Common Disease Is More Complex Than Implied by the Core Gene Omnigenic Model

Wray, Naomi R.; Wijmenga, Cisca; Sullivan, Patrick F.; Yang, Jian; Visscher, Peter M.

doi:10.1016/j.cell.2018.05.051

Cited by 251 publications

(238 citation statements)

References 80 publications

(72 reference statements)

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“…Nonetheless, the prevalence and distribution of loci we identified are similar to recent mapping experiments in S. cerevisiae that also had high power to detect loci with opposing effects on quantitative traits (Jakobson and Jarosz 2019). They are also consistent with models of complex traits, such as the "omnigenic model" (Boyle et al 2017;Wray et al 2018;Liu et al 2019); our work specifically supports the idea that many casual variants have trans-regulatory effects on expression.…”

Section: Resultssupporting

confidence: 86%

Compensatorytrans-regulatory alleles minimizing variation inTDH3expression are common withinSaccharomyces cerevisiae

Metzger

Wittkopp

2019

Evolution Letters

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Heritable variation in gene expression is common within species. Much of this variation is due to genetic differences outside of the gene with altered expression and is trans‐acting. This trans‐regulatory variation is often polygenic, with individual variants typically having small effects, making the genetic architecture and evolution of trans‐regulatory variation challenging to study. Consequently, key questions about trans‐regulatory variation remain, including the variability of trans‐regulatory variation within a species, how selection affects trans‐regulatory variation, and how trans‐regulatory variants are distributed throughout the genome and within a species. To address these questions, we isolated and measured trans‐regulatory differences affecting TDH3 promoter activity among 56 strains of Saccharomyces cerevisiae, finding that trans‐regulatory backgrounds varied approximately twofold in their effects on TDH3 promoter activity. Comparing this variation to neutral models of trans‐regulatory evolution based on empirical measures of mutational effects revealed that despite this variability in the effects of trans‐regulatory backgrounds, stabilizing selection has constrained trans‐regulatory differences within this species. Using a powerful quantitative trait locus mapping method, we identified ∼100 trans‐acting expression quantitative trait locus in each of three crosses to a common reference strain, indicating that regulatory variation is more polygenic than previous studies have suggested. Loci altering expression were located throughout the genome, and many loci were strain specific. This distribution and prevalence of alleles is consistent with recent theories about the genetic architecture of complex traits. In all mapping experiments, the nonreference strain alleles increased and decreased TDH3 promoter activity with similar frequencies, suggesting that stabilizing selection maintained many trans‐acting variants with opposing effects. This variation may provide the raw material for compensatory evolution and larger scale regulatory rewiring observed in developmental systems drift among species.

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Section: Resultssupporting

confidence: 86%

Compensatorytrans-regulatory alleles minimizing variation inTDH3expression are common withinSaccharomyces cerevisiae

Metzger

Wittkopp

2019

Evolution Letters

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“…(26) These results suggest that 1) the effect-size of deletions on NVIQ can be estimated using constraint scores, such as the "probability of being Loss-of-function Intolerant" (pLI, definition in textbox, Figure 1) (27), and 2) the effect of haploinsufficiency on NVIQ applies to a large proportion of the genome, consistent with a highly polygenic model. (28,29) Using pLI as an explanatory variable, we estimated that one third of the coding genes affect NVIQ by >1 point, when deleted.…”

Section: Introductionmentioning

confidence: 99%

Effects-sizes of deletions and duplications on autism risk across the genome

Douard

Zeribi

Schramm

et al. 2020

Preprint

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Objective: Deleterious copy number variants (CNVs) are identified in up to 20% of individuals with autism. However, only 13 genomic loci have been formally associated with autism because the majority of CNVs are too rare to perform individual association studies. To investigate the implication of undocumented CNVs in neurodevelopmental disorders, we recently developed a new framework to estimate their effect-size on intelligence quotient (IQ) and sought to extend this approach to autism susceptibility and multiple cognitive domains. Methods: We identified CNVs in two autism samples (Simons Simplex Collection and MSSNG) and two unselected populations (IMAGEN and Saguenay Youth Study). Statistical models integrating scores of genes encompassed in CNVs were used to explain their effect on autism susceptibility and multiple cognitive domains. Results: Among 9 scores of genes, the "probability-of-being loss-of-function intolerant" (pLI) best explains the effect of CNVs on IQ and autism risk. Deletions decrease IQ by a mean of 2.6 points per point of pLI. The effect of duplications on IQ is three-fold smaller.The odd ratios for autism increases when deleting or duplicating any point of pLI. This increased autism risk is similar in subgroups of individuals below or above median IQ.Once CNV effects on IQ are accounted for, autism susceptibility remains mostly unchanged for duplications but decreases for deletions. Model estimates for autism risk overlap with previously published observations. Deletions and duplications differentially affect social communication, behaviour, and phonological memory, whereas both equally affect motor skills.Conclusions: Autism risk conferred by duplications is less influenced by IQ compared to deletions. CNVs increase autism risk similarly in individuals with high and low IQ. Our model, trained on CNVs encompassing >4,500 genes, suggests highly polygenic properties of gene dosage with respect to autism risk. These models will help interpreting CNVs identified in the clinic.

