacy and toxicity. Here we present the first effective mouse model for E200KCJD, which expresses chimeric mouse/human (TgMHu2M) E199KPrP on both a null and a wt PrP background, as is the case for heterozygous patients and carriers. Mice from both lines suffered from distinct neurological symptoms as early as 5–6 month of age and deteriorated to death several months thereafter. Histopathological examination of the brain and spinal cord revealed early gliosis and age-related intraneuronal deposition of disease-associated PrP similarly to human E200K gCJD. Concomitantly we detected aggregated, proteinase K resistant, truncated and oxidized PrP forms on immunoblots. Inoculation of brain extracts from TgMHu2ME199K mice readily induced, the first time for any mutant prion transgenic model, a distinct fatal prion disease in wt mice. We believe that these mice may serve as an ideal platform for the investigation of the pathogenesis of genetic prion disease and thus for the monitoring of anti-prion treatments. PMID:22072968

Fatal prion disease in a mouse model of genetic E200K Creutzfeldt-Jakob disease.

Directory of Open Access Journals (Sweden)

Yael Friedman-Levi

2011-11-01

Full Text Available Genetic prion diseases are late onset fatal neurodegenerative disorders linked to pathogenic mutations in the prion protein-encoding gene, PRNP. The most prevalent of these is the substitution of Glutamate for Lysine at codon 200 (E200K, causing genetic Creutzfeldt-Jakob disease (gCJD in several clusters, including Jews of Libyan origin. Investigating the pathogenesis of genetic CJD, as well as developing prophylactic treatments for young asymptomatic carriers of this and other PrP mutations, may well depend upon the availability of appropriate animal models in which long term treatments can be evaluated for efficacy and toxicity. Here we present the first effective mouse model for E200KCJD, which expresses chimeric mouse/human (TgMHu2M E199KPrP on both a null and a wt PrP background, as is the case for heterozygous patients and carriers. Mice from both lines suffered from distinct neurological symptoms as early as 5-6 month of age and deteriorated to death several months thereafter. Histopathological examination of the brain and spinal cord revealed early gliosis and age-related intraneuronal deposition of disease-associated PrP similarly to human E200K gCJD. Concomitantly we detected aggregated, proteinase K resistant, truncated and oxidized PrP forms on immunoblots. Inoculation of brain extracts from TgMHu2ME199K mice readily induced, the first time for any mutant prion transgenic model, a distinct fatal prion disease in wt mice. We believe that these mice may serve as an ideal platform for the investigation of the pathogenesis of genetic prion disease and thus for the monitoring of anti-prion treatments.

Genetic contribution to neurodevelopmental outcomes in congenital heart disease: are some patients predetermined to have developmental delay?

Science.gov (United States)

Rollins, Caitlin K; Newburger, Jane W; Roberts, Amy E

2017-10-01

Neurodevelopmental impairment is common in children with moderate to severe congenital heart disease (CHD). As children live longer and healthier lives, research has focused on identifying causes of neurodevelopmental morbidity that significantly impact long-term quality of life. This review will address the role of genetic factors in predicting neurodevelopmental outcome in CHD. A robust literature suggests that among children with various forms of CHD, those with known genetic/extracardiac anomalies are at highest risk of neurodevelopmental impairment. Advances in genetic technology have identified genetic causes of CHD in an increasing percentage of patients. Further, emerging data suggest substantial overlap between mutations in children with CHD and those that have previously been associated with neurodevelopmental disorders. Innate and patient factors appear to be more important in predicting neurodevelopmental outcome than medical/surgical variables. Future research is needed to establish a broader understanding of the mutations that contribute to neurodevelopmental disorders and the variations in expressivity and penetrance.

[Advance in the methods of preimplantation genetic diagnosis for single gene diseases].

Science.gov (United States)

Ren, Yixin; Qiao, Jie; Yan, Liying

2017-06-10

More than 7000 single gene diseases have been identified and most of them lack effective treatment. As an early form of prenatal diagnosis, preimplantation genetic diagnosis (PGD) is a combination of in vitro fertilization and genetic diagnosis. PGD has been applied in clinics for more than 20 years to avoid the transmission of genetic defects through analysis of embryos at early stages of development. In this paper, a review for the recent advances in PGD for single gene diseases is provided.

Common and distinct genetic properties of ESCRT-II components in Drosophila.

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Hans-Martin Herz

Full Text Available BACKGROUND: Genetic studies in yeast have identified class E vps genes that form the ESCRT complexes required for protein sorting at the early endosome. In Drosophila, mutations of the ESCRT-II component vps25 cause endosomal defects leading to accumulation of Notch protein and increased Notch pathway activity. These endosomal and signaling defects are thought to account for several phenotypes. Depending on the developmental context, two different types of overgrowth can be detected. Tissue predominantly mutant for vps25 displays neoplastic tumor characteristics. In contrast, vps25 mutant clones in a wild-type background trigger hyperplastic overgrowth in a non-autonomous manner. In addition, vps25 mutant clones also promote apoptotic resistance in a non-autonomous manner. PRINCIPAL FINDINGS: Here, we genetically characterize the remaining ESCRT-II components vps22 and vps36. Like vps25, mutants of vps22 and vps36 display endosomal defects, accumulate Notch protein and--when the tissue is predominantly mutant--show neoplastic tumor characteristics. However, despite these common phenotypes, they have distinct non-autonomous phenotypes. While vps22 mutations cause strong non-autonomous overgrowth, they do not affect apoptotic resistance. In contrast, vps36 mutations increase apoptotic resistance, but have little effect on non-autonomous proliferation. Further characterization reveals that although all ESCRT-II mutants accumulate Notch protein, only vps22 and vps25 mutations trigger Notch activity. CONCLUSIONS/SIGNIFICANCE: The ESCRT-II components vps22, vps25 and vps36 display common and distinct genetic properties. Our data redefine the role of Notch for hyperplastic and neoplastic overgrowth in these mutants. While Notch is required for hyperplastic growth, it appears to be dispensable for neoplastic transformation.

Excessive Daytime Sleepiness Is a Common Symptom in Fabry Disease

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Thomas Duning

2009-07-01

Full Text Available Fabry disease (FD is an X-linked lysosomal storage disorder characterized by a deficient activity of the enzyme α-galactosidase A, resulting in a vasculopathic involvement of various organ systems, e.g. cerebral structures. Marked cerebral vasculopathy with subsequent white matter lesions (WML are a frequent finding in FD patients. Recent studies discussed an association between cerebral white matter changes and sleep-related disturbances of breathing, which may lead to excessive daytime sleepiness (EDS. A 56-year-old Caucasian female FD patient with EDS was admitted to our sleep laboratory. Overnight polysomnography showed a Cheyne-Stokes respiration pattern with significant O2 desaturation. MR imaging revealed confluent WML including the brain stem, but no renal or cardiac involvement. We then evaluated the clinical data of 49 genetically proven FD patients (27 males; mean age 43 years from our FD centre. With a frequency of 68%, EDS exceeds the prevalence of other common symptoms of FD (angiokeratomas 61%; acroparaesthesia 51%; renal involvement 29%; cardiac involvement 27%, and the prevalence of chronic fatigue (48%. EDS was independently associated with the physical component summary of the SF-36 data (corrected R2 =–0.323, p 2 = –0.253, p < 0.001. We conclude that EDS is a common and underdiagnosed symptom in FD patients, accompanied by a significant impact on quality of life. EDS might be caused by central breathing disorders due to an affection of brain regions associated with respiratory control in FD.

Rare genetic diseases: update on diagnosis, treatment and online resources.

