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Missing heritability

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https://www.readbyqxmd.com/read/29322552/gene-gene-and-gene-environment-interactions-in-complex-traits-in-yeast
#1
Anupama Yadav, Himanshu Sinha
One of the fundamental question in biology is how the genotype regulates the phenotype. An increasing number of studies indicate that in most cases, the effect of a genetic locus on the phenotype is context-dependent, i.e. it is influenced by the genetic background and the environment in which the phenotype is measured. Still, the majority of the studies, in both model organisms and humans, that map the genetic regulation of phenotypic variation in complex traits primarily identify additive loci with independent effects...
January 10, 2018: Yeast
https://www.readbyqxmd.com/read/29300920/simultaneous-inference-of-phenotype-associated-genes-and-relevant-tissues-from-gwas-data-via-bayesian-integration-of-multiple-tissue-specific-gene-networks
#2
Mengmeng Wu, Zhixiang Lin, Shining Ma, Ting Chen, Rui Jiang, Wing Hung Wong
Although genome-wide association studies (GWAS) have successfully identified thousands of genomic loci associated with hundreds of complex traits in the past decade, the debate about such problems as missing heritability and weak interpretability has been appealing for effective computational methods to facilitate the advanced analysis of the vast volume of existing and anticipated genetic data. Towards this goal, gene-level integrative GWAS analysis with the assumption that genes associated with a phenotype tend to be enriched in biological gene sets or gene networks has recently attracted much attention, due to such advantages as straightforward interpretation, less multiple testing burdens, and robustness across studies...
December 29, 2017: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/29289333/understanding-neurodevelopmental-disorders-the-promise-of-regulatory-variation-in-the-3-utrome
#3
REVIEW
Kai A Wanke, Paolo Devanna, Sonja C Vernes
Neurodevelopmental disorders have a strong genetic component, but despite widespread efforts, the specific genetic factors underlying these disorders remain undefined for a large proportion of affected individuals. Given the accessibility of exome sequencing, this problem has thus far been addressed from a protein-centric standpoint; however, protein-coding regions only make up ∼1% to 2% of the human genome. With the advent of whole genome sequencing we are in the midst of a paradigm shift as it is now possible to interrogate the entire sequence of the human genome (coding and noncoding) to fill in the missing heritability of complex disorders...
November 14, 2017: Biological Psychiatry
https://www.readbyqxmd.com/read/29276006/wnt-signaling-perturbations-underlie-the-genetic-heterogeneity-of-robinow-syndrome
#4
Janson J White, Juliana F Mazzeu, Zeynep Coban-Akdemir, Yavuz Bayram, Vahid Bahrambeigi, Alexander Hoischen, Bregje W M van Bon, Alper Gezdirici, Elif Yilmaz Gulec, Francis Ramond, Renaud Touraine, Julien Thevenon, Marwan Shinawi, Erin Beaver, Jennifer Heeley, Julie Hoover-Fong, Ceren D Durmaz, Halil Gurhan Karabulut, Ebru Marzioglu-Ozdemir, Atilla Cayir, Mehmet B Duz, Mehmet Seven, Susan Price, Barbara Merfort Ferreira, Angela M Vianna-Morgante, Sian Ellard, Andrew Parrish, Karen Stals, Josue Flores-Daboub, Shalini N Jhangiani, Richard A Gibbs, Han G Brunner, V Reid Sutton, James R Lupski, Claudia M B Carvalho
Locus heterogeneity characterizes a variety of skeletal dysplasias often due to interacting or overlapping signaling pathways. Robinow syndrome is a skeletal disorder historically refractory to molecular diagnosis, potentially stemming from substantial genetic heterogeneity. All current known pathogenic variants reside in genes within the noncanonical Wnt signaling pathway including ROR2, WNT5A, and more recently, DVL1 and DVL3. However, ∼70% of autosomal-dominant Robinow syndrome cases remain molecularly unsolved...
