Association of common genetic variants with brain microbleeds: A genome-wide association study.

OBJECTIVE: To identify common genetic variants associated with the presence of brain microbleeds (BMBs).

METHODS: We performed genome-wide association studies in 11 population-based cohort studies and 3 case-control or case-only stroke cohorts. Genotypes were imputed to the Haplotype Reference Consortium or 1000 Genomes reference panel. BMBs were rated on susceptibility-weighted or T2*-weighted gradient echo MRI sequences, and further classified as lobar or mixed (including strictly deep and infratentorial, possibly with lobar BMB). In a subset, we assessed the effects of ε2 and ε4 alleles on BMB counts. We also related previously identified cerebral small vessel disease variants to BMBs.

RESULTS: BMBs were detected in 3,556 of the 25,862 participants, of which 2,179 were strictly lobar and 1,293 mixed. One locus in the region reached genome-wide significance for its association with BMB (lead rs769449; odds ratio [OR] [95% confidence interval (CI)] 1.33 [1.21-1.45]; = 2.5 × 10). ε4 alleles were associated with strictly lobar (OR [95% CI] 1.34 [1.19-1.50]; = 1.0 × 10) but not with mixed BMB counts (OR [95% CI] 1.04 [0.86-1.25]; = 0.68). ε2 alleles did not show associations with BMB counts. Variants previously related to deep intracerebral hemorrhage and lacunar stroke, and a risk score of cerebral white matter hyperintensity variants, were associated with BMB.

CONCLUSIONS: Genetic variants in the region are associated with the presence of BMB, most likely due to the ε4 allele count related to a higher number of strictly lobar BMBs. Genetic predisposition to small vessel disease confers risk of BMB, indicating genetic overlap with other cerebral small vessel disease markers.