Association of common genetic variants with brain microbleeds
Maria J. Knol, Dongwei Lu, Matthew Traylor, Hieab H.H. Adams, José Rafael J Romero, Albert V. Smith, Myriam Fornage, Edith Hofer, Junfeng Liu, Isabel C. Hostettler, Michelle Luciano, Stella Trompet, Anne‐Katrin Giese, Saima Hilal, Erik B. van den Akker, Dina Vojinović, Shuo Li, Sigurður Sigurðsson, Sven J. van der Lee, Clifford R. Jack, Duncan Wilson, Pınar Yilmaz, Claudia L. Satizábal, David C. Liewald, Jeroen van der Grond, Christopher Chen, Yasaman Saba, Aad van der Lugt, Mark E. Bastin, B. Gwen Windham, Ching‐Yu Cheng, Lukas Pirpamer, Kejal Kantarci, Jayandra J. Himali, Qiong Yang, Zoë Morris, Alexa Beiser, Daniel J. Tozer, Meike W. Vernooij, Najaf Amin, Marian Beekman, Jia Yu Koh, David J. Stott, Henry Houlden, Reinhold Schmidt, Rebecca F. Gottesman, Andrew D. MacKinnon, Charles DeCarli, Vilmundur Guðnason, Ian J. Deary, Cornelia M. van Duijn, P. Eline Slagboom, Tien Yin Wong, Natalia S. Rost, J. Wouter Jukema, Thomas H. Mosley, David J. Werring, Helena Schmidt, Joanna M. Wardlaw, M. Arfan Ikram, Sudha Seshadri, Lenore J. Launer, Hugh S. Markus, for the Alzheimer's Disease Neuroimaging Initiative
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]<sub>any BMB</sub> [95% confidence interval (CI)] 1.33 [1.21–1.45]; <i>p</i> = 2.5 × 10<sup>−10</sup>). <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<sup>−6</sup>) 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.