December 16, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29228715/bayesian-and-frequentist-analysis-of-an-austrian-genome-wide-association-study-of-colorectal-cancer-and-advanced-adenomas
#5
Philipp Hofer, Michael Hagmann, Stefanie Brezina, Erich Dolejsi, Karl Mach, Gernot Leeb, Andreas Baierl, Stephan Buch, Hedwig Sutterlüty-Fall, Judith Karner-Hanusch, Michael M Bergmann, Thomas Bachleitner-Hofmann, Anton Stift, Armin Gerger, Katharina Rötzer, Josef Karner, Stefan Stättner, Melanie Waldenberger, Thomas Meitinger, Konstantin Strauch, Jakob Linseisen, Christian Gieger, Florian Frommlet, Andrea Gsur
Most genome-wide association studies (GWAS) were analyzed using single marker tests in combination with stringent correction procedures for multiple testing. Thus, a substantial proportion of associated single nucleotide polymorphisms (SNPs) remained undetected and may account for missing heritability in complex traits. Model selection procedures present a powerful alternative to identify associated SNPs in high-dimensional settings. In this GWAS including 1060 colorectal cancer cases, 689 cases of advanced colorectal adenomas and 4367 controls we pursued a dual approach to investigate genome-wide associations with disease risk applying both, single marker analysis and model selection based on the modified Bayesian information criterion, mBIC2, implemented in the software package MOSGWA...
November 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29198723/dna-methylation-analysis-identifies-loci-for-blood-pressure-regulation
#6
Melissa A Richard, Tianxiao Huan, Symen Ligthart, Rahul Gondalia, Min A Jhun, Jennifer A Brody, Marguerite R Irvin, Riccardo Marioni, Jincheng Shen, Pei-Chien Tsai, May E Montasser, Yucheng Jia, Catriona Syme, Elias L Salfati, Eric Boerwinkle, Weihua Guan, Thomas H Mosley, Jan Bressler, Alanna C Morrison, Chunyu Liu, Michael M Mendelson, André G Uitterlinden, Joyce B van Meurs, Oscar H Franco, Guosheng Zhang, Yun Li, James D Stewart, Joshua C Bis, Bruce M Psaty, Yii-Der Ida Chen, Sharon L R Kardia, Wei Zhao, Stephen T Turner, Devin Absher, Stella Aslibekyan, John M Starr, Allan F McRae, Lifang Hou, Allan C Just, Joel D Schwartz, Pantel S Vokonas, Cristina Menni, Tim D Spector, Alan Shuldiner, Coleen M Damcott, Jerome I Rotter, Walter Palmas, Yongmei Liu, Tomáš Paus, Steve Horvath, Jeffrey R O'Connell, Xiuqing Guo, Zdenka Pausova, Themistocles L Assimes, Nona Sotoodehnia, Jennifer A Smith, Donna K Arnett, Ian J Deary, Andrea A Baccarelli, Jordana T Bell, Eric Whitsel, Abbas Dehghan, Daniel Levy, Myriam Fornage
Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry...
November 30, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29168291/the-col5a3-and-mmp9-genes-interact-in-eczema-susceptibility
#7
Patricia Margaritte-Jeannin, Marie-Claude Babron, Catherine Laprise, Nolwenn Lavielle, Chloé Sarnowski, Myriam Brossard, Miriam Moffatt, Valérie Gagné-Ouellet, Adrien Etcheto, Mark Lathrop, Jocelyne Just, William O Cookson, Emmanuelle Bouzigon, Florence Demenais, Marie-Hélène Dizier
BACKGROUND: Genetic studies of eczema have identified many genes, which explain only 14% of the heritability. Missing heritability may be partly due to ignored Gene-Gene (G-G) interactions. OBJECTIVE: Our aim was to detect new interacting genes involved in eczema. METHODS: The search for G-G interaction in eczema was conducted using a two-step approach, which included as a first step, a biological selection of genes, which are involved either in the skin or epidermis development or in the collagen metabolism, and as a second-step, an interaction analysis of the selected genes...
