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Missing heritability

Andrew D Skol, Mark M Sasaki, Kenan Onel
More than 12 % of women will be diagnosed with breast cancer in their lifetime. Although there have been tremendous advances in elucidating genetic risk factors underlying both familial and sporadic breast cancer, much of the genetic contribution to breast cancer etiology remains unknown. The discovery of BRCA1 and BRCA2 over 20 years ago remains the seminal event in the field and has paved the way for the discovery of other high-penetrance susceptibility genes by linkage analysis. The advent of genome-wide association studies made possible the next wave of discoveries, in which over 80 low-penetrance and moderate-penetrance variants were identified...
October 3, 2016: Breast Cancer Research: BCR
Victoria Goeckmann, Sophie Rothammer, Ivica Medugorac
Bovine spastic paresis (BSP) is a sporadic, progressive neuromuscular disease that is thought to affect all breeds of cattle. The disease manifests as a unilateral or bilateral hyperextension of the hind limb due to increased muscle tone or permanent spasm of mainly the gastrocnemius and/or the quadriceps muscle. Clinical signs only appear in rising, standing and moving animals, which is an important diagnostic feature. Although several medical treatments have been described, surgical procedures such as neurectomy or tenectomy are generally indicated...
October 2016: Veterinary Journal
Olivia Corradin, Andrea J Cohen, Jennifer M Luppino, Ian M Bayles, Fredrick R Schumacher, Peter C Scacheri
SNPs associated with disease susceptibility often reside in enhancer clusters, or super-enhancers. Constituents of these enhancer clusters cooperate to regulate target genes and often extend beyond the linkage disequilibrium (LD) blocks containing risk SNPs identified in genome-wide association studies (GWAS). We identified 'outside variants', defined as SNPs in weak LD with GWAS risk SNPs that physically interact with risk SNPs as part of a target gene's regulatory circuitry. These outside variants further explain variation in target gene expression beyond that explained by GWAS-associated SNPs...
September 19, 2016: Nature Genetics
Stephen Harrap, Katrina Scurrah, Angela Lamantia, Justine Ellis
OBJECTIVE: Genes encoding key elements of the renin-angiotensin-aldosterone system (RAAS) cascade have been previously but inconsistently associated with blood pressure. Sex-dependency might be important here and functional genetic polymorphisms might exhibit epistatic effects. DESIGN AND METHOD: We assessed variation in the genes encoding renin (REN), angiotensinogen (AGT), angiotensin converting enzyme (ACE), angiotensin II type 1 receptor (AGTR1) and aldosterone synthase (CYP11B2)...
September 2016: Journal of Hypertension
Peter Nilsson
A number of chronic disease conditions tend to cluster in families with an increased risk in first-degree relatives, but also an increased risk in second-degree relatives. This fact is most often referred to as the heritability (heredity) of these diseases and explained by the influence of genetic factors, or shared environment, even if the more specific details or mechanism leading to disease are not known. New methods have to be explored in screening studies and register linkage studies to define and measure consequences of a positive family history of disease...
September 2016: Journal of Hypertension
Chuncheng Lu, Yang Wen, Weiyue Hu, Feng Lu, Yufeng Qin, Ying Wang, Shilin Li, Shuping Yang, Yuan Lin, Cheng Wang, Li Jin, Hongbing Shen, Jiahao Sha, Xinru Wang, Zhibin Hu, Yankai Xia
The Y chromosome has high genetic variability with low rates of parallel and back mutations, which make up the most informative haplotyping system. To examine whether Y chromosome haplogroups (Y-hgs) could modify the effects of autosomal variants on non-obstructive azoospermia (NOA), based on our previous genome-wide association study (GWAS), we conducted a genetic interaction analysis in GWAS subjects. Logistic regression analysis demonstrated a protective effect of Y-hg O3e(*) on NOA. Then, we explored the potential interaction between Y-hg O3e(*) and autosomal variants...