Science.gov (United States)

Pogue, Robert E; Cavalcanti, Denise P; Shanker, Shreya; Andrade, Rosangela V; Aguiar, Lana R; de Carvalho, Juliana L; Costa, Fabrício F

2018-01-01

Rare genetic diseases collectively impact a significant portion of the world's population. For many diseases there is limited information available, and clinicians can find difficulty in differentiating between clinically similar conditions. This leads to problems in genetic counseling and patient treatment. The biomedical market is affected because pharmaceutical and biotechnology industries do not see advantages in addressing rare disease treatments, or because the cost of the treatments is too high. By contrast, technological advances including DNA sequencing and analysis, together with computer-aided tools and online resources, are allowing a more thorough understanding of rare disorders. Here, we discuss how the collection of various types of information together with the use of new technologies is facilitating diagnosis and, consequently, treatment of rare diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

Common Diseases of Poultry in Kaduna State: Perspective of a ...

African Journals Online (AJOL)

Several reports on prevailing poultry diseases across some states in Nigeria have been documented. The common prevailing poultry diseases in Kaduna Sate ... As a single entity, Coccidiosis appeared to be the most occurring disease ... Private Veterinary Clinics have pivotal role to play in disease reporting in the country.

[The genetics of addictions].

Science.gov (United States)

Ibañez Cuadrado, Angela

2008-01-01

The addictions are common chronic psychiatric diseases which represent a serious worldwide public-health problem. They have a high prevalence and negative effects at individual, family and societal level, with a high sanitary cost. Epidemiological genetic research has revealed that addictions are moderately to highly heritable. Also the investigation has evidenced that environmental and genetic factors contribute to individual differences in vulnerability to addictions. Advances in the neurobiology of addiction joined to the development of new molecular genetic technologies, have led to the identification of a variety of underlying genes and pathways in addiction process, leading to the description of common molecular mechanisms in substance and behaviour dependencies. Identifying gene-environment interactions is a crucial issue in future research. Other major goal in genetic research is the identification of new therapeutic targets for treatment and prevention.

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

Science.gov (United States)

Klink, Barbara; Schlingelhof, Ben; Klink, Martin; Stout-Weider, Karen; Patt, Stephan; Schrock, Evelin

2010-01-01

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. Methods: The oligodendroglial and the “classic” glioblastoma parts of 13 GBMO were analyzed separately by interphase fluorescence in situ hybridization (FISH) on paraffin sections using a custom probe set (regions 1p, 1q, 7q, 10q, 17p, 19q, cen18, 21q) and by comparative genomic hybridization (CGH) of microdissected paraffin embedded tumor tissue. Results: We identified four distinct genetic subtypes in 13 GBMOs: an “astrocytic” subtype (9/13) characterized by +7/−10; an “oligodendroglial” subtype with −1p/−19q (1/13); an “intermediate” subtype showing +7/−1p (1/13), and an “other” subtype having none of the former aberrations typical for gliomas (2/13). The different histological tumor parts of GBMO revealed common genetic changes in all tumors and showed additional aberrations specific for each part. Conclusion: Our findings demonstrate the monoclonal origin of GBMO followed by the development of the astrocytic and oligodendroglial components. The diagnostic determination of the genetic signatures may allow for a better prognostication of the patients. PMID:20966543

Shared genetic contribution to ischemic stroke and Alzheimer's disease

Science.gov (United States)

Adib‐Samii, Poneh; Harold, Denise; Dichgans, Martin; Williams, Julie; Lewis, Cathryn M.; Markus, Hugh S.; Fornage, Myriam; Holliday, Elizabeth G; Sharma, Pankaj; Bis, Joshua C; Psaty, Bruce M; Seshadri, Sudha; Nalls, Mike A; Devan, William J; Boncoraglio, Giorgio; Malik, Rainer; Mitchell, Braxton D; Kittner, Steven J; Ikram, M Arfan; Clarke, Robert; Rosand, Jonathan; Meschia, James F; Sudlow, Cathie; Rothwell, Peter M; Levi, Christopher; Bevan, Steve; Kilarski, Laura L; Walters, Matthew; Thijs, Vincent; Slowik, Agnieszka; Lindgren, Arne; de Bakker, Paul I W; Lambert, Jean‐Charles; Ibrahim‐Verbaas, Carla A; Harold, Denise; Naj, Adam C; Sims, Rebecca; Bellenguez, Céline; Jun, Gyungah; DeStefano, Anita L; Bis, Joshua C; Beecham, Gary W; Grenier‐Boley, Benjamin; Russo, Giancarlo; Thornton‐Wells, Tricia A; Jones, Nicola; Smith, Albert V; Chouraki, Vincent; Thomas, Charlene; Ikram, M Arfan; Zelenika, Diana; Vardarajan, Badri N; Kamatani, Yoichiro; Lin, Chiao‐Feng; Gerrish, Amy; Schmidt, Helena; Kunkle, Brian; Dunstan, Melanie L; Ruiz, Agustin; Bihoreau, Marie‐Thçrèse; Choi, Seung‐Hoan; Reitz, Christiane; Pasquier, Florence; Hollingworth, Paul; Ramirez, Alfredo; Hanon, Olivier; Fitzpatrick, Annette L; Buxbaum, Joseph D; Campion, Dominique; Crane, Paul K; Baldwin, Clinton; Becker, Tim; Gudnason, Vilmundur; Cruchaga, Carlos; Craig, David; Amin, Najaf; Berr, Claudine; Lopez, Oscar L; De Jager, Philip L; Deramecourt, Vincent; Johnston, Janet A; Evans, Denis; Lovestone, Simon; Letenneur, Luc; Morón, Francisco J; Rubinsztein, David C; Eiriksdottir, Gudny; Sleegers, Kristel; Goate, Alison M; Fiçvet, Nathalie; Huentelman, Matthew J; Gill, Michael; Brown, Kristelle; Kamboh, M Ilyas; Keller, Lina; Barberger‐Gateau, Pascale; McGuinness, Bernadette; Larson, Eric B; Green, Robert; Myers, Amanda J; Dufouil, Carole; Todd, Stephen; Wallon, David; Love, Seth; Rogaeva, Ekaterina; Gallacher, John; St George‐Hyslop, Peter; Clarimon, Jordi; Lleo, Alberto; Bayer, Anthony; Tsuang, Debby W; Yu, Lei; Tsolaki, Magda; Bossù, Paola; Spalletta, Gianfranco; Proitsi, Petroula; Collinge, John; Sorbi, Sandro; Sanchez‐Garcia, Florentino; Fox, Nick C; Hardy, John; Deniz Naranjo, Maria Candida; Bosco, Paolo; Clarke, Robert; Brayne, Carol; Galimberti, Daniela; Mancuso, Michelangelo; Matthews, Fiona; Moebus, Susanne; Mecocci, Patrizia; Del Zompo, Maria; Maier, Wolfgang; Hampel, Harald; Pilotto, Alberto; Bullido, Maria; Panza, Francesco; Caffarra, Paolo; Nacmias, Benedetta; Gilbert, John R; Mayhaus, Manuel; Lannfelt, Lars; Hakonarson, Hakon; Pichler, Sabrina; Carrasquillo, Minerva M; Ingelsson, Martin; Beekly, Duane; Alvarez, Victoria; Zou, Fanggeng; Valladares, Otto; Younkin, Steven G; Coto, Eliecer; Hamilton‐Nelson, Kara L; Gu, Wei; Razquin, Cristina; Pastor, Pau; Mateo, Ignacio; Owen, Michael J; Faber, Kelley M; Jonsson, Palmi V; Combarros, Onofre; O'Donovan, Michael C; Cantwell, Laura B; Soininen, Hilkka; Blacker, Deborah; Mead, Simon; Mosley, Thomas H; Bennett, David A; Harris, Tamara B; Fratiglioni, Laura; Holmes, Clive; de Bruijn, Renee F A G; Passmore, Peter; Montine, Thomas J; Bettens, Karolien; Rotter, Jerome I; Brice, Alexis; Morgan, Kevin; Foroud, Tatiana M; Kukull, Walter A; Hannequin, Didier; Powell, John F; Nalls, Michael A; Ritchie, Karen; Lunetta, Kathryn L; Kauwe, John S K; Boerwinkle, Eric; Riemenschneider, Matthias; Boada, Mercè; Hiltunen, Mikko; Martin, Eden R; Schmidt, Reinhold; Rujescu, Dan; Wang, Li‐San; Dartigues, Jean‐François; Mayeux, Richard; Tzourio, Christophe; Hofman, Albert; Nöthen, Markus M; Graff, Caroline; Psaty, Bruce M; Jones, Lesley; Haines, Jonathan L; Holmans, Peter A; Lathrop, Mark; Pericak‐Vance, Margaret A; Launer, Lenore J; Farrer, Lindsay A; van Duijn, Cornelia M; Van Broeckhoven, Christine; Moskvina, Valentina; Seshadri, Sudha; Williams, Julie; Schellenberg, Gerard D; Amouyel, Philippe

