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Missing heritability

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
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
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 16, 2018: PLoS Biology
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
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
Shlomo Yeshurun, Anthony J Hannan
In recent years, striking new evidence has demonstrated non-genetic inheritance of acquired traits associated with parental environmental exposures. In particular, this transgenerational modulation of phenotypic traits is of direct relevance to psychiatric disorders, including depression, post-traumatic stress disorder, and other anxiety disorders. Here we review the recent progress in this field, with an emphasis on acquired traits of psychiatric illnesses transmitted epigenetically via the male lineage. We discuss the transgenerational effects of paternal exposure to stress vs...
March 8, 2018: Molecular Psychiatry
Shijia Zhu, Gang Fang
Motivation: For many traits, causal loci uncovered by genetic-mapping studies explain only a minority of the heritable contribution to trait variation. Multiple explanations for this 'missing heritability' have been proposed. SNP-SNP interaction (epistasis), as one of the compelling models, has been widely studied. However, the genome-wide scan of epistasis, especially for quantitative traits, poses huge computational challenges. Moreover, covariate adjustment is largely ignored in epistasis analysis due to the massive extra computational undertaking...
March 2, 2018: Bioinformatics
Chenglong Yu, Bernhard T Baune, Ma-Li Wong, Julio Licinio
BACKGROUND: Major depressive disorder (MDD) is a leading contributor to global disease burden. Recent studies have shown that genetic factors play significant roles in the susceptibility to this condition; however, the underlying genetic basis currently remains largely unknown. Short tandem repeat (STR) has been proposed as an explanatory factor in the "missing heritability" of complex diseases or traits. METHODS: We investigated STR variations from 15 MDD patients and 10 ethnically matched healthy controls based on their deep whole-genome sequencing (WGS) data...
February 24, 2018: Journal of Affective Disorders
Mirta Basha, Bénédicte Demeer, Nicole Revencu, Raphael Helaers, Stephanie Theys, Sami Bou Saba, Odile Boute, Bernard Devauchelle, Geneviève Francois, Bénédicte Bayet, Miikka Vikkula
BACKGROUND: Oral clefts, that is, clefts of the lip and/or cleft palate (CL/P), are the most common craniofacial birth defects with an approximate incidence of ~1/700. To date, physicians stratify patients with oral clefts into either syndromic CL/P (syCL/P) or non-syndromic CL/P (nsCL/P) depending on whether the CL/P is associated with another anomaly or not. In general, patients with syCL/P follow Mendelian inheritance, while those with nsCL/P have a complex aetiology and, as such, do not adhere to Mendelian inheritance...
March 2, 2018: Journal of Medical Genetics
John N Constantino
A recent generation of family studies has revealed that autism can be predicted from an array of neurobehavioural susceptibilities that are appreciable before the syndrome is diagnosed, and that each may be traceable to partially-independent sets of genetic variation. Some of these liabilities are not necessarily specific to ASD-those that are non-specific could account for a significant share of the 'missing heritability' of autism, would (by definition) contribute to pleiotropy, and relate to so-called 'co-morbidities', which are inappropriately named if they actually contribute to (or exacerbate) the severity of autism itself...
March 2, 2018: International Review of Psychiatry
Alessia Russo, Cornelia Di Gaetano, Giovanni Cugliari, Giuseppe Matullo
Worldwide, hypertension still represents a serious health burden with nine million people dying as a consequence of hypertension-related complications. Essential hypertension is a complex trait supported by multifactorial genetic inheritance together with environmental factors. The heritability of blood pressure (BP) is estimated to be 30-50%. A great effort was made to find genetic variants affecting BP levels through Genome-Wide Association Studies (GWAS). This approach relies on the "common disease-common variant" hypothesis and led to the identification of multiple genetic variants which explain, in aggregate, only 2-3% of the genetic variance of hypertension...
February 28, 2018: International Journal of Molecular Sciences
Marcus W Feldman, Sohini Ramachandran
Standard models for the determination of phenotypes from genes are grounded in simple assumptions that are inherent in the modern evolutionary synthesis (MES), which was developed in the 1930s, 1940s and 1950s. The MES was framed in the context of Mendelian genetic transmission enhanced by the Fisherian view of the way discretely inherited genes determine continuously quantitative phenotypes. The statistical models that are used to estimate and interpret genetic contributions to human phenotypes-including behavioural traits-are constructed within the framework of the MES...
April 5, 2018: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
Gang Chen, Wen-da Xue, Jun Zhu
Elucidation of the systems biology foundation underlying the effect of Fangji, which are multi-herbal traditional Chinese medicine (TCM) formulas, is one of the major aims in the field. The numerous bioactive ingredients of a Fangji deal with the multiple targets of a complex disease, which is influenced by a number of genes and their interactions with the environment. Genome-wide association study (GWAS) is an unbiased approach for dissecting the genetic variants underlying complex diseases and individual response to a given treatment...
February 8, 2018: Acta Pharmacologica Sinica
Anthony J Hannan
Accumulating evidence suggests that many classes of DNA repeats exhibit attributes that distinguish them from other genetic variants, including the fact that they are more liable to mutation; this enables them to mediate genetic plasticity. The expansion of tandem repeats, particularly of short tandem repeats, can cause a range of disorders (including Huntington disease, various ataxias, motor neuron disease, frontotemporal dementia, fragile X syndrome and other neurological disorders), and emerging data suggest that tandem repeat polymorphisms (TRPs) can also regulate gene expression in healthy individuals...
February 5, 2018: Nature Reviews. Genetics
Meriem Benfodda, Steven Gazal, Vincent Descamps, Nicole Basset-Seguin, Lydia Deschamps, Luc Thomas, Philippe Saiag, Roberto Zanetti, Lidia Sacchetto, Giovanna Chiorino, Maria Scatolini, Bernard Grandchamp, Nadem Soufir
Genetic predisposition to cutaneous malignant melanoma (CMM) involves highly penetrant predisposing genes and low and intermediate penetrant predisposing alleles. However, the missing heritability in (CMM) is still high. For such and in order to identify new genetic factors for CMM, we conducted an exome sequencing study in high-risk CMM patients. Two rounds of exome sequencing were successively performed in 33 and 27 high-risk patients. We focused on genes carrying rare nonsense, frameshift, and splice variants (allelic frequency <1%) that were present in both series of exomes...
January 23, 2018: Genes, Chromosomes & Cancer
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
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
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
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...
January 4, 2018: American Journal of Human Genetics
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
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