Population-specific and trans-ancestry genome-wide analyses identify distinct and shared genetic risk loci for coronary artery disease

Nat Genet. 2020 Nov;52(11):1169-1177. doi: 10.1038/s41588-020-0705-3. Epub 2020 Oct 5.

Abstract

To elucidate the genetics of coronary artery disease (CAD) in the Japanese population, we conducted a large-scale genome-wide association study of 168,228 individuals of Japanese ancestry (25,892 cases and 142,336 controls) with genotype imputation using a newly developed reference panel of Japanese haplotypes including 1,781 CAD cases and 2,636 controls. We detected eight new susceptibility loci and Japanese-specific rare variants contributing to disease severity and increased cardiovascular mortality. We then conducted a trans-ancestry meta-analysis and discovered 35 additional new loci. Using the meta-analysis results, we derived a polygenic risk score (PRS) for CAD, which outperformed those derived from either Japanese or European genome-wide association studies. The PRS prioritized risk factors among various clinical parameters and segregated individuals with increased risk of long-term cardiovascular mortality. Our data improve the clinical characterization of CAD genetics and suggest the utility of trans-ancestry meta-analysis for PRS derivation in non-European populations.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Alleles
  • Cholestanetriol 26-Monooxygenase / genetics
  • Chromosome Mapping
  • Coronary Artery Disease / genetics*
  • Coronary Artery Disease / mortality
  • Genetic Pleiotropy
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study*
  • Genotype
  • Humans
  • Japan
  • Middle Aged
  • Pedigree
  • Risk Factors

Substances

  • CYP27A1 protein, human
  • Cholestanetriol 26-Monooxygenase