2016: Scientific Reports
Shefali Setia Verma, Jessica N Cooke Bailey, Anastasia Lucas, Yuki Bradford, James G Linneman, Michael A Hauser, Louis R Pasquale, Peggy L Peissig, Murray H Brilliant, Catherine A McCarty, Jonathan L Haines, Janey L Wiggs, Tamara R Vrabec, Gerard Tromp, Marylyn D Ritchie
Primary open angle glaucoma (POAG) is a complex disease and is one of the major leading causes of blindness worldwide. Genome-wide association studies have successfully identified several common variants associated with glaucoma; however, most of these variants only explain a small proportion of the genetic risk. Apart from the standard approach to identify main effects of variants across the genome, it is believed that gene-gene interactions can help elucidate part of the missing heritability by allowing for the test of interactions between genetic variants to mimic the complex nature of biology...
September 2016: PLoS Genetics
Wenbao Yu, Seungyeoun Lee, Taesung Park
MOTIVATION: Gene-gene interaction (GGI) is one of the most popular approaches for finding and explaining the missing heritability of common complex traits in genome-wide association studies. The multifactor dimensionality reduction (MDR) method has been widely studied for detecting GGI effects. However, there are several disadvantages of the existing MDR-based approaches, such as the lack of an efficient way of evaluating the significance of multi-locus models and the high computational burden due to intensive permutation...
September 1, 2016: Bioinformatics
Sungyoung Lee, Sungkyoung Choi, Young Jin Kim, Bong-Jo Kim, Heungsun Hwang, Taesung Park
MOTIVATION: To address 'missing heritability' issue, many statistical methods for pathway-based analyses using rare variants have been proposed to analyze pathways individually. However, neglecting correlations between multiple pathways can result in misleading solutions, and pathway-based analyses of large-scale genetic datasets require massive computational burden. We propose a Pathway-based approach using HierArchical components of collapsed RAre variants Of High-throughput sequencing data (PHARAOH) for the analysis of rare variants by constructing a single hierarchical model that consists of collapsed gene-level summaries and pathways and analyzes entire pathways simultaneously by imposing ridge-type penalties on both gene and pathway coefficient estimates; hence our method considers the correlation of pathways without constraint by a multiple testing problem...
September 1, 2016: Bioinformatics
Silvia Sookoian, Diego Flichman, Romina Scian, Cristian Rohr, Hernán Dopazo, Tomas Fernández Gianotti, Julio San Martino, Gustavo O Castaño, Carlos J Pirola
Non-alcoholic fatty liver disease (NAFLD) is associated with mitochondrial dysfunction, a decreased liver mitochondrial DNA (mtDNA) content, and impaired energy metabolism. To understand the clinical implications of mtDNA diversity in the biology of NAFLD, we applied deep-coverage whole sequencing of the liver mitochondrial genomes. We used a multistage study design, including a discovery phase, a phenotype-oriented study to assess the mutational burden in patients with steatohepatitis at different stages of liver fibrosis, and a replication study to validate findings in loci of interest...
August 31, 2016: Journal of Pathology
Peter Kühnen, Daniela Handke, Robert A Waterland, Branwen J Hennig, Matt Silver, Anthony J Fulford, Paula Dominguez-Salas, Sophie E Moore, Andrew M Prentice, Joachim Spranger, Anke Hinney, Johannes Hebebrand, Frank L Heppner, Lena Walzer, Carsten Grötzinger, Jörg Gromoll, Susanna Wiegand, Annette Grüters, Heiko Krude
The estimated heritability of human BMI is close to 75%, but identified genetic variants explain only a small fraction of interindividual body-weight variation. Inherited epigenetic variants identified in mouse models named "metastable epialleles" could in principle explain this "missing heritability." We provide evidence that methylation in a variably methylated region (VMR) in the pro-opiomelanocortin gene (POMC), particularly in postmortem human laser-microdissected melanocyte-stimulating hormone (MSH)-positive neurons, is strongly associated with individual BMI...
