Abstract
Background: Despite a high heritability, only few stroke risk genes are known. Genetic association studies performed in a hospital-based setting may fail to detect genes modulating both stroke susceptibility and severity, given early deaths at the acute stage. This selection bias is avoided when studying incident stroke in a population-based setting. Methods: We conducted a meta-analysis of genome-wide association studies of incident stroke in 11 community-based longitudinal studies from the Cohorts of Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Genome-wide Cox regressions were performed adjusting for age, gender and population substructure, using 1000GpIv3 imputed genotypes. Results were combined using inverse variance weighted meta-analysis. Results: The study sample comprised 65,204 participants (71.5% women) of European ancestry, aged 66.2±8.0 years at DNA draw, followed up for 10.8±3.8 years. In 11 studies, 3,389 participants developed incident stroke, and in 8 studies, 2,223 developed incident ischemic stroke (IS): 531 cardioembolic [CE] and 1,576 atherothrombotic [AT]. The most significant association with incident stroke was for a novel variant on chr9p23 (MAF=0.35), HR=1.15 [95%CI:1.09[[Unable to Display Character: &#8210;]]1.21], p=8.5х10-8: p=2.54x10-5 for IS; 1.19x10-4, AT-IS; and 0.019, CE-IS. Associations were in the same direction for all participating studies, and 5 additional SNPs in this locus reached p<10-6. The most significant association with incident IS was for rs11833579 [NINJ2], HR=1.21[1.13[[Unable to Display Character: &#8210;]]1.30], p=2.1х10-7, but p-random-effects=9.54x10-3 (p-heterogeneity=0.02, I2=57.9%). We replicated published associations for CE-IS (rs6843082-G [PITX2], HR=1.30[1.13-1.49], p=1.95x10-4) and for large artery stroke with AT-IS (rs2107595-A [HDAC9], HR=1.13[1.03[[Unable to Display Character: &#8210;]]1.24], p=0.012) Conclusion: In the largest GWAS of incident stroke, we detected one novel association with all stroke, requiring confirmation in independent samples. Expansion of the discovery sample and replication of findings are planned in the coming months. Detecting genetic variants associated with incident stroke may provide important clues for understanding pathways involved in stroke susceptibility and tolerance to acute vascular brain injury.
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