Association of common genetic variants with brain microbleeds: A genome-wide association study.
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Knol Maria J, Lu Dongwei, Traylor Matthew, Adams Hieab H H, Romero José Rafael J, Smith Albert V, Fornage Myriam, Hofer Edith, Liu Junfeng, Hostettler Isabel C, Luciano Michelle, Trompet Stella, Giese Anne-Katrin, Hilal Saima, van den Akker Erik B, Vojinovic Dina, Li Shuo, Sigurdsson Sigurdur, van der Lee Sven J, Jack Clifford R, Wilson Duncan, Yilmaz Pinar, Satizabal Claudia L, Liewald David C M, van der Grond Jeroen, Chen Christopher, Saba Yasaman, van der Lugt Aad, Bastin Mark E, Windham B Gwen, Cheng Ching Yu, Pirpamer Lukas, Kantarci Kejal, Himali Jayandra J, Yang Qiong, Morris Zoe, Beiser Alexa S, Tozer Daniel J, Vernooij Meike W, Amin Najaf, Beekman Marian, Koh Jia Yu, Stott David J, Houlden Henry, Schmidt Reinhold, Gottesman Rebecca F, MacKinnon Andrew D, DeCarli Charles, Gudnason Vilmundur, Deary Ian J, van Duijn Cornelia M, Slagboom P Eline, Wong Tien Yin, Rost Natalia S, Jukema J Wouter, Mosley Thomas H, Werring David J, Schmidt Helena, Wardlaw Joanna M, Ikram M Arfan, Seshadri Sudha, Launer Lenore J, Markus Hugh S, Alzheimer's Disease Neuroimaging Initiative
Аннотация
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.