Genome-wide meta-analysis identifies 3 novel loci associated with stroke

Abstract

We conducted a European-only and transancestral genome-wide association meta-analysis in 72,147 stroke patients and 823,869 controls using data from UK Biobank (UKB) and the MEGASTROKE consortium. We identified an exonic polymorphism in NOS3 (rs1799983, p.Glu298Asp; p = 2.2E-8, odds ratio [OR] = 1.05, 95% confidence interval [CI] = 1.04-1.07) and variants in an intron of COL4A1 (rs9521634; p = 3.8E-8, OR = 1.04, 95% CI = 1.03-1.06) and near DYRK1A (rs720470; p = 6.1E-9, OR = 1.05, 95% CI = 1.03-1.07) at genome-wide significance for stroke. Effect sizes of known stroke loci were highly correlated between UKB and MEGASTROKE. Using Mendelian randomization, we further show that genetic variation in the nitric oxide synthase-nitric oxide pathway in part affects stroke risk via variation in blood pressure. Ann Neurol 2018;84:934-939.

Figure 1

Manhattan plot and regional association plots for the 3 novel risk loci identified in the current study. (A) Manhattan plot for any stroke in the transancestral meta‐analysis. The dotted line marks the threshold of genome‐wide significance. Novel loci are marked on the top. Note that NOS3 reached genome‐wide significance in the European‐only analysis. (B–D) Regional association plots for lead variants at the 3 novel loci: (B) NOS3, (C) COL4A1, and (D) DYRK1A. Shown is the region for the top signal ± 500 kb. The y‐axis represents the &minus;log(p value) from the European‐only fixed‐effects genome‐wide association study (GWAS) meta‐analysis (NOS3) or transancestral fixed‐effects GWAS meta‐analysis (COL4A1 and DYRK1A). Variants in linkage disequilibrium with the lead variant are shown in red (r ² > 0.6), orange (r ² > 0.4), yellow (r ² > 0.2), and gray (r ² < 0.2). OR = odds ratio; RAF = risk allele frequency.

Figure 2

Association of common variants in the nitric oxide synthase–nitric oxide (NOS‐NO) signaling pathway with blood pressure and with any stroke. For each single nucleotide polymorphism in the NOS‐NO signaling pathway, the effect for (A) systolic blood pressure (SBP) and (B) diastolic blood pressure (DBP) is displayed on the x‐axis and the odds ratio for any stroke from the European‐only analysis is displayed on the y‐axis together with their respective standard errors. The solid and dashed lines display the inverse variance weighted (IVW) effect estimate and 95% confidence interval (CI), respectively. Estimates for SBP and DBP were derived from UKB. Estimates for stroke were derived from inverse variance fixed effects meta‐analyses of MEGASTROKE and UK Biobank.