November 23, 2017: Clinical and Experimental Allergy: Journal of the British Society for Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/29143599/epistasis-physical-capacity-related-genes-and-exceptional-longevity-fndc5-gene-interactions-with-candidate-genes-foxoa3-and-apoe
#8
Noriyuki Fuku, Roberto Díaz-Peña, Yasumichi Arai, Yukiko Abe, Hirofumi Zempo, Hisashi Naito, Haruka Murakami, Motohiko Miyachi, Carlos Spuch, José A Serra-Rexach, Enzo Emanuele, Nobuyoshi Hirose, Alejandro Lucia
BACKGROUND: Forkhead box O3A (FOXOA3) and apolipoprotein E (APOE) are arguably the strongest gene candidates to influence human exceptional longevity (EL, i.e., being a centenarian), but inconsistency exists among cohorts. Epistasis, defined as the effect of one locus being dependent on the presence of 'modifier genes', may contribute to explain the missing heritability of complex phenotypes such as EL. We assessed the potential association of epistasis among candidate polymorphisms related to physical capacity, as well as antioxidant defense and cardiometabolic traits, and EL in the Japanese population...
November 14, 2017: BMC Genomics
https://www.readbyqxmd.com/read/29110756/apol1-nephropathy-a-population-genetics-and-evolutionary-medicine-detective-story
#9
REVIEW
Etty Kruzel-Davila, Walter G Wasser, Karl Skorecki
Common DNA sequence variants rarely have a high-risk association with a common disease. When such associations do occur, evolutionary forces must be sought, such as in the association of apolipoprotein L1 (APOL1) gene risk variants with nondiabetic kidney diseases in populations of African ancestry. The variants originated in West Africa and provided pathogenic resistance in the heterozygous state that led to high allele frequencies owing to an adaptive evolutionary selective sweep. However, the homozygous state is disadvantageous and is associated with a markedly increased risk of a spectrum of kidney diseases encompassing hypertension-attributed kidney disease, focal segmental glomerulosclerosis, human immunodeficiency virus nephropathy, sickle cell nephropathy, and progressive lupus nephritis...
November 2017: Seminars in Nephrology
https://www.readbyqxmd.com/read/29110346/on-meta-and-mega-analyses-for-gene-environment-interactions
#10
Jing Huang, Yulun Liu, Steve Vitale, Trevor M Penning, Alexander S Whitehead, Ian A Blair, Anil Vachani, Margie L Clapper, Joshua E Muscat, Philip Lazarus, Paul Scheet, Jason H Moore, Yong Chen
Gene-by-environment (G × E) interactions are important in explaining the missing heritability and understanding the causation of complex diseases, but a single, moderately sized study often has limited statistical power to detect such interactions. With the increasing need for integrating data and reporting results from multiple collaborative studies or sites, debate over choice between mega- versus meta-analysis continues. In principle, data from different sites can be integrated at the individual level into a "mega" data set, which can be fit by a joint "mega-analysis...
November 7, 2017: Genetic Epidemiology
https://www.readbyqxmd.com/read/29108034/genetic-evaluation-for-birth-and-conformation-traits-in-dual-purpose-belgian-blue-cattle-using-a-mixed-inheritance-model
#11
R R Mota, P Mayeres, C Bastin, G Glorieux, C Bertozzi, S Vanderick, H Hammami, F G Colinet, N Gengler
The segregation of the causal mutation () in the muscular hypertrophy gene in dual-purpose Belgian Blue (dpBB) cattle is considered to result in greater calving difficulty (dystocia). Establishing adapted genetic evaluations might overcome this situation through efficient selection. However, the heterogeneity of dpBB populations at the locus implies separating the major gene and other polygenic effects in complex modeling. The use of mixed inheritance models may be an interesting option because they simultaneously assume both influences...
October 2017: Journal of Animal Science
https://www.readbyqxmd.com/read/29099282/dna-methylation-and-obesity-traits-an-epigenome-wide-association-study-the-regicor-study
#12
Sergi Sayols-Baixeras, Isaac Subirana, Alba Fernández-Sanlés, Mariano Sentí, Carla Lluís-Ganella, Jaume Marrugat, Roberto Elosua
Obesity is associated with increased risk of several diseases and has become epidemic. Obesity is highly heritable but the genetic variants identified by genome-wide association studies explain only limited variability. Epigenetics could contribute to explain the missing variability. The study aim was to discover differential methylation patterns related to obesity. We designed an epigenome-wide association study with a discovery phase in a subsample of 641 REGICOR study participants, validated by analysis of 2,515 participants in the Framingham Offspring Study...
