2018 George Lyman Duff Memorial Lecture

Abstract

Recent studies have led to a broader understanding of the genetic architecture of coronary artery disease and demonstrate that it largely derives from the cumulative effect of multiple common risk alleles individually of small effect size rather than rare variants with large effects on coronary artery disease risk. The tools applied include genome-wide association studies encompassing over 200 000 individuals complemented by bioinformatic approaches including imputation from whole-genome data sets, expression quantitative trait loci analyses, and interrogation of ENCODE (Encyclopedia of DNA Elements), Roadmap Epigenetic Project, and other data sets. Over 160 genome-wide significant loci associated with coronary artery disease risk have been identified using the genome-wide association studies approach, 90% of which are situated in intergenic regions. Here, I will describe, in part, our research over the last decade performed in collaboration with a series of bright trainees and an extensive number of groups and individuals around the world as it applies to our understanding of the genetic basis of this complex disease. These studies include computational approaches to better understand missing heritability and identify causal pathways, experimental approaches, and progress in understanding at the molecular level the function of the multiple risk loci identified and potential applications of these genomic data in clinical medicine and drug discovery.

Pharmacogenomics-based systematic review of coronary artery disease based on personalized medicine procedure

“…McPherson defined that the genetic architecture of CAD is mostly driven by the combined impact of numerous common variants, each of which contributes little to disease risk when considered separately. This is in contrast to rare variants having significant influences on the incidence of coronary disease [ 18 ]. The identification of these common variations follows the publication of massive genome-wide association studies (GWAS) on a bigger view [ 19 , 20 ].…”

Polygenic Risk Scores in Predicting Coronary Artery Disease in Symptomatic Patients. A Validation Study

“…In addition to these clinical risk factors, genetic risk scores, often referred to as polygenic risk scores (PRSs), have been shown to independently predict the development of CAD [2][3][4][5][6] . The potential use of genetic data in clinics is based on robust evidence and the importance of family history, with an estimated 40%-60% CAD heritability 6,7) .…”

Incremental Value of Polygenic Risk Scores in Primary Prevention of Coronary Heart Disease

“…Risk prediction for CHD using PRS has been extensively studied over the past 10 to 15 years . The biological plausibility and potential clinical utility of PRS in CHD is rooted in the importance of family history, with estimates of heritability of CHD of up to 50% . However, family history is often not well captured and is a crude measure of inherited risk.…”

“…Furthermore, most people do not harbor a known pathogenic or disease-causing rare variant in a single gene that can account for the familial risk. Genome-wide association studies have identified at least 160 SNVs that may each contribute to the overall risk of CHD, but individually have small effect sizes. Advances in whole-genome sequencing as well as improved computing capabilities have allowed the derivation of PRSs that contain millions of SNVs.…”