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Missing heritability

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https://www.readbyqxmd.com/read/29782925/the-developmental-genetics-of-canalization
#1
REVIEW
Benedikt Hallgrimsson, Rebecca M Green, David Katz, Jennifer L Fish, Francois P J Bernier, Charles C Roseman, Nathan M Young, James M Cheverud, Ralph S Marcucio
Canalization, or robustness to genetic or environmental perturbations, is fundamental to complex organisms. While there is strong evidence for canalization as an evolved property that varies among genotypes, the developmental and genetic mechanisms that produce this phenomenon are very poorly understood. For evolutionary biology, understanding how canalization arises is important because, by modulating the phenotypic variation that arises in response to genetic differences, canalization is a determinant of evolvability...
May 18, 2018: Seminars in Cell & Developmental Biology
https://www.readbyqxmd.com/read/29779058/genetics-of-resistant-hypertension-the-missing-heritability-and-opportunities
#2
REVIEW
Samantha K Teixeira, Alexandre C Pereira, Jose E Krieger
PURPOSE OF THE REVIEW: Blood pressure regulation in humans has long been known to be a genetically determined trait. The identification of causal genetic modulators for this trait has been unfulfilling at the least. Despite the recent advances of genome-wide genetic studies, loci associated with hypertension or blood pressure still explain a very low percentage of the overall variation of blood pressure in the general population. This has precluded the translation of discoveries in the genetics of human hypertension to clinical use...
May 19, 2018: Current Hypertension Reports
https://www.readbyqxmd.com/read/29745849/pathway-based-approach-using-hierarchical-components-of-rare-variants-to-analyze-multiple-phenotypes
#3
Sungyoung Lee, Yongkang Kim, Sungkyoung Choi, Heungsun Hwang, Taesung Park
BACKGROUND: As one possible solution to the "missing heritability" problem, many methods have been proposed that apply pathway-based analyses, using rare variants that are detected by next generation sequencing technology. However, while a number of methods for pathway-based rare-variant analysis of multiple phenotypes have been proposed, no method considers a unified model that incorporate multiple pathways. RESULTS: Simulation studies successfully demonstrated advantages of multivariate analysis, compared to univariate analysis, and comparison studies showed the proposed approach to outperform existing methods...
May 8, 2018: BMC Bioinformatics
https://www.readbyqxmd.com/read/29728367/integration-of-enhancer-promoter-interactions-with-gwas-summary-results-identifies-novel-schizophrenia-associated-genes-and-pathways
#4
Chong Wu, Wei Pan
It remains challenging to boost statistical power of GWAS to identify more risk variants or loci that can account for "missing heritability". Furthermore, since most identified variants are not in gene coding regions, a biological interpretation of their function largely lacks. On the other hand, recent biotechnological advances have made it feasible to experimentally measure the three-dimensional organization of the genome, including enhancer-promoter interactions in high resolutions. Due to the well known critical roles of enhancer-promoter interactions in regulating gene expression programs, such data have been applied to link GWAS risk variants to their putative target genes, gaining insights into underlying biological mechanisms...
May 4, 2018: Genetics
https://www.readbyqxmd.com/read/29727690/a-mixed-effects-model-for-powerful-association-tests-in-integrative-functional-genomics
#5
Yu-Ru Su, Chongzhi Di, Stephanie Bien, Licai Huang, Xinyuan Dong, Goncalo Abecasis, Sonja Berndt, Stephane Bezieau, Hermann Brenner, Bette Caan, Graham Casey, Jenny Chang-Claude, Stephen Chanock, Sai Chen, Charles Connolly, Keith Curtis, Jane Figueiredo, Manish Gala, Steven Gallinger, Tabitha Harrison, Michael Hoffmeister, John Hopper, Jeroen R Huyghe, Mark Jenkins, Amit Joshi, Loic Le Marchand, Polly Newcomb, Deborah Nickerson, John Potter, Robert Schoen, Martha Slattery, Emily White, Brent Zanke, Ulrike Peters, Li Hsu
Genome-wide association studies (GWASs) have successfully identified thousands of genetic variants for many complex diseases; however, these variants explain only a small fraction of the heritability. Recently, genetic association studies that leverage external transcriptome data have received much attention and shown promise for discovering novel variants. One such approach, PrediXcan, is to use predicted gene expression through genetic regulation. However, there are limitations in this approach. The predicted gene expression may be biased, resulting from regularized regression applied to moderately sample-sized reference studies...
