Genetics of coronary artery disease: genome-wide association studies and beyond

Genome-wide association (GWA) studies on coronary artery disease (CAD) have been very successful, identifying a total of 32 susceptibility loci so far. Although these loci have provided valuable insights into the etiology of CAD, their cumulative effect explains surprisingly little of the total CAD heritability. In this review, we first highlight and describe the type of genetic variants potentially underlying the missing heritability of CAD: single nucleotide polymorphisms (SNPs) or structural variants, each of which may either be common or rare. Although finding missing heritability is important, we further argue in this review that it constitutes only a first step towards a fuller understanding of the etiology of CAD development. To close the gap between the genotype and phenotype, we propose a systems genetics approach in the post-GWA study era. This approach that integrates genetic, epigenetic, transcriptomic, proteomic, metabolic and intermediate outcome variables has potential to significantly aid the understanding of CAD etiology.