2016-01-01

Objective Increasing evidence suggests epidemiological and pathological links between Alzheimer's disease (AD) and ischemic stroke (IS). We investigated the evidence that shared genetic factors underpin the two diseases. Methods Using genome‐wide association study (GWAS) data from METASTROKE + (15,916 IS cases and 68,826 controls) and the International Genomics of Alzheimer's Project (IGAP; 17,008 AD cases and 37,154 controls), we evaluated known associations with AD and IS. On the subset of data for which we could obtain compatible genotype‐level data (4,610 IS cases, 1,281 AD cases, and 14,320 controls), we estimated the genome‐wide genetic correlation (rG) between AD and IS, and the three subtypes (cardioembolic, small vessel, and large vessel), using genome‐wide single‐nucleotide polymorphism (SNP) data. We then performed a meta‐analysis and pathway analysis in the combined AD and small vessel stroke data sets to identify the SNPs and molecular pathways through which disease risk may be conferred. Results We found evidence of a shared genetic contribution between AD and small vessel stroke (rG [standard error] = 0.37 [0.17]; p = 0.011). Conversely, there was no evidence to support shared genetic factors in AD and IS overall or with the other stroke subtypes. Of the known GWAS associations with IS or AD, none reached significance for association with the other trait (or stroke subtypes). A meta‐analysis of AD IGAP and METASTROKE + small vessel stroke GWAS data highlighted a region (ATP5H/KCTD2/ICT1) associated with both diseases (p = 1.8 × 10−8). A pathway analysis identified four associated pathways involving cholesterol transport and immune response. Interpretation Our findings indicate shared genetic susceptibility to AD and small vessel stroke and highlight potential causal pathways and loci. Ann Neurol 2016;79:739–747 PMID:26913989

Genetics of Unilateral and Bilateral Age-Related Macular Degeneration Severity Stages

NARCIS (Netherlands)

Schick, T.; Altay, L.; Viehweger, E.; Hoyng, C.B.; Hollander, A.I. den; Felsch, M.; Fauser, S.

2016-01-01

BACKGROUND: Age-related macular degeneration (AMD) is a common disease causing visual impairment and blindness. Various gene variants are strongly associated with late stage AMD, but little is known about the genetics of early forms of the disease. This study evaluated associations of genetic

State of play in direct-to-consumer genetic testing for lifestyle-related diseases: market, marketing content, user experiences and regulation.

Science.gov (United States)

Saukko, Paula

2013-02-01

Direct-to-consumer (DTC) genetic tests have aroused controversy. Critics have argued many of the tests are not backed by scientific evidence, misguide their customers and should be regulated more stringently. Proponents suggest that finding out genetic susceptibilities for diseases could encourage healthier behaviours and makes the results of genetics research available to the public. This paper reviews the state of play in DTC genetic testing, focusing on tests identifying susceptibilities for lifestyle-related diseases. It will start with mapping the market for the tests. The paper will review (1) research on the content of the online marketing of DTC tests, (2) studies on the effects of DTC genetic tests on customers and (3) academic and policy proposals on how to regulate the tests. Current studies suggest that the marketing of DTC genetic tests often exaggerates their predictive powers, which could misguide consumers. However, research indicates that the tests do not seem to have major negative effects (worry and confusion) but neither do they engender positive effects (lifestyle change) on current users. Research on regulation of the tests has most commonly suggested regulating the marketing claims of the companies. In conclusion, the risks and benefits of DTC genetic tests are less significant than what has been predicted by critics and proponents, which will be argued reflects broader historical trends transforming health and medicine.

Investigation of Genetic Variants Associated with Alzheimer Disease in Parkinson Disease Cognition.

Science.gov (United States)

Barrett, Matthew J; Koeppel, Alexander F; Flanigan, Joseph L; Turner, Stephen D; Worrall, Bradford B

2016-01-01

Meta-analysis of genome-wide association studies have implicated multiple single nucleotide polymorphisms (SNPs) and associated genes with Alzheimer disease. The role of these SNPs in cognitive impairment in Parkinson disease (PD) remains incompletely evaluated. The objective of this study was to test alleles associated with risk of Alzheimer disease for association with cognitive impairment in Parkinson disease (PD). Two datasets with PD subjects accessed through the NIH database of Genotypes and Phenotypes contained both single nucleotide polymorphism (SNP) arrays and mini-mental state exam (MMSE) scores. Genetic data underwent rigorous quality control and we selected SNPs for genes associated with AD other than APOE. We constructed logistic regression and ordinal regression models, adjusted for sex, age at MMSE, and duration of PD, to assess the association between selected SNPs and MMSE score. In one dataset, PICALM rs3851179 was associated with cognitive impairment (MMSE  70 years old (OR = 2.3; adjusted p-value = 0.017; n = 250) but not in PD subjects ≤ 70 years old. Our finding suggests that PICALM rs3851179 could contribute to cognitive impairment in older patients with PD. It is important that future studies consider the interaction of age and genetic risk factors in the development of cognitive impairment in PD.

Host genetics of Epstein-Barr virus infection, latency and disease.

Science.gov (United States)

Houldcroft, Charlotte J; Kellam, Paul

2015-03-01

Epstein-Barr virus (EBV) infects 95% of the adult population and is the cause of infectious mononucleosis. It is also associated with 1% of cancers worldwide, such as nasopharyngeal carcinoma, Hodgkin's lymphoma and Burkitt's lymphoma. Human and cancer genetic studies are now major forces determining gene variants associated with many cancers, including nasopharyngeal carcinoma and Hodgkin's lymphoma. Host genetics is also important in infectious disease; however, there have been no large-scale efforts towards understanding the contribution that human genetic variation plays in primary EBV infection and latency. This review covers 25 years of studies into host genetic susceptibility to EBV infection and disease, from candidate gene studies, to the first genome-wide association study of EBV antibody response, and an EBV-status stratified genome-wide association study of Hodgkin's lymphoma. Although many genes are implicated in EBV-related disease, studies are often small, not replicated or followed up in a different disease. Larger, appropriately powered genomic studies to understand the host response to EBV will be needed to move our understanding of the biology of EBV infection beyond the handful of genes currently identified. Fifty years since the discovery of EBV and its identification as a human oncogenic virus, a glimpse of the future is shown by the first whole-genome and whole-exome studies, revealing new human genes at the heart of the host-EBV interaction. © 2014 The Authors Reviews in Medical Virology published by John Wiley & Sons Ltd.

Hypothesis: Cryptosporidium genetic diversity mirrors national disease notification rate

OpenAIRE

Takumi, Katsuhisa; Cacci?, Simone M.; van der Giessen, Joke; Xiao, Lihua; Sprong, Hein

2015-01-01

Background Cryptosporidiosis is a gastrointestinal disease affecting many people worldwide. Disease incidence is often unknown and surveillance of human cryptosporidiosis is installed in only a handful of developed countries. A genetic marker that mirrors disease incidence is potentially a powerful tool for monitoring the two primary human infected species of Cryptosporidium. Methods We used the molecular epidemiological database with Cryptosporidium isolates from ZoopNet, which currently con...