May 3, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29717274/detecting-epistasis-within-chromatin-regulatory-circuitry-reveals-cand2-as-a-novel-susceptibility-gene-for-obesity
#6
Shan-Shan Dong, Shi Yao, Yi-Xiao Chen, Yan Guo, Yu-Jie Zhang, Hui-Min Niu, Ruo-Han Hao, Hui Shen, Qing Tian, Hong-Wen Deng, Tie-Lin Yang
BACKGROUND: Genome-wide association studies have identified many susceptibility loci for obesity. However, missing heritability problem is still challenging and ignorance of genetic interactions is believed to be an important cause. Current methods for detecting interactions usually do not consider regulatory elements in non-coding regions. Interaction analyses within chromatin regulatory circuitry may identify new susceptibility loci. METHODS: We developed a pipeline named interaction analyses within chromatin regulatory circuitry (IACRC), to identify genetic interactions impacting body mass index (BMI)...
May 1, 2018: International Journal of Obesity: Journal of the International Association for the Study of Obesity
https://www.readbyqxmd.com/read/29697366/fuzzy-set-based-generalized-multifactor-dimensionality-reduction-analysis-of-gene-gene-interactions
#7
Hye-Young Jung, Sangseob Leem, Taesung Park
BACKGROUND: Gene-gene interactions (GGIs) are a known cause of missing heritability. Multifactor dimensionality reduction (MDR) is one of most commonly used methods for GGI detection. The generalized multifactor dimensionality reduction (GMDR) method is an extension of MDR method that is applicable to various types of traits, and allows covariate adjustments. Our previous Fuzzy MDR (FMDR) is another extension for overcoming simple binary classification. FMDR uses continuous member-ship values instead of binary membership values 0 and 1, improving power for detecting causal SNPs and more intuitive interpretations in real data analysis...
April 20, 2018: BMC Medical Genomics
https://www.readbyqxmd.com/read/29677560/effective-discovery-of-rare-variants-by-pooled-target-capture-sequencing-a-comparative-analysis-with-individually-indexed-target-capture-sequencing
#8
Seungjin Ryu, Jeehae Han, Trina M Norden-Krichmar, Nicholas J Schork, Yousin Suh
Identification of all genetic variants associated with complex traits is one of the most important goals in modern human genetics. Genome-wide association studies (GWAS) have been successfully applied to identify common variants, which thus far explain only small portion of heritability. Interests in rare variants have been increasingly growing as an answer for this missing heritability. While next-generation sequencing allows detection of rare variants, its cost is still prohibitively high to sequence a large number of human DNA samples required for rare variant association studies...
March 30, 2018: Mutation Research
https://www.readbyqxmd.com/read/29675634/investigation-of-circle-of-willis-variants-and-hemodynamic-parameters-in-twins-using-transcranial-color-coded-doppler-sonography
#9
Bianka Forgó, Ádám Domonkos Tárnoki, Dávid László Tárnoki, Levente Littvay, Corrado Fagnani, Maria Antonietta Stazi, Giorgio Meneghetti, Emanuela Medda, Filippo Farina, Claudio Baracchini
Morphological and hemodynamic variations of the circle of Willis (CW) may have an important impact on cerebrovascular events. However, the environmental and genetic influence remains unclear. For this reason we studied the variations and hemodynamic parameters of the CW in twins using transcranial color-coded sonography (TCCS). Sixty-four twins, 19 monozygotic (MZ) and 13 dizygotic (DZ) pairs from the Italian Twin Registry (average age 45.0 ± 13.7 years) underwent TCCS and risk factor assessment. We examined CW morphology and recorded peak systolic velocity (PSV), end-diastolic velocity (EDV) and pulsatility index (PI)...
