Association of common genetic variants with brain microbleeds: A genome-wide association study.
Association of common genetic variants with brain microbleeds: A genome-wide association study.
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DOI：
10.1212/wnl.0000000000010852
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发表时间：
2020-12-15
期刊：
影响因子：
9.9
通讯作者：
Alzheimer's Disease Neuroimaging Initiative
中科院分区：
文献类型：
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作者：
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 AK;Hilal S;van den Akker EB;Vojinovic D;Li S;Sigurdsson S;van der Lee SJ;Jack CR Jr;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
确定与脑微出血（BMB）相关的常见遗传变异。我们在11项基于人群的队列研究和3项病例对照或仅病例卒中队列中进行了全基因组关联研究。基因型被输入到单倍型参考联盟或1000基因组参考组。BMB在磁敏感加权或T2* 加权梯度回波MRI序列上进行评级，并进一步分类为肺叶或混合型（包括严格的深部和幕下，可能伴有肺叶BMB）。在一个子集中，我们评估了APOE ε2和ε4等位基因对BMB计数的影响。我们还将先前发现的脑小血管疾病变异与BMB相关。在25，862名参与者中，有3，556人检测到BMB，其中2，179人为严格的肺叶，1，293人为混合型。APOE区域的一个基因座与BMB的关联达到了全基因组意义（主要单核苷酸多态性rs769449;比值比[OR]任何BMB [95%置信区间（CI）] 1.33 [1.21-1.45]; p = 2.5 × 10 - 10）。APOE ε4等位基因与严格的肺叶相关（OR [95% CI] 1.34 [1.19-1.50]; p = 1.0 × 10−6），但与混合BMB计数无关（OR [95% CI] 1.04 [0.86-1.25]; p = 0.68）。APOE ε2等位基因与BMB计数无相关性。先前与深部脑出血和腔隙性卒中相关的变异，以及脑白色高信号变异的风险评分，与BMB相关。APOE区域的遗传变异与BMB的存在相关，最可能是由于APOE ε4等位基因计数与更高数量的严格肺叶BMB相关。小血管疾病的遗传易感性赋予BMB的风险，表明与其他脑小血管疾病标志物的遗传重叠。
To identify common genetic variants associated with the presence of brain microbleeds (BMBs). 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. 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. 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.