Genetic diversity within and among two-spotted spider mite resistant and susceptible common bean genotypes

Directory of Open Access Journals (Sweden)

Zeinab YOUSEFI

2017-12-01

Full Text Available Two-spotted spider mite (Tetranychus urticae C. L. Koch, 1836, is one of the most destructive herbivores of common bean. Very little is known about the diversity among resistant sources in this crop. The present study was conducted to characterize 22 resistant and susceptible common bean genotypes by 8 Simple Sequence Repeats (SSRs and 8 Random Amplified Polymorphic DNA (RAPD markers. These SSR and RAPD primers produced 100 % and 81.8 % polymorphic bands. Based on RAPD fingerprints and SSR profiles, pairwise genetic similarity ranged from 0.0 to 0.857 and from 0.125 to 1, respectively. The resistant and susceptible common bean accessions were grouped together in the dendrograms generated from RAPD and SSR clustering analyses. The results indicate that RAPD and SSR analysis could be successfully used for the estimation of genetic diversity among genotypes. SSR markers could group genotypes according to their resistibility and susceptibility to the spotted spider mite but RAPD could not. Therefore, the SSR markers can facilitate the development of resistant common bean cultivars through breeding programs against T. urticae.

Abundant genetic overlap between blood lipids and immune-mediated diseases indicates shared molecular genetic mechanisms.

Directory of Open Access Journals (Sweden)

Ole A Andreassen

Full Text Available Epidemiological studies suggest a relationship between blood lipids and immune-mediated diseases, but the nature of these associations is not well understood. We used genome-wide association studies (GWAS to investigate shared single nucleotide polymorphisms (SNPs between blood lipids and immune-mediated diseases. We analyzed data from GWAS (n~200,000 individuals, applying new False Discovery Rate (FDR methods, to investigate genetic overlap between blood lipid levels [triglycerides (TG, low density lipoproteins (LDL, high density lipoproteins (HDL] and a selection of archetypal immune-mediated diseases (Crohn's disease, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, celiac disease, psoriasis and sarcoidosis. We found significant polygenic pleiotropy between the blood lipids and all the investigated immune-mediated diseases. We discovered several shared risk loci between the immune-mediated diseases and TG (n = 88, LDL (n = 87 and HDL (n = 52. Three-way analyses differentiated the pattern of pleiotropy among the immune-mediated diseases. The new pleiotropic loci increased the number of functional gene network nodes representing blood lipid loci by 40%. Pathway analyses implicated several novel shared mechanisms for immune pathogenesis and lipid biology, including glycosphingolipid synthesis (e.g. FUT2 and intestinal host-microbe interactions (e.g. ATG16L1. We demonstrate a shared genetic basis for blood lipids and immune-mediated diseases independent of environmental factors. Our findings provide novel mechanistic insights into dyslipidemia and immune-mediated diseases and may have implications for therapeutic trials involving lipid-lowering and anti-inflammatory agents.

The sense and nonsense of direct-to-consumer genetic testing for cardiovascular disease

NARCIS (Netherlands)

Janssens, A. C. J. W.; Wilde, A. A. M.; van Langen, I. M.

2011-01-01

Expectations are high that increasing knowledge of the genetic basis of cardiovascular disease will eventually lead to personalised medicine-to preventive and therapeutic interventions that are targeted to at-risk individuals on the basis of their genetic profiles. Most cardiovascular diseases are

Coronary Artery Disease

DEFF Research Database (Denmark)

Christiansen, Morten Krogh

2017-01-01

A family history of coronary artery disease (CAD) is an important risk factor for adverse coronary events, in particular if the disease has an early onset. The risk of CAD is influenced by genetic and environmental factors with a greater genetic contribution earlier in life. Through recent years......), and to characterize and quantify subclinical atherosclerosis in their relatives. Furthermore, the aim was to explore the impact of common genetic risk variants on the age of onset, familial clustering and disease severity. In study I, 143 patients with early- onset CAD were recruited from the Western Denmark Heart...... Registry and risk factor control was evaluated. The study revealed that risk factors are common in early-onset CAD and that a large room for risk factor improvement remains. In study II, we used coronary computed tomography angiography to compare the coronary plaque burden and characteristics between 88...

Genetic background in nonalcoholic fatty liver disease: A comprehensive review

Science.gov (United States)

Macaluso, Fabio Salvatore; Maida, Marcello; Petta, Salvatore

2015-01-01

In the Western world, nonalcoholic fatty liver disease (NAFLD) is considered as one of the most significant liver diseases of the twenty-first century. Its development is certainly driven by environmental factors, but it is also regulated by genetic background. The role of heritability has been widely demonstrated by several epidemiological, familial, and twin studies and case series, and likely reflects the wide inter-individual and inter-ethnic genetic variability in systemic metabolism and wound healing response processes. Consistent with this idea, genome-wide association studies have clearly identified Patatin-like phosholipase domain-containing 3 gene variant I148M as a major player in the development and progression of NAFLD. More recently, the transmembrane 6 superfamily member 2 E167K variant emerged as a relevant contributor in both NAFLD pathogenesis and cardiovascular outcomes. Furthermore, numerous case-control studies have been performed to elucidate the potential role of candidate genes in the pathogenesis and progression of fatty liver, although findings are sometimes contradictory. Accordingly, we performed a comprehensive literature search and review on the role of genetics in NAFLD. We emphasize the strengths and weaknesses of the available literature and outline the putative role of each genetic variant in influencing susceptibility and/or progression of the disease. PMID:26494964

Association of the insertion allele of the common ACE gene polymorphism with type 2 diabetes mellitus among Kuwaiti cardiovascular disease patients.

Science.gov (United States)

Al-Serri, Ahmad; Ismael, Fatma G; Al-Bustan, Suzanne A; Al-Rashdan, Ibrahim

2015-12-01

The D allele of the common angiotensin-converting enzyme (ACE) I/D gene polymorphism (rs4646994) predisposes to type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). However, results on which allele predisposes to disease susceptibility remain controversial in Asian populations. This study was performed to evaluate the association of the common ACE I/D gene polymorphism with both T2DM and CVD susceptibility in an Arab population. We genotyped the ACE I/D polymorphisms by direct allele-specific PCR in 183 healthy controls and 400 CVD patients with diabetes (n=204) and without (n=196). Statistical analysis comparing between the different groups were conducted using R statistic package "SNPassoc". Two genetic models were used: the additive and co-dominant models. The I allele was found to be associated with T2DM (OR=1.84, p=0.00009) after adjusting for age, sex and body mass index. However, there was no association with CVD susceptibility (p>0.05). The ACE I allele is found to be associated with T2DM; however, no association was observed with CVD. The inconsistency between studies is suggested to be attributed to genetic diversity due to the existence of sub-populations found in Asian populations. © The Author(s) 2015.

Genetics, genomes and cloning the biotechnology revolution

CERN Document Server

CERN. Geneva

1999-01-01

As this century draws to a close, spectacular advances in the fields of genomics and genetics are opening up dramatic new horizons for medicine. For much of the 20th century, genetic research has focused on rare diseases caused by mutations in a particular gene. However, more recently it has been realised that common genetic variations (polymorphisms), interacting with the environment, can influence an individual's susceptibility to diseases widely represented in our populations (e.g. mental illness and asthma), redefining the term "genetic disease". Officially starting in 1990, the Human Genome Project was a $3-billion, 15-year program to find the estimated 80,000 human genes and determine the sequence of the 3 billion DNA building blocks that underlie all of human biology and its diversity. The resulting boom in genetic information and technologies, not only from humans, but from many other organisms, means that we now have new tools to understand and treat normal and disease states. This information is bei...