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“…These analyses confirmed the validity of our previous suggestion about herpesviruses as a component cause of MS and showed that this is not common to the other diseases considered in this study.A related issue is the clarification of the biological consequences of the observed associations. Elegant studies are resolving the functional implications of individual disease-associated variants (Gregory et al, 2012;Steri et al, 2017).Given the complex nature of multifactorial diseases (Wray et al, 2018), and particularly for translation into clinical benefit, a more general understanding of how gene-environment interactions generate gene expression alterations is also necessary (Gallagher and Chen-Plotkin, 2018). We therefore analyzed transcriptomes from the peripheral blood of persons with MS to verify whether genes that are nominally associated with MS, and are part of our interactomes, were more frequently present among dysregulated genes (see workflow in Figure1).…”

mentioning

confidence: 99%

“…Given the complex nature of multifactorial diseases (Wray et al, 2018), and particularly for translation into clinical benefit, a more general understanding of how gene-environment interactions generate gene expression alterations is also necessary (Gallagher and Chen-Plotkin, 2018). We therefore analyzed transcriptomes from the peripheral blood of persons with MS to verify whether genes that are nominally associated with MS, and are part of our interactomes, were more frequently present among dysregulated genes (see workflow in Figure1).…”

mentioning

confidence: 99%

Significant enrichment of Herpesvirus interactors in GWAS data suggests causal inferences for the association between Epstein Barr virus and multiple sclerosis

Mechelli

Umeton

Srinivasan

et al. 2019

Preprint

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We exploited genetic information to assess the role of non-genetic factors in multifactorial diseases. To this aim we isolated candidate "interactomes" (i.e. groups of genes whose products are known to physically interact with environmental exposures and biological processes, plausibly relevant for disease pathogenesis) and analyzed nominal statistical evidence of association with genetic predisposition to multiple sclerosis (MS) and other inflammatory and non-inflammatory complex disorders. The interaction between genotype and Herpesviruses emerged as specific for MS, with Epstein Barr virus (EBV) showing higher levels of significance compared to Human Herpesvirus 8 (HHV8) and, more evidently, to cytomegalovirus (CMV). In accord with this result, when we classified the MS-associated genes contained in the interactomes into canonical pathways, the analysis converged towards biological functions of B cells, in particular the CD40 pathway. When we analyzed peripheral blood transcriptomes in persons with MS, we found a significant dysregulation of MS-associated genes belonging to the EBV interactome in primary progressive MS.This study indicates that the interaction between herpesviruses and predisposing genetic background is of causal significance in MS, and provides a mechanistic explanation for the long-recognized association between EBV and this condition.Many studies on environmental exposures in multifactorial diseases are correlative and associative in nature, hence the need to focus on causality and mechanism (Fischbach, 2018). Genome-wide association studies (GWAS) have the capability to inform about the causal relevance of associations between environmental exposures and disease. However, the difficulty in extracting value from the study of gene-environment interactions limits the interpretation of GWAS, therefore hindering what could be a virtuous 'genes-to-environment-to genes-again' iterative learning process (Visscher et al., 2017).In principle, Mendelian randomization allows to test for a causal effect of an epidemiological association. With this method, an environmental exposure is deemed to be plausibly causal if a genetic variant influencing the exposure is also directly associated with the disease (Davey Smith and Hemani, 2014). However, the influence of genetic variants on environmental exposures that associate with multifactorial diseases is far from being fully understood, particularly at the genome-wide level. More actionable data are available about the interaction, at the protein level, between human gene products and exposures. Furthermore, it has been shown that interacting disease-associated proteins have the propensity to influence each other in biologically relevant modules (Menche et al., 2015). Hence, in an approach akin to Mendelian randomization, we tested the possible causal significance of environmental exposures by measuring, at the genome-wide level, which genetic variants interacting with the exposure (i.e. influencing the exposure) were significantly enriched in MS GWAS data. ...

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Common Disease Is More Complex Than Implied by the Core Gene Omnigenic Model

Cited by 251 publications

References 80 publications

Compensatorytrans-regulatory alleles minimizing variation inTDH3expression are common withinSaccharomyces cerevisiae

Compensatorytrans-regulatory alleles minimizing variation inTDH3expression are common withinSaccharomyces cerevisiae

Effects-sizes of deletions and duplications on autism risk across the genome

Significant enrichment of Herpesvirus interactors in GWAS data suggests causal inferences for the association between Epstein Barr virus and multiple sclerosis

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