Association of common genetic variants with brain microbleeds

Abstract

<h3>Objective</h3> To identify common genetic variants associated with the presence of brain microbleeds (BMBs). <h3>Methods</h3> 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 <i>APOE</i> ε2 and ε4 alleles on BMB counts. We also related previously identified cerebral small vessel disease variants to BMBs. <h3>Results</h3> 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 <i>APOE</i> region reached genome-wide significance for its association with BMB (lead <i>single nucleotide polymorphism</i> rs769449; odds ratio [OR]_{any BMB} [95% confidence interval (CI)] 1.33 [1.21–1.45]; <i>p</i> = 2.5 × 10⁻¹⁰). <i>APOE</i> ε4 alleles were associated with strictly lobar (OR [95% CI] 1.34 [1.19–1.50]; <i>p</i> = 1.0 × 10⁻⁶) but not with mixed BMB counts (OR [95% CI] 1.04 [0.86–1.25]; <i>p</i> = 0.68). <i>APOE</i> 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. <h3>Conclusions</h3> Genetic variants in the <i>APOE</i> region are associated with the presence of BMB, most likely due to the <i>APOE</i> 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.