Bias, accuracy and impact of indirect genetic effects in infectious diseases

Directory of Open Access Journals (Sweden)

Debby eLipschutz-Powell

2012-10-01

Full Text Available Selection for improved host response to infectious disease offers a desirable alternative to chemical treatment but has proven difficult in practice, due to low heritability estimates of disease traits. Disease data from field studies is often binary, indicating whether an individual has become infected or not following exposure to an infectious disease. Numerous studies have shown that from this data one can infer genetic variation in individuals’ underlying susceptibility. In a previous study, we showed that with an Indirect Genetic Effect (IGE model it is possible to capture some genetic variation in infectivity, if present, as well as in susceptibility. Infectivity is the propensity of transmitting infection upon contact with a susceptible individual. It is an important factor determining the severity of an epidemic. However, there are severe shortcomings with the Standard IGE models as they do not accommodate the dynamic nature of disease data. Here we adjust the Standard IGE model to (1 make expression of infectivity dependent on the individuals’ disease status (Case Model and (2 to include timing of infection (Case-ordered Model. The models are evaluated by comparing impact of selection, bias and accuracy of each model using simulated binary disease data. These were generated for populations with known variation in susceptibility and infectivity thus allowing comparisons between estimated and true breeding values. Overall the Case Model provided better estimates for host genetic susceptibility and infectivity compared to the Standard Model in terms of bias, impact and accuracy. Furthermore, these estimates were strongly influenced by epidemiological characteristics. However, surprisingly, the Case Ordered model performed considerably worse than the Standard and the Case Models, pointing towards limitations in incorporating disease dynamics into conventional variance component estimation methodology and software used in animal breeding.

Huntington\\'s disease: Genetic heterogeneity in black African patients

African Journals Online (AJOL)

Objective. Huntington's disease (HD) has been reported to occur rarely in black patients. A new genetic variant– Huntington's disease-like 2 (HDL2) – occurring more frequently in blacks, has recently been described. The absence of an expanded trinucleotide repeat at the chromosome 4 HD locus was previously regarded ...

Do common eiders nest in kin groups? Microgeographic genetic structure in a philopatric sea duck

Science.gov (United States)

Sonsthagen, S.A.; Talbot, S.L.; Lanctot, Richard B.; McCracken, K.G.

2010-01-01

We investigated local genetic associations among female Pacific common eiders (Somateria mollissima v-nigrum) nesting in a stochastic Arctic environment within two groups of barrier islands (Simpson Lagoon and Mikkelsen Bay) in the Beaufort Sea, Alaska. Nonrandom genetic associations were observed among nesting females using regional spatial autocorrelation analyses for distance classes up to 1000 m in Simpson Lagoon. Nearest-neighbour analyses identified clusters of genetically related females with positive lr values observed for 0-13% and 0-7% of the comparisons in Simpson Lagoon and Mikkelsen Bay, respectively, across years. These results indicate that a proportion of females are nesting in close proximity to more genetically related individuals, albeit at low frequency. Such kin groupings may form through active association between relatives or through natal philopatry and breeding site fidelity. Eiders nest in close association with driftwood, which is redistributed annually by seasonal storms. Yet, genetic associations were still observed. Microgeographic structure may thus be more attributable to kin association than natal philopatry and site fidelity. However, habitat availability may also influence the level of structure observed. Regional structure was present only within Simpson Lagoon and this island group includes at least three islands with sufficient driftwood for colonies, whereas only one island at Mikkelsen Bay has these features. A long-term demographic study is needed to understand more fully the mechanisms that lead to fine-scale genetic structure observed in common eiders breeding in the Beaufort Sea. ?? Published 2010. This article is a US Government work and is in the public domain in the USA.

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

Hierarchical spatial genetic structure of Common Eiders (Somateria mollissima) breeding along a migratory corridor

Science.gov (United States)

Sonsthagen, S.A.; Talbot, S.L.; Lanctot, Richard B.; Scribner, K.T.; McCracken, K.G.

2009-01-01

Documentation of spatial genetic discordance among breeding populations of Arctic-nesting avian species is important, because anthropogenic change is altering environmental linkages at micro- and macrogeographic scales. We estimated levels of population subdivision within Pacific Common Eiders (Somateria mollissima v-nigrum) breeding on 12 barrier islands in the western Beaufort Sea, Alaska, using molecular markers and capture—mark—recapture (CMR) data. Common Eider populations were genetically structured on a microgeographic scale. Regional comparisons between populations breeding on island groups separated by 90 km (Mikkelsen Bay and Simpson Lagoon) revealed structuring at 14 microsatellite loci (F ST = 0.004, P Sea are strongly philopatric to island groups rather than to a particular island. Despite the apparent high site fidelity of females, coalescence-based models of gene flow suggest that asymmetrical western dispersal occurs between island groups and is likely mediated by Mikkelsen Bay females stopping early on spring migration at Simpson Lagoon to breed. Alternatively, late-arriving females may be predisposed to nest in Simpson Lagoon because of the greater availability and wider distribution of nesting habitat. Our results indicate that genetic discontinuities, mediated by female philopatry, can exist at microgeographic scales along established migratory corridors.

Genetic shifting: a novel approach for controlling vector-borne diseases.

Science.gov (United States)

Powell, Jeffrey R; Tabachnick, Walter J

2014-06-01

Rendering populations of vectors of diseases incapable of transmitting pathogens through genetic methods has long been a goal of vector geneticists. We outline a method to achieve this goal that does not involve the introduction of any new genetic variants to the target population. Rather we propose that shifting the frequencies of naturally occurring alleles that confer refractoriness to transmission can reduce transmission below a sustainable level. The program employs methods successfully used in plant and animal breeding. Because no artificially constructed genetically modified organisms (GMOs) are introduced into the environment, the method is minimally controversial. We use Aedes aegypti and dengue virus (DENV) for illustrative purposes but point out that the proposed program is generally applicable to vector-borne disease control. Copyright © 2014 Elsevier Ltd. All rights reserved.

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

DEFF Research Database (Denmark)

Frikke-Schmidt, Ruth

2010-01-01

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

Veterinary care and welfare management in common marmosets

NARCIS (Netherlands)

Bakker, Jaco

2017-01-01

The BPRC houses a self-sustaining breeding colony of common marmosets (Callithrix jacchus) for the purpose of conducting biomedical research. Their immunological, physiological, and genetic proximity to humans make marmosets useful as model for specific human diseases. In order to ensure reliable

Analogs of human genetic skin disease in domesticated animals

Directory of Open Access Journals (Sweden)

Justin Finch, MD

2017-09-01

The genetic skin diseases we will review are pigmentary mosaicism, piebaldism, albinism, Griscelli syndrome, ectodermal dysplasias, Waardenburg syndrome, and mucinosis in both humans and domesticated animals.

Immunodeficiencies and autoimmune diseases: common variable immunodeficiency and Crohn-like

OpenAIRE

Saldaña-Dueñas, Cristina; Rubio-Iturria, Saioa

2016-01-01

Background: Common variable immunodeficiency (CVI) gives a major risk of principally respiratory and digestive infections. It is associated with autoimmune diseases, granulomatous process and neoplasias. The digestive clinic is common, in 10% of patients it is the only symptom, and 60% present chronic diarrhea. Clinically it can be confused and related with other pathologies such as inflammatory bowel disease which is infrequent (2-13%). Case report: We present the case of a patient with CVI ...

Genetic Modification of the Lung Directed Toward Treatment of Human Disease.

