Genetics of Coronary Artery Disease

Main Results From GWAS and Recent Gene-Centric Approaches

Family² and twin³ studies provided convincing evidence that CAD clusters in families and has a heritable component^2–5; however, the delineation of the specific genetic architecture that predisposes to CAD has been challenging, with initial candidate gene approaches yielding inconsistent results.⁶ In contrast to candidate gene approaches that focus on genetic variation in genes whose gene products are known to play an important role in cardiovascular physiology, GWAS simultaneously assess the association with CAD of hundreds of thousands of genetic variants distributed across the whole genome. Therefore, GWAS represent an essentially unbiased approach that is not limited by the current (patho)physiological understanding of CVD and bears the potential of discovering completely new molecular mechanisms that predispose to CAD.

In 2007, the first GWAS for CAD were published.^7–9 The main finding was a locus on chromosome 9p21, which is still the most consistently associated CAD locus to date.¹⁰ Subsequent studies revealed that this locus is related to a broad spectrum of vascular phenotypes, including CAD and myocardial infarction,^7–9 coronary artery calcification,¹¹ peripheral artery disease,^12,13 and abdominal aortic aneurysm.¹⁴ To increase power for the detection of genetic variants with smaller effect sizes, large consortia have been built that combine genetic-epidemiological data from multiple cohorts and tens …