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

TitleAssociation of common genetic variants with brain microbleeds: A genome-wide association study.
Publication TypeJournal Article
Year of Publication2020
AuthorsKnol MJ, Lu D, Traylor M, Adams HHH, Romero JRafael J, 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, B Windham G, Cheng CYu, Pirpamer L, Kantarci K, Himali JJ, Yang Q, Morris Z, Beiser AS, Tozer DJ, Vernooij MW, Amin N, Beekman M, Koh JYu, Stott DJ, Houlden H, Schmidt R, Gottesman RF, MacKinnon AD, DeCarli C, Gudnason V, Deary IJ, van Duijn CM, P Slagboom E, Wong T Y, Rost NS, J Jukema W, Mosley TH, Werring DJ, Schmidt H, Wardlaw JM, M Ikram A, Seshadri S, Launer LJ, Markus HS
Corporate AuthorsAlzheimer's Disease Neuroimaging Initiative
Date Published2020 12 15
KeywordsAged, Aged, 80 and over, Alleles, Apolipoprotein E2, Apolipoprotein E4, Apolipoproteins E, Case-Control Studies, Cerebral Hemorrhage, Cerebral Small Vessel Diseases, Cohort Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk, White Matter

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 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 region reached genome-wide significance for its association with BMB (lead rs769449; odds ratio [OR] [95% confidence interval (CI)] 1.33 [1.21-1.45]; = 2.5 × 10). ε4 alleles were associated with strictly lobar (OR [95% CI] 1.34 [1.19-1.50]; = 1.0 × 10) but not with mixed BMB counts (OR [95% CI] 1.04 [0.86-1.25]; = 0.68). 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 region are associated with the presence of BMB, most likely due to the 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.

Alternate JournalNeurology
PubMed ID32913026
PubMed Central IDPMC7836652
Grant ListG9521010 / MRC_ / Medical Research Council / United Kingdom
MC_PC_14089 / MRC_ / Medical Research Council / United Kingdom
RG/16/4/32218 / BHF_ / British Heart Foundation / United Kingdom
MC_EX_MR/M009203/1 / MRC_ / Medical Research Council / United Kingdom
MR/R024065/1 / MRC_ / Medical Research Council / United Kingdom
MR/M009203/1 / MRC_ / Medical Research Council / United Kingdom