Science.gov (United States)

Sondhi, Dolan; Stiles, Katie M; De, Bishnu P; Crystal, Ronald G

2017-01-01

Genetic modification therapy is a promising therapeutic strategy for many diseases of the lung intractable to other treatments. Lung gene therapy has been the subject of numerous preclinical animal experiments and human clinical trials, for targets including genetic diseases such as cystic fibrosis and α1-antitrypsin deficiency, complex disorders such as asthma, allergy, and lung cancer, infections such as respiratory syncytial virus (RSV) and Pseudomonas, as well as pulmonary arterial hypertension, transplant rejection, and lung injury. A variety of viral and non-viral vectors have been employed to overcome the many physical barriers to gene transfer imposed by lung anatomy and natural defenses. Beyond the treatment of lung diseases, the lung has the potential to be used as a metabolic factory for generating proteins for delivery to the circulation for treatment of systemic diseases. Although much has been learned through a myriad of experiments about the development of genetic modification of the lung, more work is still needed to improve the delivery vehicles and to overcome challenges such as entry barriers, persistent expression, specific cell targeting, and circumventing host anti-vector responses.

Genetic anaylsis of a disease resistance gene from loblolly pine

Science.gov (United States)

Yinghua Huang; Nili Jin; Alex Diner; Chuck Tauer; Yan Zhang; John Damicone

2003-01-01

Rapid advances in molecular genetics provide great opportunities for studies of host defense mechanisms. Examination of plant responses to disease at the cellular and molecular level permits both discovery of changes in gene expression in the tissues attacked by pathogens, and identification of genetic components involved in the interaction between host and pathogens....

Depression and Alzheimer's disease: is stress the initiating factor in a common neuropathological cascade?

DEFF Research Database (Denmark)

Aznar, Susana; Knudsen, Gitte M

2011-01-01

. This suggests the existence of common neuropathological mechanisms behind depression and AD. Here we propose that the brain changes associated with depressive episodes that compromise the brain's ability to cope with stress may constitute risk factors for development of AD. Furthermore, in individuals......The existence of a high co-morbidity between Alzheimer's disease (AD) and depression has been known for a long time. More interesting though are recent studies indicating that depression and number of depressive episodes earlier in life is associated with increased risk of AD development...... with a genetic linkage to depression, there may be an increased vulnerability towards the initiation of a detrimental neurodegenerative cascade. The following review will deal with the various observations reported within the different neurobiological systems known to be involved and affected in depression, like...

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…

Dancing in the dark? The status of late-onset Alzheimer's disease genetics.

Science.gov (United States)

Bertram, L; Tanzi, R E

2001-10-01

Alzheimer's disease (AD) is a genetically complex and heterogeneous disorder. Recent estimates suggest that possibly over 70% of the genetic variance for the disease remains unaccounted for by apolipoprotein E (APOE) and the three known early-onset AD genes (APP, PSEN1, PSEN2). Specifically, one recent segregation analysis predicted the existence of up to four additional susceptibility genes having a similar or greater effect than APOE. However, most of the nearly three dozen putative AD loci proposed to date have only been inconsistently replicated in follow up analyses and more studies are necessary to distinguish false-positive findings from genuine signals. Novel AD genes will not only provide valuable clues for the development of novel therapeutic approaches, but will also allow the development of new genetic risk-profiling strategies that are an essential prerequisite for early prediction/prevention of this devastating disease. In this review, we will present a brief overview of analytic tools in complex disease genetics, as well as a summary of recent linkage and association findings indicating the existence of novel late-onset AD genes on chromosomes 12, 10, and 9.

Genetics Home Reference: glycogen storage disease type I

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... resulting from uric acid crystals in the joints (gout), kidney disease, and high blood pressure in the ... particular ethnic groups? Genetic Changes Mutations in two genes, G6PC and SLC37A4 , cause GSDI. G6PC gene mutations ...

Breastfeeding and genetic factors in the etiology of inflammatory bowel disease in children

Institute of Scientific and Technical Information of China (English)

Theresa A Mikhailov; Sylvia E Furner

2009-01-01

Inflammatory bowel disease is a chronic, debilitating disorder of the gastrointestinal tract. The etiology of inflammatory bowel disease has not been elucidated, but is thought to be multifactorial with both environmental and genetic influences. A large body of research has been conducted to elucidate the etiology of inflammatory bowel disease. This article reviews this literature, emphasizing the studies of breastfeeding and the studies of genetic factors, particularly NOD2 polymorphisms.

Uptake of genetic testing and long-term tumor surveillance in von Hippel-Lindau disease

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Chávez Mireya

2010-01-01

Full Text Available Abstract Background von Hippel-Lindau (VHL disease is a hereditary cancer syndrome caused by germline mutations in the VHL gene. Patients have significant morbidity and mortality secondary to vascular tumors. Disease management is centered on tumor surveillance that allows early detection and treatment. Presymptomatic genetic testing is therefore recommended, including in at-risk children. Methods We tested 17 families (n = 109 individuals for VHL mutations including 43 children under the age of 18. Personalized genetic counseling was provided pre and post-test and the individuals undergoing presymptomatic testing filled out questionnaires gathering socio-demographic, psychological and psychiatric data. Mutation analysis was performed by direct sequencing of the VHL gene. Mutation-carriers were screened for VHL disease-related tumors and were offered follow-up annual examinations. Results Mutations were identified in 36 patients, 17 of whom were asymptomatic. In the initial screening, we identified at least one tumor in five of 17 previously asymptomatic individuals. At the end of five years, only 38.9% of the mutation-carriers continued participating in our tumor surveillance program. During this time, 14 mutation carriers developed a total of 32 new tumors, three of whom died of complications. Gender, education, income, marital status and religiosity were not found to be associated with adherence to the surveillance protocol. Follow-up adherence was also independent of pre-test depression, severity of disease, or number of affected family members. The only statistically significant predictor of adherence was being symptomatic at the time of testing (OR = 5; 95% CI 1.2 - 20.3; p = 0.02. Pre-test anxiety was more commonly observed in patients that discontinued follow-up (64.7% vs. 35.3%; p = 0.01. Conclusions The high initial uptake rate of genetic testing for VHL disease, including in minors, allowed the discontinuation of unnecessary screening

Genetic enhancement of macroautophagy in vertebrate models of neurodegenerative diseases.

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Ejlerskov, Patrick; Ashkenazi, Avraham; Rubinsztein, David C

2018-04-03

Most of the neurodegenerative diseases that afflict humans manifest with the intraneuronal accumulation of toxic proteins that are aggregate-prone. Extensive data in cell and neuronal models support the concept that such proteins, like mutant huntingtin or alpha-synuclein, are substrates for macroautophagy (hereafter autophagy). Furthermore, autophagy-inducing compounds lower the levels of such proteins and ameliorate their toxicity in diverse animal models of neurodegenerative diseases. However, most of these compounds also have autophagy-independent effects and it is important to understand if similar benefits are seen with genetic strategies that upregulate autophagy, as this strengthens the validity of this strategy in such diseases. Here we review studies in vertebrate models using genetic manipulations of core autophagy genes and describe how these improve pathology and neurodegeneration, supporting the validity of autophagy upregulation as a target for certain neurodegenerative diseases. Copyright © 2018 Elsevier Inc. All rights reserved.

Identification of Novel Genetic Loci Associated with Thyroid Peroxidase Antibodies and Clinical Thyroid Disease

DEFF Research Database (Denmark)

Medici, Marco; Porcu, Eleonora; Pistis, Giorgio

2014-01-01

, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68-2.81, P = 8.1×10(-8)), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26-1.82, P = 2.9×10(-6)), as well......Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease.......12-1.39, P = 6.2×10(-5)). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18-2.10, P = 1.9×10(-3)). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease...

A comparative study of LRRK2, PINK1 and genetically undefined familial Parkinson's disease.

