Association of common genetic variants with brain microbleeds: A genome-wide association study.
Knol MJ., Lu D., Traylor M., Adams HHH., Romero JRJ., Smith AV., Fornage M., Hofer E., Liu J., Hostettler IC., Luciano M., Trompet S., Giese A-K., Hilal S., van den Akker EB., Vojinovic D., Li S., Sigurdsson S., van der Lee SJ., Jack CR., Wilson D., Yilmaz P., Satizabal CL., Liewald DCM., van der Grond J., Chen C., Saba Y., van der Lugt A., Bastin ME., Windham BG., Cheng CY., Pirpamer L., Kantarci K., Himali JJ., Yang Q., Morris Z., Beiser AS., Tozer DJ., Vernooij MW., Amin N., Beekman M., Koh JY., Stott DJ., Houlden H., Schmidt R., Gottesman RF., MacKinnon AD., DeCarli C., Gudnason V., Deary IJ., van Duijn CM., Slagboom PE., Wong TY., Rost NS., Jukema JW., Mosley TH., Werring DJ., Schmidt H., Wardlaw JM., Ikram MA., Seshadri S., Launer LJ., Markus HS., Alzheimer's Disease Neuroimaging Initiative None.
OBJECTIVE: To identify common genetic variants associated with the presence of brain microbleeds (BMBs). 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. 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 APOE ε2 and ε4 alleles on BMB counts. We also related previously identified cerebral small vessel disease variants to BMBs. RESULTS: 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 APOE region reached genome-wide significance for its association with BMB (lead single nucleotide polymorphism rs769449; odds ratio [OR]any BMB [95% confidence interval (CI)] 1.33 [1.21-1.45]; p = 2.5 × 10-10). APOE ε4 alleles were associated with strictly lobar (OR [95% CI] 1.34 [1.19-1.50]; p = 1.0 × 10-6) 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 BMBs. Genetic predisposition to small vessel disease confers risk of BMB, indicating genetic overlap with other cerebral small vessel disease markers.