April 19, 2018: International Journal of Cardiovascular Imaging
https://www.readbyqxmd.com/read/29650961/identification-of-rare-sequence-variation-underlying-heritable-pulmonary-arterial-hypertension
#10
Stefan Gräf, Matthias Haimel, Marta Bleda, Charaka Hadinnapola, Laura Southgate, Wei Li, Joshua Hodgson, Bin Liu, Richard M Salmon, Mark Southwood, Rajiv D Machado, Jennifer M Martin, Carmen M Treacy, Katherine Yates, Louise C Daugherty, Olga Shamardina, Deborah Whitehorn, Simon Holden, Micheala Aldred, Harm J Bogaard, Colin Church, Gerry Coghlan, Robin Condliffe, Paul A Corris, Cesare Danesino, Mélanie Eyries, Henning Gall, Stefano Ghio, Hossein-Ardeschir Ghofrani, J Simon R Gibbs, Barbara Girerd, Arjan C Houweling, Luke Howard, Marc Humbert, David G Kiely, Gabor Kovacs, Robert V MacKenzie Ross, Shahin Moledina, David Montani, Michael Newnham, Andrea Olschewski, Horst Olschewski, Andrew J Peacock, Joanna Pepke-Zaba, Inga Prokopenko, Christopher J Rhodes, Laura Scelsi, Werner Seeger, Florent Soubrier, Dan F Stein, Jay Suntharalingam, Emilia M Swietlik, Mark R Toshner, David A van Heel, Anton Vonk Noordegraaf, Quinten Waisfisz, John Wharton, Stephen J Wort, Willem H Ouwehand, Nicole Soranzo, Allan Lawrie, Paul D Upton, Martin R Wilkins, Richard C Trembath, Nicholas W Morrell
Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-β pathway, particularly the bone morphogenetic protein type 2 receptor (BMPR2), underlies most heritable forms of PAH. To identify the missing heritability we perform whole-genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses reveal significant overrepresentation of rare variants in ATP13A3, AQP1 and SOX17, and provide independent validation of a critical role for GDF2 in PAH...
April 12, 2018: Nature Communications
https://www.readbyqxmd.com/read/29650795/how-much-of-the-missing-heritability-of-als-is-hidden-in-known-als-genes
#11
EDITORIAL
Philip Van Damme
No abstract text is available yet for this article.
April 12, 2018: Journal of Neurology, Neurosurgery, and Psychiatry
https://www.readbyqxmd.com/read/29581422/low-frequency-and-rare-variants-may-contribute-to-elucidate-the-genetics-of-major-depressive-disorder
#12
Chenglong Yu, Mauricio Arcos-Burgos, Bernhard T Baune, Volker Arolt, Udo Dannlowski, Ma-Li Wong, Julio Licinio
Major depressive disorder (MDD) is a common but serious psychiatric disorder with significant levels of morbidity and mortality. Recent genome-wide association studies (GWAS) on common variants increase our understanding of MDD; however, the underlying genetic basis remains largely unknown. Many studies have been proposed to explore the genetics of complex diseases from a viewpoint of the "missing heritability" by considering low-frequency and rare variants, copy-number variations, and other types of genetic variants...
March 27, 2018: Translational Psychiatry
https://www.readbyqxmd.com/read/29575407/the-evolution-of-individuality-revisited
#13
Arunas L Radzvilavicius, Neil W Blackstone
Evolutionary theory is formulated in terms of individuals that carry heritable information and are subject to selective pressures. However, individuality itself is a trait that had to evolve - an individual is not an indivisible entity, but a result of evolutionary processes that necessarily begin at the lower level of hierarchical organisation. Traditional approaches to biological individuality focus on cooperation and relatedness within a group, division of labour, policing mechanisms and strong selection at the higher level...
March 25, 2018: Biological Reviews of the Cambridge Philosophical Society
https://www.readbyqxmd.com/read/29572226/a-large-scale-exome-wide-association-study-of-han-chinese-women-identifies-three-novel-loci-predisposing-to-breast-cancer
#14
Bo Zhang, Men-Yun Chen, Yu-Jun Sheng, Xian-Bo Zhuo, Ping Gao, Fu-Sheng Zhou, Bo Liang, Jun Zu, Qin Zhang, Sufyan Suleman, Yi-Hui Xu, Min-Gui Xu, Jin-Kai Xu, Chen-Cheng Liu, Nikolaos Giannareas, Ji-Han Xia, Yuan Zhao, Zhong-Lian Huang, Zhen Yang, Huaidong Cheng, Na Li, Yan-Yan Hong, Wei Li, Min-Jun Zhang, Ke-Da Yu, Guoliang Li, Meng-Hong Sun, Zhen-Dong Chen, Gong-Hong Wei, Zhi-Ming Shao
Genome-wide association studies have identified more than 90 susceptibility loci for breast cancer. However, the missing heritability is evident, and the contributions of coding variants to breast cancer susceptibility have not yet been systematically evaluated. Here we present a large-scale whole-exome association study for breast cancer consisting of 24,162 individuals (10,055 cases and 14,107 controls). In addition to replicating known susceptibility loci (e.g. ESR1, FGFR2 and TOX3), we identify two novel missense variants in C21orf58 (rs13047478, Pmeta = 4...
