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

Published on Sep 10, 2020in Neurology8.77
· DOI :10.1212/WNL.0000000000010852
Maria J. Knol6
Estimated H-index: 6
(EUR: Erasmus University Rotterdam),
Dongwei Lu (University of Cambridge)+ 60 AuthorsAlzheimer’s Disease Neuroimaging Initiative29
Estimated H-index: 29
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.
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