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Nishioka, Kenya; Kefi, Mounir; Jasinska-Myga, Barbara; Wider, Christian; Vilariño-Güell, Carles; Ross, Owen A; Heckman, Michael G; Middleton, Lefkos T; Ishihara-Paul, Lianna; Gibson, Rachel A; Amouri, Rim; Ben Yahmed, Samia; Ben Sassi, Samia; Zouari, Mourad; El Euch, Ghada; Farrer, Matthew J; Hentati, Faycal

2010-04-01

Genetic classification of Parkinson's disease (PD) subtypes may become the preferred diagnostic tool for neurologists. Herein we compare clinical features from a large cohort of patients with familial PD of unknown aetiology or attributable to distinct genetic forms. Comprehensive neurological examinations were performed in 231 familial PD patients from Tunisia. Analysis was previously performed to screen for mutations in leucine rich repeat kinase 2 (LRRK2), PTEN induced kinase 1 (PINK1) and parkin (PRKN). Clinical features were compared between patients with genetically undefined PD (n=107) and those with LRRK2 (n=73) and PINK1 (n=42) mutations using regression analyses adjusted for gender, age of onset and disease duration. PRKN cases (n=9) were too few for meaningful statistical analysis. In comparison with genetically undefined patients, LRRK2 mutation carriers had more severe motor symptoms (median Unified Parkinson's Disease Rating Scale scores approximately 1.6 times higher, pundefined patients. As expected, PINK1 patients had younger ages and ages at disease onset, and a longer disease duration compared with LRRK2 mutation carriers and genetically undefined patients. Clinical differences between LRRK2, PINK1 and genetically undefined familial PD appear more pronounced than previously appreciated, and may prove useful in clinical practice. As future therapies are targeted to specific protein abnormalities, identifying the genetic causes and associated clinical and pathological features will determine diagnosis, preventative medicine and drug intervention strategies.

Genetic characterization and disease mechanism of retinitis pigmentosa; current scenario.

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Ali, Muhammad Umar; Rahman, Muhammad Saif Ur; Cao, Jiang; Yuan, Ping Xi

2017-08-01

Retinitis pigmentosa is a group of genetically transmitted disorders affecting 1 in 3000-8000 individual people worldwide ultimately affecting the quality of life. Retinitis pigmentosa is characterized as a heterogeneous genetic disorder which leads by progressive devolution of the retina leading to a progressive visual loss. It can occur in syndromic (with Usher syndrome and Bardet-Biedl syndrome) as well as non-syndromic nature. The mode of inheritance can be X-linked, autosomal dominant or autosomal recessive manner. To date 58 genes have been reported to associate with retinitis pigmentosa most of them are either expressed in photoreceptors or the retinal pigment epithelium. This review focuses on the disease mechanisms and genetics of retinitis pigmentosa. As retinitis pigmentosa is tremendously heterogeneous disorder expressing a multiplicity of mutations; different variations in the same gene might induce different disorders. In recent years, latest technologies including whole-exome sequencing contributing effectively to uncover the hidden genesis of retinitis pigmentosa by reporting new genetic mutations. In future, these advancements will help in better understanding the genotype-phenotype correlations of disease and likely to develop new therapies.

Genetics of asthma

DEFF Research Database (Denmark)

Thomsen, Simon F

2015-01-01

Asthma runs in families, and children of asthmatic parents are at increased risk of asthma. Prediction of disease risk is pivotal for the clinician when counselling atopic families. However, this is not always an easy task bearing in mind the vast and ever-increasing knowledge about asthma genetics....... The advent of new genotyping technologies has made it possible to sequence in great detail the human genome for asthma-associated variants, and accordingly, recent decades have witnessed an explosion in the number of rare and common variants associated with disease risk. This review presents an overview...... of methods and advances in asthma genetics in an attempt to help the clinician keep track of the most important knowledge in the field....

Genetic biomarkers for brain hemisphere differentiation in Parkinson's Disease

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Hourani, Mou'ath; Mendes, Alexandre; Berretta, Regina; Moscato, Pablo

2007-11-01

This work presents a study on the genetic profile of the left and right hemispheres of the brain of a mouse model of Parkinson's disease (PD). The goal is to characterize, in a genetic basis, PD as a disease that affects these two brain regions in different ways. Using the same whole-genome microarray expression data introduced by Brown et al. (2002) [1], we could find significant differences in the expression of some key genes, well-known to be involved in the mechanisms of dopamine production control and PD. The problem of selecting such genes was modeled as the MIN (α,β)—FEATURE SET problem [2]; a similar approach to that employed previously to find biomarkers for different types of cancer using gene expression microarray data [3]. The Feature Selection method produced a series of genetic signatures for PD, with distinct expression profiles in the Parkinson's model and control mice experiments. In addition, a close examination of the genes composing those signatures shows that many of them belong to genetic pathways or have ontology annotations considered to be involved in the onset and development of PD. Such elements could provide new clues on which mechanisms are implicated in hemisphere differentiation in PD.

Amniotic Fluid Stem Cells: A Novel Source for Modeling of Human Genetic Diseases

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Ivana Antonucci

2016-04-01

Full Text Available In recent years, great interest has been devoted to the use of Induced Pluripotent Stem cells (iPS for modeling of human genetic diseases, due to the possibility of reprogramming somatic cells of affected patients into pluripotent cells, enabling differentiation into several cell types, and allowing investigations into the molecular mechanisms of the disease. However, the protocol of iPS generation still suffers from technical limitations, showing low efficiency, being expensive and time consuming. Amniotic Fluid Stem cells (AFS represent a potential alternative novel source of stem cells for modeling of human genetic diseases. In fact, by means of prenatal diagnosis, a number of fetuses affected by chromosomal or Mendelian diseases can be identified, and the amniotic fluid collected for genetic testing can be used, after diagnosis, for the isolation, culture and differentiation of AFS cells. This can provide a useful stem cell model for the investigation of the molecular basis of the diagnosed disease without the necessity of producing iPS, since AFS cells show some features of pluripotency and are able to differentiate in cells derived from all three germ layers “in vitro”. In this article, we describe the potential benefits provided by using AFS cells in the modeling of human genetic diseases.

Use of Contemporary Genetics in Cardiovascular Diagnosis

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George, Alfred L.

2015-01-01

An explosion of knowledge regarding the genetic and genomic basis for rare and common diseases has provided a framework for revolutionizing the practice of medicine. Achieving the reality of a genomic medicine era requires that basic discoveries are effectively translated into clinical practice through implementation of genetic and genomic testing. Clinical genetic tests have become routine for many inherited disorders and can be regarded as the standard-of-care in many circumstances including disorders affecting the cardiovascular system. New, high-throughput methods for determining the DNA sequence of all coding exons or complete genomes are being adopted for clinical use to expand the speed and breadth of genetic testing. Along with these extraordinary advances have emerged new challenges to practicing physicians for understanding when and how to use genetic testing along with how to appropriately interpret test results. This review will acquaint readers with general principles of genetic testing including newer technologies, test interpretation and pitfalls. The focus will be on testing genes responsible for monogenic disorders and on other emerging applications such as pharmacogenomic profiling. The discussion will be extended to the new paradigm of direct-to-consumer genetic testing and the value of assessing genomic risk for common diseases. PMID:25421045

Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease

OpenAIRE

Gan-Or, Ziv; Dion, Patrick A; Rouleau, Guy A

2015-01-01

Parkinson disease (PD), once considered as a prototype of a sporadic disease, is now known to be considerably affected by various genetic factors, which interact with environmental factors and the normal process of aging, leading to PD. Large studies determined that the hereditary component of PD is at least 27%, and in some populations, single genetic factors are responsible for more than 33% of PD patients. Interestingly, many of these genetic factors, such as LRRK2, GBA, SMPD1, SNCA, PARK2...

Analysis of the genetic basis of disease in the context of worldwide human relationships and migration.

