COL4A2 is associated with lacunar ischemic stroke and deep ICH: Meta-analyses among 21,500 cases and 40,600 controls

Abstract

Objective: To determine whether common variants in familial cerebral small vessel disease (SVD) genes confer risk of sporadic cerebral SVD.

Methods: We meta-analyzed genotype data from individuals of European ancestry to determine associations of common single nucleotide polymorphisms (SNPs) in 6 familial cerebral SVD genes (COL4A1, COL4A2, NOTCH3, HTRA1, TREX1, and CECR1) with intracerebral hemorrhage (ICH) (deep, lobar, all; 1,878 cases, 2,830 controls) and ischemic stroke (IS) (lacunar, cardioembolic, large vessel disease, all; 19,569 cases, 37,853 controls). We applied data quality filters and set statistical significance thresholds accounting for linkage disequilibrium and multiple testing.

Results: A locus in COL4A2 was associated (significance threshold p < 3.5 × 10^-4) with both lacunar IS (lead SNP rs9515201: odds ratio [OR] 1.17, 95% confidence interval [CI] 1.11-1.24, p = 6.62 × 10^-8) and deep ICH (lead SNP rs4771674: OR 1.28, 95% CI 1.13-1.44, p = 5.76 × 10^-5). A SNP in HTRA1 was associated (significance threshold p < 5.5 × 10^-4) with lacunar IS (rs79043147: OR 1.23, 95% CI 1.10-1.37, p = 1.90 × 10^-4) and less robustly with deep ICH. There was no clear evidence for association of common variants in either COL4A2 or HTRA1 with non-SVD strokes or in any of the other genes with any stroke phenotype.

Conclusions: These results provide evidence of shared genetic determinants and suggest common pathophysiologic mechanisms of distinct ischemic and hemorrhagic cerebral SVD stroke phenotypes, offering new insights into the causal mechanisms of cerebral SVD.

Figure 1. COL4A2 regional association plots for (A) lacunar ischemic stroke, (B) deep ICH, and (C) HTRA1 regional association plot for lacunar ischemic stroke

Only SNPs passing the post–meta-analysis filters (heterogeneity I² < 50%, p > 0.001, ≥50% cases contributing data) are displayed. Red dashed lines mark the relevant Nyholt significance p thresholds. Dots mark individual SNPs with respect to their chromosomal position (x-axis) and p value for association between each SNP and phenotype (left y-axis). The SNP in purple is the most strongly associated (lead) SNP; linkage disequilibrium with this lead SNP determines the colors for other SNPs, as seen from the r² color coding on figure. Recombination rates (right y-axis), shown by the continuous blue lines, are measured as frequency of exchange per unit physical distance (centimorgan [cM]/mega base pair [Mb]). ICH = intracerebral hemorrhage; SNP = single nucleotide polymorphism.

Figure 2. Associations of COL4A2 and HTRA1 SNPs across all phenotypes

Diamonds represent pooled ORs across all case-control collections for each phenotype, with the line through the diamond showing its 95% CI. Associations significant at relevant Nyholt threshold are shown in red; nonsignificant associations with SVD phenotypes are shown in black; and nonsignificant associations with non-SVD phenotypes are shown in gray. CE = cardioembolic; CI = confidence interval; ICH = intracerebral hemorrhage; IS = ischemic stroke; LVD = large vessel disease; OR = odds ratio; SNP = single nucleotide polymorphism.