March 23, 2018: Cancer Research
https://www.readbyqxmd.com/read/29563569/haplotype-heritability-mapping-method-uncovers-missing-heritability-of-complex-traits
#15
Masoud Shirali, Sara A Knott, Ricardo Pong-Wong, Pau Navarro, Chris S Haley
We propose a novel approach to analyze genomic data that incorporates haplotype information for detecting rare variants within a regional heritability mapping framework. The performance of our approach was tested in a simulation study based on human genotypes. The phenotypes were simulated by generating regional variance using either SNP(s) or haplotype(s). Regional genomic relationship matrices, constructed with either a SNP-based or a haplotype-based estimator, were employed to estimate the regional variance...
March 21, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29560826/gxgrare-gene-gene-interaction-analysis-method-for-rare-variants-from-high-throughput-sequencing-data
#16
Minseok Kwon, Sangseob Leem, Joon Yoon, Taesung Park
BACKGROUND: With the rapid advancement of array-based genotyping techniques, genome-wide association studies (GWAS) have successfully identified common genetic variants associated with common complex diseases. However, it has been shown that only a small proportion of the genetic etiology of complex diseases could be explained by the genetic factors identified from GWAS. This missing heritability could possibly be explained by gene-gene interaction (epistasis) and rare variants. There has been an exponential growth of gene-gene interaction analysis for common variants in terms of methodological developments and practical applications...
March 19, 2018: BMC Systems Biology
https://www.readbyqxmd.com/read/29553866/targeted-deep-sequencing-of-the-pear1-locus-for-platelet-aggregation-in-european-and-african-american-families
#17
Ali R Keramati, Lisa R Yanek, Kruthika Iyer, Margaret A Taub, Ingo Ruczinski, Diane M Becker, Lewis C Becker, Nauder Faraday, Rasika A Mathias
Coronary artery disease (CAD) remains a major cause of mortality and morbidity worldwide. The aggregation of activated platelets on a ruptured atherosclerotic plaque is a critical step in most acute cardiovascular events like myocardial infarction. Platelet aggregation both at baseline and after aspirin is highly heritable. Genome-wide association studies (GWAS) have identified a common variant within the first intron of the platelet endothelial aggregation receptor1 (PEAR1), to be robustly associated with platelet aggregation...
March 19, 2018: Platelets
https://www.readbyqxmd.com/read/29547617/a-population-genetic-interpretation-of-gwas-findings-for-human-quantitative-traits
#18
Yuval B Simons, Kevin Bullaughey, Richard R Hudson, Guy Sella
Human genome-wide association studies (GWASs) are revealing the genetic architecture of anthropomorphic and biomedical traits, i.e., the frequencies and effect sizes of variants that contribute to heritable variation in a trait. To interpret these findings, we need to understand how genetic architecture is shaped by basic population genetics processes-notably, by mutation, natural selection, and genetic drift. Because many quantitative traits are subject to stabilizing selection and because genetic variation that affects one trait often affects many others, we model the genetic architecture of a focal trait that arises under stabilizing selection in a multidimensional trait space...
March 2018: PLoS Biology
https://www.readbyqxmd.com/read/29528821/lynch-syndrome-genomics-update-and-imaging-review
#19
Veronica L Cox, Anas A Saeed Bamashmos, Wai Chin Foo, Shiva Gupta, Sireesha Yedururi, Naveen Garg, Hyunseon Christine Kang
Lynch syndrome is the most common hereditary cancer syndrome, the most common cause of heritable colorectal cancer, and the only known heritable cause of endometrial cancer. Other cancers associated with Lynch syndrome include cancers of the ovary, stomach, urothelial tract, and small bowel, and less frequently, cancers of the brain, biliary tract, pancreas, and prostate. The oncogenic tendency of Lynch syndrome stems from a set of genomic alterations of mismatch repair proteins. Defunct mismatch repair proteins cause unusually high instability of regions of the genome called microsatellites...
March 2018: Radiographics: a Review Publication of the Radiological Society of North America, Inc
https://www.readbyqxmd.com/read/29523830/re-assessment-of-multiple-testing-strategies-for-more-efficient-genome-wide-association-studies
#20
Takahiro Otani, Hisashi Noma, Jo Nishino, Shigeyuki Matsui
Although enormous costs have been dedicated to discovering relevant disease-related genetic variants, especially in genome-wide association studies (GWASs), only a small fraction of estimated heritability can be explained by these results. This is the so-called missing heritability problem. The conventional use of overly conservative multiple testing strategies based on controlling the familywise error rate (FWER), in particular with a genome-wide significance threshold of P <5 × 10-8 , is one of the most important issues from a statistical perspective...
March 9, 2018: European Journal of Human Genetics: EJHG
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