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Erik Corona

2013-05-01

Full Text Available Genetic diversity across different human populations can enhance understanding of the genetic basis of disease. We calculated the genetic risk of 102 diseases in 1,043 unrelated individuals across 51 populations of the Human Genome Diversity Panel. We found that genetic risk for type 2 diabetes and pancreatic cancer decreased as humans migrated toward East Asia. In addition, biliary liver cirrhosis, alopecia areata, bladder cancer, inflammatory bowel disease, membranous nephropathy, systemic lupus erythematosus, systemic sclerosis, ulcerative colitis, and vitiligo have undergone genetic risk differentiation. This analysis represents a large-scale attempt to characterize genetic risk differentiation in the context of migration. We anticipate that our findings will enable detailed analysis pertaining to the driving forces behind genetic risk differentiation.

The expanding universe of inflammatory bowel disease genetics.

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Achkar, Jean-Paul; Duerr, Richard

2008-07-01

Genetic factors play an important role in the pathogenesis of inflammatory bowel disease. In this review, we will provide an update on the rapid advances in the discovery of inflammatory bowel disease, primarily Crohn's disease, associated genes. Seven recently published Crohn's disease genome-wide association studies have confirmed prior findings related to the nucleotide-binding oligomerization domain 2 (NOD2) gene and the IBD5 locus. In addition, 10 novel loci have been identified and well replicated. Several promising associations between Crohn's disease and gene variants have been identified and replicated, the two most widely replicated being variants in the IL23R and ATG16L1 genes. These findings highlight and further support the importance of the immune system and its interactions with the intestinal microflora in the pathogenesis of inflammatory bowel disease.

Genetic Variation and Adaptation in Africa: Implications for Human Evolution and Disease

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Gomez, Felicia; Hirbo, Jibril; Tishkoff, Sarah A.

2014-01-01

Because modern humans originated in Africa and have adapted to diverse environments, African populations have high levels of genetic and phenotypic diversity. Thus, genomic studies of diverse African ethnic groups are essential for understanding human evolutionary history and how this leads to differential disease risk in all humans. Comparative studies of genetic diversity within and between African ethnic groups creates an opportunity to reconstruct some of the earliest events in human population history and are useful for identifying patterns of genetic variation that have been influenced by recent natural selection. Here we describe what is currently known about genetic variation and evolutionary history of diverse African ethnic groups. We also describe examples of recent natural selection in African genomes and how these data are informative for understanding the frequency of many genetic traits, including those that cause disease susceptibility in African populations and populations of recent African descent. PMID:24984772

Molecular and Chemical Genetic Approaches to Developmental Origins of Aging and Disease in Zebrafish

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Sasaki, Tomoyuki; Kishi, Shuji

2013-01-01

The incidence of diseases increases rapidly with age, accompanied by progressive deteriorations of physiological functions in organisms. Aging-associated diseases are sporadic but mostly inevitable complications arising from senescence. Senescence is often considered the antithesis of early development, but yet there may be factors and mechanisms in common between these two phenomena over the dynamic process of aging. The association between early development and late-onset disease with advancing age is thought to come from a consequence of developmental plasticity, the phenomenon by which one genotype can give rise to a range of physiologically and/or morphologically adaptive states in response to different environmental or genetic perturbations. On the one hand, we hypothesized that the future aging process can be predictive based on adaptivity during the early developmental period. Modulating the thresholds of adaptive plasticity by chemical genetic approaches, we have been investigating whether any relationship exists between the regulatory mechanisms that function in early development and in senescence using the zebrafish (Danio rerio), a small freshwater fish and a useful model animal for genetic studies. We have successfully conducted experiments to isolate zebrafish mutants expressing apparently altered senescence phenotypes during embryogenesis (“embryonic senescence”), subsequently showing shortened lifespan in adulthoods. We anticipate that previously uncharacterized developmental genes may mediate the aging process and play a pivotal role in senescence. On the other hand, unexpected senescence-related genes might also be involved in the early developmental process and regulation. The ease of manipulation using the zebrafish system allows us to conduct an exhaustive exploration of novel genes and small molecular compounds that can be linked to the senescence phenotype, and thereby facilitates searching for the evolutionary and developmental origins

Inclusion and exclusion in the globalisation of genomics; the case of rare genetic disease in Brazil.

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Gibbon, Sahra; Aureliano, Waleska

2018-04-01

Within the context of a globalising agenda for genetic research where 'global health' is increasingly seen as necessarily informed by and having to account for genomics, the focus on rare genetic diseases is becoming prominent. Drawing from ethnographic research carried out separately by both authors in Brazil, this paper examines how an emerging focus on two different arenas of rare genetic disease, cancer genetics and a class of degenerative neurological diseases known as Ataxias, is subject to and a product of the dynamics of inclusion and exclusion as this concerns participation in research and access to health care. It examines how in these different cases 'rarenesss' has been diversely situated and differently politicised and how clinicians, patients and their families grapple with the slippery boundaries between research, rights to health and the limits of care, therapy or prevention. It illustrates how attention to rare genetic disease in Brazil emerges at the intersection of a particular history of genetic research and public health infrastructure, densely complicated feedback loops between clinical care and research, patient mobilisation around the 'judicialisation' of health and recent state legislation regarding rare disease in Brazil. It highlights the relevance of local configurations in the way rare genetic disease is being made relevant for and by different communities.

Coronary artery disease-associated genetic variants and biomarkers of inflammation

DEFF Research Database (Denmark)

Christiansen, Morten Krogh; Larsen, Sanne Bøjet; Nyegaard, Mette

2017-01-01

score was calculated to assess the combined risk associated with all the genetic variants. A multiple linear regression model was used to assess associations between the genetic risk score, single SNPs, and the five inflammatory biomarkers. RESULTS:The minor allele (G) (CAD risk allele) of rs2075650......INTRODUCTION:Genetic constitution and inflammation both contribute to development of coronary artery disease (CAD). Several CAD-associated single-nucleotide polymorphisms (SNPs) have recently been identified, but their functions are largely unknown. We investigated the associations between CAD...

Infectious diseases: Surveillance, genetic modification and simulation

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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.

Periodontal disease associated to systemic genetic disorders.

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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.

Journal of Genetics | Indian Academy of Sciences

Indian Academy of Sciences (India)

Home; Journals; Journal of Genetics. Veena S. Rao. Articles written in Journal of Genetics. Volume 88 Issue 1 April 2009 pp 113-118 Research Note. A common variant in chromosome 9p21 associated with coronary artery disease in Asian Indians · Arindam Maitra Debabrata Dash Shibu John Prathima R. Sannappa ...

Peroxisome Proliferator-Activated Receptor Genetic Polymorphisms and Nonalcoholic Fatty Liver Disease: Any Role in Disease Susceptibility?

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Paola Dongiovanni

2013-01-01

Full Text Available Nonalcoholic fatty liver disease (NAFLD defines a wide spectrum of liver diseases that extend from simple steatosis, that is, increased hepatic lipid content, to nonalcoholic steatohepatitis (NASH, a condition that may progress to cirrhosis with its associated complications. Nuclear hormone receptors act as intracellular lipid sensors that coordinate genetic networks regulating lipid metabolism and energy utilization. This family of transcription factors, in particular peroxisome proliferator-activated receptors (PPARs, represents attractive drug targets for the management of NAFLD and NASH, as well as related conditions such as type 2 diabetes and the metabolic syndrome. The impact on the regulation of lipid metabolism observed for PPARs has led to the hypothesis that genetic variants within the human PPARs genes may be associated with human disease such as NAFLD, the metabolic syndrome, and/or coronary heart disease. Here we review the available evidence on the association between PPARs genetic polymorphism and the susceptibility to NAFLD and NASH, and we provide a meta-analysis of the available evidence. The impact of PPAR variants on the susceptibility to NASH in specific subgroup of patients, and in particular on the response to therapies, especially those targeting PPARs, represents promising new areas of investigation.

[Neurosis and genetic theory of etiology and pathogenesis of ulcer disease].