November 3, 2017: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/29091582/multivariate-association-between-single-nucleotide-polymorphisms-in-alzgene-linkage-regions-and-structural-changes-in-the-brain-discovery-refinement-and-validation
#13
Elena Szefer, Donghuan Lu, Farouk Nathoo, Mirza Faisal Beg, Jinko Graham
Using publicly-available data from the Alzheimer's Disease Neuroimaging Initiative, we investigate the joint association between single-nucleotide polymorphisms (SNPs) in previously established linkage regions for Alzheimer's disease (AD) and rates of decline in brain structure. In an initial, discovery stage of analysis, we applied a weighted RV test to assess the association between 75,845 SNPs in the Alzgene linkage regions and rates of change in structural MRI measurements for 56 brain regions affected by AD, in 632 subjects...
November 1, 2017: Statistical Applications in Genetics and Molecular Biology
https://www.readbyqxmd.com/read/29083200/the-paradox-of-intelligence-heritability-and-malleability-coexist-in-hidden-gene-environment-interplay
#14
Bruno Sauce, Louis D Matzel
Intelligence can have an extremely high heritability, but also be malleable; a paradox that has been the source of continuous controversy. Here we attempt to clarify the issue, and advance a frequently overlooked solution to the paradox: Intelligence is a trait with unusual properties that create a large reservoir of hidden gene-environment (GE) networks, allowing for the contribution of high genetic and environmental influences on individual differences in IQ. GE interplay is difficult to specify with current methods, and is underestimated in standard metrics of heritability (thus inflating estimates of "genetic" effects)...
October 30, 2017: Psychological Bulletin
https://www.readbyqxmd.com/read/29081689/assessing-the-heritability-of-complex-traits-in-humans-methodological-challenges-and-opportunities
#15
REVIEW
Alexandra J Mayhew, David Meyre
The goal of this review article is to provide a conceptual based summary of how heritability estimates for complex traits such as obesity are determined and to explore the future directions of research in the heritability field. The target audience are researchers who use heritability data rather than those conducting heritability studies. The article provides an introduction to key concepts critical to understanding heritability studies including: i) definitions of heritability: broad sense versus narrow sense heritability; ii) how data for heritability studies are collected: twin, adoption, family and population-based studies; and iii) analytical techniques: path analysis, structural equations and mixed or regressive models of complex segregation analysis...
August 2017: Current Genomics
https://www.readbyqxmd.com/read/29059373/genome-wide-interaction-study-of-smoking-behavior-and-non-small-cell-lung-cancer-risk-in-caucasian-population
#16
Yafang Li, Xiangjun Xiao, Younghun Han, Olga Gorlova, David Qian, Natasha Leighl, Jakob S Johansen, Matt Barnett, Chu Chen, Gary Goodman, Angela Cox, Fiona Taylor, Penella Woll, H-Erich Wichmann, Judith Manz, Thomas Muley, Angela Risch, Albert Rosenberger, Susanne M Arnold, Eric B Haura, Ciprian Bolca, Ivana Holcatova, Vladimir Janout, Milica Kontic, Jolanta Lissowska, Anush Mukeria, Simona Ognjanovic, Tadeusz M Orlowski, Ghislaine Scelo, Beata Swiatkowska, David Zaridze, Per Bakke, Vidar Skaug, Shanbeh Zienolddiny, Eric J Duell, Lesley M Butler, Richard Houlston, María Soler Artigas, Kjell Grankvist, Mikael Johansson, Frances A Shepherd, Michael W Marcus, Hans Brunnström, Jonas Manjer, Olle Melander, David C Muller, Kim Overvad, Antonia Trichopoulou, Rosario Tumino, Geoffrey Liu, Stig E Bojesen, Xifeng Wu, Loic Le Marchand, Demetrios Albanes, Heike Bickeböller, Melinda C Aldrich, William S Bush, Adonina Tardon, Gad Rennert, M Dawn Teare, John K Field, Lambertus A Kiemeney, Philip Lazarus, Aage Haugen, Stephen Lam, Matthew B Schabath, Angeline S Andrew, Pier Alberto Bertazzi, Angela C Pesatori, David C Christiani, Neil Caporaso, Mattias Johansson, James D McKay, Paul Brennan, Rayjean J Hung, Christopher I Amos
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Both environmental and genetic risk factors contribute to lung carcinogenesis. We conducted a genome-wide interaction analysis between SNPs and smoking status (never vs ever smokers) in a European-descent population. We adopted a two-step analysis strategy in the discovery stage: we first conducted a case-only interaction analysis to assess the relationship between SNPs and smoking behavior using 13,336 NSCLC cases. Candidate SNPs with p-value less than 0...