September 13, 2016: Cell Metabolism
Qian-Jie Tang, Hao-Ming Lin, Guo-Dong He, Ju-E Liu, Hong Wu, Xin-Xin Li, Wan-Ping Zhong, Lan Tang, Jin-Xiu Meng, Meng-Zhen Zhang, Han-Ping Li, Ji-Yan Chen, Shi-Long Zhong, Lai-You Wang
AIM: To investigate whether plasma miRNAs targeting CYP3A4/5 have an impact on the variance of pharmacokinetics of clopidogrel. MATERIALS & METHODS: The contribution of 13 miRNAs to the CYP3A4/5 gene expression and activity was investigated in 55 liver tissues. The association between plasma miRNAs targeting CYP3A4/5 mRNA and clopidogrel pharmacokinetics was analyzed in 31 patients with coronary heart disease who received 300 mg loading dose of clopidogrel. RESULTS: Among 13 miRNAs, miR-142 was accounting for 12...
September 2016: Pharmacogenomics
Kwangsik Nho, Emrin Horgusluoglu, Sungeun Kim, Shannon L Risacher, Dokyoon Kim, Tatiana Foroud, Paul S Aisen, Ronald C Petersen, Clifford R Jack, Leslie M Shaw, John Q Trojanowski, Michael W Weiner, Robert C Green, Arthur W Toga, Andrew J Saykin
BACKGROUND: Pathogenic mutations in PSEN1 are known to cause familial early-onset Alzheimer's disease (EOAD) but common variants in PSEN1 have not been found to strongly influence late-onset AD (LOAD). The association of rare variants in PSEN1 with LOAD-related endophenotypes has received little attention. In this study, we performed a rare variant association analysis of PSEN1 with quantitative biomarkers of LOAD using whole genome sequencing (WGS) by integrating bioinformatics and imaging informatics...
2016: BMC Medical Genomics
Yulun Liu, Yong Chen, Paul Scheet
With varying, but substantial, proportions of heritability remaining unexplained by summaries of single-SNP genetic variation, there is a demand for methods that extract maximal information from genetic association studies. One source of variation that is difficult to assess is genetic interactions. A major challenge for naive detection methods is the large number of possible combinations, with a requisite need to correct for multiple testing. Assumptions of large marginal effects, to reduce the search space, may be restrictive and miss higher order interactions with modest marginal effects...
November 2016: Genetic Epidemiology
Nick Shrine, Martin D Tobin, Claudia Schurmann, María Soler Artigas, Jennie Hui, Terho Lehtimäki, Olli T Raitakari, Craig E Pennell, Qi Wei Ang, David P Strachan, Georg Homuth, Sven Gläser, Stephan B Felix, David M Evans, John Henderson, Raquel Granell, Lyle J Palmer, Jennifer Huffman, Caroline Hayward, Generation Scotland, Anders Malarstig, Bill Musk, Alan L James, Louise V Wain
BACKGROUND: Genome-wide association studies of Single Nucleotide Polymorphisms (SNPs) have identified 55 SNPs associated with lung function. However, little is known about the effect of copy number variants (CNVs) on lung function, although CNVs represent a significant proportion of human genetic polymorphism. To assess the effect of CNVs on lung function quantitative traits, we measured copy number at 2788 previously characterised, common copy number variable regions in 6 independent cohorts (n = 24,237) using intensity data from SNP genotyping experiments...
2016: BMC Genetics
Patrícia Abrantes, Alexandra Rosa, Vânia Francisco, Inês Sousa, Joana M Xavier, Sofia A Oliveira
BACKGROUND AND AIMS: Peripheral arterial disease (PAD) and venous thromboembolism (VTE) are vascular traits sharing common modifiable and non-modifiable risk factors. These vascular pathologies have known nuclear-encoded genetic risk factors and the mitochondrial DNA may account for part of the missing heritability. To determine if PAD and VTE have a dual genetic control (mitochondrial and nuclear), we hereby investigated the association of mitochondrial DNA polymorphisms and haplogroups with these vascular traits...
