Dataset Information

The Genetic Architecture of Coronary Artery Disease: Current Knowledge and Future Opportunities.

ABSTRACT: We provide an overview of our current understanding of the genetic architecture of coronary artery disease (CAD) and discuss areas of research that provide excellent opportunities for further exploration.Large-scale studies in human populations, coupled with rapid advances in genetic technologies over the last decade, have clearly established the association of common genetic variation with risk of CAD. However, the effect sizes of the susceptibility alleles are for the most part modest and collectively explain only a small fraction of the overall heritability. By comparison, evidence that rare variants make a substantial contribution to risk of CAD has been somewhat disappointing thus far, suggesting that other biological mechanisms have yet to be discovered. Emerging data suggests that novel pathways involved in the development of CAD can be identified through complementary and integrative systems genetics strategies in mice or humans. There is also convincing evidence that gut bacteria play a previously unrecognized role in the development of CAD, particularly through metabolism of certain dietary nutrients that lead to proatherogenic metabolites in the circulation. A major effort is now underway to functionally understand the newly discovered genetic and biological associations for CAD, which could lead to the development of potentially novel therapeutic strategies. Other important areas of investigation for understanding the pathophysiology of CAD, including epistatic interactions between genes or with either sex and environmental factors, have not been studied on a broad scope and represent additional opportunities for future studies.

SUBMITTER: Hartiala J

PROVIDER: S-EPMC5783155 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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The Genetic Architecture of Coronary Artery Disease: Current Knowledge and Future Opportunities.

Hartiala Jaana J Schwartzman William S WS Gabbay Julian J Ghazalpour Anatole A Bennett Brian J BJ Allayee Hooman H

Current atherosclerosis reports 20170201 2

<h4>Purpose of review</h4>We provide an overview of our current understanding of the genetic architecture of coronary artery disease (CAD) and discuss areas of research that provide excellent opportunities for further exploration.<h4>Recent findings</h4>Large-scale studies in human populations, coupled with rapid advances in genetic technologies over the last decade, have clearly established the association of common genetic variation with risk of CAD. However, the effect sizes of the susceptibi ...[more]

PMID: 28130654

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Project description:RationaleCoronary artery disease (CAD) is a complex phenotype driven by genetic and environmental factors. Ninety-seven genetic risk loci have been identified to date, but the identification of additional susceptibility loci might be important to enhance our understanding of the genetic architecture of CAD.ObjectiveTo expand the number of genome-wide significant loci, catalog functional insights, and enhance our understanding of the genetic architecture of CAD.Methods and resultsWe performed a genome-wide association study in 34 541 CAD cases and 261 984 controls of UK Biobank resource followed by replication in 88 192 cases and 162 544 controls from CARDIoGRAMplusC4D. We identified 75 loci that replicated and were genome-wide significant (P<5×10-8) in meta-analysis, 13 of which had not been reported previously. Next, to further identify novel loci, we identified all promising (P<0.0001) loci in the CARDIoGRAMplusC4D data and performed reciprocal replication and meta-analyses with UK Biobank. This led to the identification of 21 additional novel loci reaching genome-wide significance (P<5×10-8) in meta-analysis. Finally, we performed a genome-wide meta-analysis of all available data revealing 30 additional novel loci (P<5×10-8) without further replication. The increase in sample size by UK Biobank raised the number of reconstituted gene sets from 4.2% to 13.9% of all gene sets to be involved in CAD. For the 64 novel loci, 155 candidate causal genes were prioritized, many without an obvious connection to CAD. Fine mapping of the 161 CAD loci generated lists of credible sets of single causal variants and genes for functional follow-up. Genetic risk variants of CAD were linked to development of atrial fibrillation, heart failure, and death.ConclusionsWe identified 64 novel genetic risk loci for CAD and performed fine mapping of all 161 risk loci to obtain a credible set of causal variants. The large expansion of reconstituted gene sets argues in favor of an expanded omnigenic model view on the genetic architecture of CAD.

Dataset Information

The Genetic Architecture of Coronary Artery Disease: Current Knowledge and Future Opportunities.

Publications

The Genetic Architecture of Coronary Artery Disease: Current Knowledge and Future Opportunities.

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