Genetics and Genomics of Coronary Artery Disease: What We Have Learned.

Research over the past 2 decades has provided a broader understanding of the genetic architecture of coronary artery disease (CAD) and shows that it derives in large part from the cumulative effect of multiple common risk alleles that are individually of small effect size but cumulatively have large effects on CAD risk. The tools applied include genome-wide association study (GWAS), which encompasses thousands of individuals, complemented by deep sequencing and extensive omic data sets. More than 300 genome-wide significant loci associated with CAD risk have been identified using the GWAS approach; 90% of these are situated in intergenic regions. Our research at the University of Ottawa Heart Institute has been carried out in collaboration with an extensive number of groups and individuals around the world. These studies include computational approaches to better understand missing heritability and identify causal pathways, experimental approaches to reveal, at the molecular level, the function of the multiple risk loci. In addition to providing new insight into the biology of atherosclerosis and its clinical sequelae, GWAS findings have important applications in clinical cardiovascular medicine. These include Mendelian randomization analyses to identify causal biomarkers and generation of polygenic risk scores to improve CAD risk prediction and guide decision-making regarding preventive therapies.