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

<p><strong>Objective:</strong> To identify common genetic variants associated with the presence of brain microbleeds (BMB).</p> <p><strong>Methods:</strong> 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 <em>APOE</em> ε2 and ε4 alleles on BMB counts. We also related previously identified cerebral small vessel disease variants to BMB.</p> <p><strong>Results: </strong>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 <em>APOE</em> region reached genome-wide significance for its association with BMB (lead SNP rs769449; OR_{any BMB} (95% CI)=1.33 (1.21-1.45); p=2.5x10-10). <em>APOE</em> 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). <em>APOE</em> 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.</p> <p><strong>Conclusions: </strong>Genetic variants in the <em>APOE</em> region are associated with the presence of BMB, most likely due to the <em>APOE</em> 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.</p>