Genetic Risk Scores in Premature Coronary Artery Disease
Still Only One Piece of the Prevention Puzzle
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See Article by Thériault et al
Just over a decade has passed since the publication of the seminal genome-wide association studies identifying the first common susceptibility locus for coronary artery disease (CAD) at the 9p21 locus.1,2 Considerable progress has ensued through ever-expanding meta-analyses of case–control and cohort studies organized by multiple consortia.3 The most recent large-scale meta-analysis published in 2015 by CARDIoGRAMplusC4D involved genome-wide genetic data imputed to the 1000 genomes panel for the first time.4 This analysis extended the number of loci reaching genome-wide significance to 58 and identified 202 variants in 129 loci with a P value lower than a false discovery rate threshold of 5%. Overall, these loci explain ≈25% of the heritability of CAD when assuming a multifactorial liability-threshold model, a prevalence of disease of 5%, and a total heritability of CAD of 40%.4
The findings of genome-wide association studies to date provide important insights on the genetic architecture of CAD, the causal mechanisms at play, and the predictive power of genetics. First, they confirm the long-suspected polygenic nature of CAD. The increases in risk among variants on the false discovery rate list were found to be uniformly under 15% per allele for common, and no >53% per allele for rare variants.4 This observation combined with the modest overall variance explained to date suggests that there are many more, as yet unidentified, variants that contribute to the risk of CAD. Second, they corroborate the role of known causal biological pathways of atherosclerosis; whereas at the same time illuminate the importance of new ones.4 The latter is underscored by the observation that only a minority of the CAD loci uncovered to date are also strong signals in genetic studies of traditional risk factors with nearly all of this pleiotropy …