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 (BMB). 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. BMB were rated on susceptibility-weighted or T2*-weighted gradient echo magnetic resonance imaging 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 APOE e2 and e4 alleles on BMB counts. We also related previously identified cerebral small vessel disease variants to BMB. Results BMB 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 APOE region reached genome-wide significance for its association with BMB (lead SNP rs769449; ORany BMB (95% CI)=1.33 (1.21-1.45); p=2.5x10-10). APOE e4 alleles were associated with strictly lobar (OR (95% CI)=1.34 (1.19-1.50); p=1.0x10-6) but not with mixed BMB counts (OR (95% CI)=1.04 (0.86-1.25); p=0.68). APOE e2 alleles did not show associations with BMB counts. Variants previously related to deep intracerebral haemorrhage and lacunar stroke, and a risk score of cerebral white matter hyperintensity variants, were associated with BMB. Conclusions Genetic variants in the APOE region are associated with the presence of BMB, most likely due to the APOE e4 allele count related to a higher number of strictly lobar BMB. Genetic predisposition to small vessel disease confers risk of BMB, indicating genetic overlap with other cerebral small vessel disease markers.