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 ε2 and ε4 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 ε4 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 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 APOE region are associated with the
presence of BMB, most likely due to the APOE ε4 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.