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Phenome-wide functional dissection of pleiotropic effects highlights key molecular pathways for human complex traits.

ABSTRACT: Over the recent decades, genome-wide association studies (GWAS) have dramatically changed the understanding of human genetics. A recent genetic data release by UK Biobank (UKB) has allowed many researchers worldwide to have comprehensive look into the genetic architecture of thousands of human phenotypes. In this study, we used GWAS summary statistics derived from the UKB cohort to investigate functional mechanisms of pleiotropic effects across the human phenome. We find that highly pleiotropic variants often correspond to broadly expressed genes with ubiquitous functions, such as matrisome components and cell growth regulators; and tend to colocalize with tissue-shared eQTLs. At the same time, signaling pathway components are more prevalent among highly pleiotropic genes compared to regulatory proteins such as transcription factors. Our results suggest that protein-level pleiotropy mediated by ubiquitously expressed genes is the most prevalent mechanism of pleiotropic genetic effects across the human phenome.

SUBMITTER: Shikov AE

PROVIDER: S-EPMC6978431 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Phenome-wide functional dissection of pleiotropic effects highlights key molecular pathways for human complex traits.

Shikov Anton E AE Skitchenko Rostislav K RK Predeus Alexander V AV Barbitoff Yury A YA

Scientific reports 20200123 1

Over the recent decades, genome-wide association studies (GWAS) have dramatically changed the understanding of human genetics. A recent genetic data release by UK Biobank (UKB) has allowed many researchers worldwide to have comprehensive look into the genetic architecture of thousands of human phenotypes. In this study, we used GWAS summary statistics derived from the UKB cohort to investigate functional mechanisms of pleiotropic effects across the human phenome. We find that highly pleiotropic ...[more]

PMID: 31974475

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Project description:BackgroundCausality between plasma triglyceride (TG) levels and atherosclerotic cardiovascular disease (ASCVD) risk remains controversial despite more than four decades of study and two recent landmark trials, STRENGTH, and REDUCE-IT. Further unclear is the association between TG levels and non-atherosclerotic diseases across organ systems.MethodsHere, we conducted a phenome-wide, two-sample Mendelian randomization (MR) analysis using inverse-variance weighted (IVW) regression to systematically infer the causal effects of plasma TG levels on 2600 disease traits in the European ancestry population of UK Biobank. For replication, we externally tested 221 nominally significant associations (p<0.05) in an independent cohort from FinnGen. To account for potential horizontal pleiotropy and the influence of invalid instrumental variables, we performed sensitivity analyses using MR-Egger regression, weighted median estimator, and MR-PRESSO. Finally, we used multivariable MR (MVMR) controlling for correlated lipid fractions to distinguish the independent effect of plasma TG levels.ResultsOur results identified seven disease traits reaching Bonferroni-corrected significance in both the discovery (p<1.92 × 10-5) and replication analyses (p<2.26 × 10-4), suggesting a causal relationship between plasma TG levels and ASCVDs, including coronary artery disease (OR 1.33, 95% CI 1.24-1.43, p=2.47 × 10-13). We also identified 12 disease traits that were Bonferroni-significant in the discovery or replication analysis and at least nominally significant in the other analysis (p<0.05), identifying plasma TG levels as a novel potential risk factor for nine non-ASCVD diseases, including uterine leiomyoma (OR 1.19, 95% CI 1.10-1.29, p=1.17 × 10-5).ConclusionsTaking a phenome-wide, two-sample MR approach, we identified causal associations between plasma TG levels and 19 disease traits across organ systems. Our findings suggest unrealized drug repurposing opportunities or adverse effects related to approved and emerging TG-lowering agents, as well as mechanistic insights for future studies.FundingRD is supported by the National Institute of General Medical Sciences of the National Institutes of Health (NIH) (R35-GM124836) and the National Heart, Lung, and Blood Institute of the NIH (R01-HL139865 and R01-HL155915).

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Phenome-wide functional dissection of pleiotropic effects highlights key molecular pathways for human complex traits.

Publications

Phenome-wide functional dissection of pleiotropic effects highlights key molecular pathways for human complex traits.

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