October 20, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/29058049/bayesian-estimation-and-use-of-high-throughput-remote-sensing-indices-for-quantitative-genetic-analyses-of-leaf-growth
#17
Robert L Baker, Wen Fung Leong, Nan An, Marcus T Brock, Matthew J Rubin, Stephen Welch, Cynthia Weinig
We develop Bayesian function-valued trait models that mathematically isolate genetic mechanisms underlying leaf growth trajectories by factoring out genotype-specific differences in photosynthesis. Remote sensing data can be used instead of leaf-level physiological measurements. Characterizing the genetic basis of traits that vary during ontogeny and affect plant performance is a major goal in evolutionary biology and agronomy. Describing genetic programs that specifically regulate morphological traits can be complicated by genotypic differences in physiological traits...
October 20, 2017: TAG. Theoretical and Applied Genetics. Theoretische und Angewandte Genetik
https://www.readbyqxmd.com/read/29051702/finding-the-sources-of-missing-heritability-within-rare-variants-through-simulation
#18
Baishali Bandyopadhyay, Veda Chanda, Yupeng Wang
Thousands of genome-wide association studies (GWAS) have been conducted to identify the genetic variants associated with complex disorders. However, only a small proportion of phenotypic variances can be explained by the reported variants. Moreover, many GWAS failed to identify genetic variants associated with disorders displaying hereditary features. The "missing heritability" problem can be partly explained by rare variants. We simulated a causality scenario that gestational ages, a quantitative trait that can distinguish preterm (<37 weeks) and term births, were significantly correlated with the rare variant aggregations at 1000 single-nucleotide polymorphism loci...
2017: Bioinformatics and Biology Insights
https://www.readbyqxmd.com/read/29039294/a-comparison-of-heritability-estimates-by-classical-twin-modeling-and-based-on-genome-wide-genetic-relatedness-for-cardiac-conduction-traits
#19
Ilja M Nolte, Joeri A Jansweijer, Hariette Riese, Folkert W Asselbergs, Pim van der Harst, Timothy D Spector, Yigal M Pinto, Harold Snieder, Yalda Jamshidi
Twin studies have found that ~50% of variance in electrocardiogram (ECG) traits can be explained by genetic factors. However, genetic variants identified through genome-wide association studies explain less than 10% of the total trait variability. Some have argued that the equal environment assumption for the classical twin model might be invalid, resulting in inflated narrow-sense heritability (h 2) estimates, thus explaining part of the 'missing h 2'. Genomic relatedness restricted maximum likelihood (GREML) estimation overcomes this issue...
October 17, 2017: Twin Research and Human Genetics: the Official Journal of the International Society for Twin Studies
https://www.readbyqxmd.com/read/29038864/improved-detection-of-genetic-loci-in-estimated-glomerular-filtration-rate-and-type-2-diabetes-using-a-pleiotropic-cfdr-method
#20
Hui-Min Liu, Jing-Yang He, Qiang Zhang, Wan-Qiang Lv, Xin Xia, Chang-Qing Sun, Wei-Dong Zhang, Hong-Wen Deng
Genome-wide association studies (GWAS) have been shown to have the potential of explaining more of the "missing heritability" of complex human phenotypes by improving statistical approaches. Here, we applied a genetic-pleiotropy-informed conditional false discovery rate (cFDR) to capture additional polygenic effects associated with estimated glomerular filtration rate (creatinine) (eGFRcrea) and type 2 diabetes (T2D). The cFDR analysis improves the identification of pleiotropic variants by incorporating potentially shared genetic mechanisms between two related traits...
October 16, 2017: Molecular Genetics and Genomics: MGG
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