Peering Into the Future of CAD Genomics
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About 10 years ago, the promise of genome-wide association studies (GWASs) for reducing the burden of coronary artery disease (CAD) was in crisis. GWASs had not enabled the genetic prediction of CAD in populations. Nor had they revealed novel pathobiology. Even GWASs including up to 2000 cases of CAD, an ambitious proposition at the time, found only a single common association at chromosomal position 9p21 that surpassed the stringent significance threshold required for common variants on a genome-wide basis (ie, P<5×10−8).1–4 Although this signal was robust, it only minimally accounted for the family-based heritability and thus risk of CAD,5 and its biological mechanism of action could not be discerned because it mapped to an extended intergenic region. Subsequent GWAS over the following few years incrementally identified more CAD loci but still failed to account appreciably for CAD heritability.
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What was wrong? Did family-based heritability overestimate the role of genetics in populations? Did the heritability reside in rare instead of common genetic variants?6 Was there a need to consider gene-by-environment interactions? Certainly, all of these explanations contribute to a complete picture of CAD genetics. However, since the initial CAD GWASs, it has also been recognized that the heritability of CAD, like other complex traits, is substantially composed of many more variants than had been anticipated, each with a small effect. Such a genetic architecture, consisting of hundreds or even thousands of small genetic influences, can only be dissected with large samples; and the carefully nurtured cohort studies that have been highly effective for conventional CAD epidemiology are typically not large enough. In other words, as …