Shared Genetic Susceptibility to Ischemic Stroke and Coronary Artery Disease: A Genome-Wide Analysis of Common Variants

Stroke. 2014 Jan;45(1):24-36. doi: 10.1161/STROKEAHA.113.002707. Epub 2013 Nov 21.

Abstract

Background and purpose: Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases.

Methods: Genome-wide association data were obtained from the METASTROKE, Coronary Artery Disease Genome-wide Replication and Meta-analysis (CARDIoGRAM), and Coronary Artery Disease (C4D) Genetics consortia. We first analyzed common variants reaching a nominal threshold of significance (P<0.01) for CAD for their association with IS and vice versa. We then examined specific overlap across phenotypes for variants that reached a high threshold of significance. Finally, we conducted a joint meta-analysis on the combined phenotype of IS or CAD. Corresponding analyses were performed restricted to the 2167 individuals with the ischemic large artery stroke (LAS) subtype.

Results: Common variants associated with CAD at P<0.01 were associated with a significant excess risk for IS and for LAS and vice versa. Among the 42 known genome-wide significant loci for CAD, 3 and 5 loci were significantly associated with IS and LAS, respectively. In the joint meta-analyses, 15 loci passed genome-wide significance (P<5×10(-8)) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Because these loci had prior evidence for genome-wide significance for CAD, we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 (PIS=1.62×10(-7)) and ABO (PIS=2.6×10(-4)), as well as at HDAC9 (PLAS=2.32×10(-12)), 9p21 (PLAS=3.70×10(-6)), RAI1-PEMT-RASD1 (PLAS=2.69×10(-5)), EDNRA (PLAS=7.29×10(-4)), and CYP17A1-CNNM2-NT5C2 (PLAS=4.9×10(-4)).

Conclusions: Our results demonstrate substantial overlap in the genetic risk of IS and particularly the LAS subtype with CAD.

Keywords: coronary artery disease; genetics; meta-analysis; polymorphism, single nucleotide; stroke.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Brain Ischemia / epidemiology*
  • Brain Ischemia / genetics*
  • Coronary Artery Disease / epidemiology*
  • Coronary Artery Disease / genetics*
  • Data Interpretation, Statistical
  • Genetic Predisposition to Disease / epidemiology*
  • Genome-Wide Association Study
  • Humans
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Reproducibility of Results
  • Risk Factors
  • Stroke / epidemiology*
  • Stroke / genetics*

Associated data

  • ISRCTN/ISRCTN48489393

Grant support