Shared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants

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.

Figure 1

QQ plots for individual vascular phenotypes considering variants reaching a low threshold of significance (p<0.01) in alternate vascular phenotypes: CAD variants in all IS (left) and all IS variants in CAD (right) (A), CAD variants in LAS (left) and LAS variants in CAD (right) (B); CAD variants in CES (left) and CES variants in CAD (right) (C). SNPs with effects going into the same direction in the respective samples are shown in black. SNPs with effects going into opposite directions in the respective samples are shown in light blue. Data were drawn from METASTROKE, CARDIoGRAM and C4D. Red line: expected line corresponding to a normal distribution; black lines represent 95% confidence intervals of the expected distribution. For display purposes variants from the 9p21 locus are omitted from the figure. p-values correspond to the analysis of directionally consistent SNPs (black line).

Figure 2

Manhattan plots of –log₁₀(p) against genomic position: Results are shown for (A) the combined endpoint of all IS or CAD and (B) the combined endpoint of LAS or CAD. Genome-wide meta-analysis association results by genomic position at autosomal SNPs. Data were drawn from METASTROKE and CARDIoGRAM.

Figure 2

Manhattan plots of –log₁₀(p) against genomic position: Results are shown for (A) the combined endpoint of all IS or CAD and (B) the combined endpoint of LAS or CAD. Genome-wide meta-analysis association results by genomic position at autosomal SNPs. Data were drawn from METASTROKE and CARDIoGRAM.

Figure 3

Regional association plots (left) and corresponding Spearman correlation plots (right) of p-values for individual variants of (A) the chr12q24/SH2B3 locus for IS and CAD and (B) the RAI1-PEMT-RASD1 locus for LAS and CAD. For clarity, only a subset of variants is displayed (see Supplementary Figure II for all variants). Data were drawn from METASTROKE and CARDIoGRAM.

Figure 4

Regional association plots (left) and corresponding Spearman correlation plots (right) of (A) the SORT1 locus for IS and CAD, (B) the TCF21 locus for LAS and CAD, and (C) the HDAC9 locus for LAS and CAD. For clarity, only a subset of variants is displayed (see Supplementary Figure II for all variants). Data were drawn from METASTROKE and CARDIoGRAM.