September 2016: Atherosclerosis
Chaowen Jiang, Shilong Yu, Pin Qian, Ruiling Guo, Ruijie Zhang, Zhi Ao, Qi Li, Guoming Wu, Yan Chen, Jin Li, Changzheng Wang, Wei Yao, Jiancheng Xu, Guisheng Qian, Fuyun Ji
It has been well established that besides environmental factors, genetic factors are also associated with lung cancer risk. However, to date, the prior identified genetic variants and loci only explain a small fraction of the familial risk of lung cancer. Hence it is vital to investigate the remaining missing heritability to understand the development and process of lung cancer. In the study, to test our hypothesis that the previously identified breast cancer risk-associated genetic polymorphisms at the TOX3/LOC643714 locus might contribute to lung cancer risk, 16 SNPs at the TOX3/LOC643714 locus were evaluated in a Han Chinese population based on a case-control study...
July 28, 2016: Oncotarget
Stavroula Kanoni, Nicholas Gd Masca, Kathleen E Stirrups, Tibor V Varga, Helen R Warren, Robert A Scott, Lorraine Southam, Weihua Zhang, Hanieh Yaghootkar, Martina Müller-Nurasyid, Alexessander Couto Alves, Rona J Strawbridge, Lazaros Lataniotis, Nikman An Hashim, Céline Besse, Anne Boland, Peter S Braund, John M Connell, Anna Dominiczak, Aliki-Eleni Farmaki, Stephen Franks, Harald Grallert, Jan-Håkan Jansson, Maria Karaleftheri, Sirkka Keinänen-Kiukaanniemi, Angela Matchan, Dorota Pasko, Annette Peters, Neil Poulter, Nigel W Rayner, Frida Renström, Olov Rolandsson, Maria Sabater-Lleal, Bengt Sennblad, Peter Sever, Denis Shields, Angela Silveira, Alice V Stanton, Konstantin Strauch, Maciej Tomaszewski, Emmanouil Tsafantakis, Melanie Waldenberger, Alexandra If Blakemore, George Dedoussis, Stefan A Escher, Jaspal S Kooner, Mark I McCarthy, Colin N A Palmer, Anders Hamsten, Mark J Caulfield, Timothy M Frayling, Martin D Tobin, Marjo-Riitta Jarvelin, Eleftheria Zeggini, Christian Gieger, John C Chambers, Nick J Wareham, Patricia B Munroe, Paul W Franks, Nilesh J Samani, Panos Deloukas
It has been hypothesised that low frequency (1-5% MAF) and rare (<1% MAF) variants with large effect sizes may contribute to the missing heritability in complex traits. Here we report an association analysis of lipid traits (total cholesterol, LDL-cholesterol, HDL-cholesterol triglycerides) in up to 27,312 individuals with a comprehensive set of low frequency coding variants (ExomeChip), combined with conditional analysis in the known lipid loci. No new locus reached genome-wide significance. However, we found a new lead variant in 26 known lipid association regions of which 16 were >1000 fold more significant than the previous sentinel variant and not in close LD (6 had MAF < 5%)...
July 27, 2016: Human Molecular Genetics
Thomas E Reed, Phillip Gienapp, Marcel E Visser
Key life history traits such as breeding time and clutch size are frequently both heritable and under directional selection, yet many studies fail to document microevolutionary responses. One general explanation is that selection estimates are biased by the omission of correlated traits that have causal effects on fitness, but few valid tests of this exist. Here, we show, using a quantitative genetic framework and six decades of life-history data on two free-living populations of great tits Parus major, that selection estimates for egg-laying date and clutch size are relatively unbiased...
October 2016: Evolution; International Journal of Organic Evolution
Z Hawi, T D R Cummins, J Tong, M Arcos-Burgos, Q Zhao, N Matthews, D P Newman, B Johnson, A Vance, H S Heussler, F Levy, S Easteal, N R Wray, E Kenny, D Morris, L Kent, M Gill, M A Bellgrove
Attention-deficit hyperactivity disorder (ADHD) is a prevalent and highly heritable disorder of childhood with negative lifetime outcomes. Although candidate gene and genome-wide association studies have identified promising common variant signals, these explain only a fraction of the heritability of ADHD. The observation that rare structural variants confer substantial risk to psychiatric disorders suggests that rare variants might explain a portion of the missing heritability for ADHD. Here we believe we performed the first large-scale next-generation targeted sequencing study of ADHD in 152 child and adolescent cases and 188 controls across an a priori set of 117 genes...
July 26, 2016: Molecular Psychiatry
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