Genetic variation at 16q24.2 is associated with small vessel stroke.
Genetic variation at 16q24.2 is associated with small vessel stroke.
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DOI：
10.1002/ana.24840
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发表时间：
2017-03
影响因子：
11.2
通讯作者：
International Stroke Genetics Consortium
中科院分区：
文献类型：
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作者：
Traylor M;Malik R;Nalls MA;Cotlarciuc I;Radmanesh F;Thorleifsson G;Hanscombe KB;Langefeld C;Saleheen D;Rost NS;Yet I;Spector TD;Bell JT;Hannon E;Mill J;Chauhan G;Debette S;Bis JC;Longstreth WT Jr;Ikram MA;Launer LJ;Seshadri S;METASTROKE, UK Young Lacunar DNA Study, NINDS Stroke Genetics Network, Neurology Working Group of the CHARGE Consortium;Hamilton-Bruce MA;Jimenez-Conde J;Cole JW;Schmidt R;Słowik A;Lemmens R;Lindgren A;Melander O;Grewal RP;Sacco RL;Rundek T;Rexrode K;Arnett DK;Johnson JA;Benavente OR;Wasssertheil-Smoller S;Lee JM;Pulit SL;Wong Q;Rich SS;de Bakker PI;McArdle PF;Woo D;Anderson CD;Xu H;Heitsch L;Fornage M;Jern C;Stefansson K;Thorsteinsdottir U;Gretarsdottir S;Lewis CM;Sharma P;Sudlow CL;Rothwell PM;Boncoraglio GB;Thijs V;Levi C;Meschia JF;Rosand J;Kittner SJ;Mitchell BD;Dichgans M;Worrall BB;Markus HS;International Stroke Genetics Consortium
全基因组关联研究（GWAS）已成功确定与卒中和卒中亚型的关联，但尚未确定仅与小血管卒中（SVS）的任何关联。SVS占所有缺血性卒中的四分之一，是脑小血管疾病的主要表现，是血管性认知障碍的主要原因。对神经系统特征的研究表明，年轻发病病例的遗传负担增加。我们通过进行发病年龄知情的GWAS Meta分析（包括大型年轻发病SVS人群）来利用这种增加的遗传负担，以确定与卒中的新相关性。我们使用了一个三阶段的发病年龄告知GWAS来识别与卒中相关的新的遗传变异。在确定与SVS相关的新位点后，我们评估了其对其他小血管疾病表型的影响，以及对附近基因的信使RNA（mRNA）表达的影响，以及对全血和胎儿大脑中附近CpG位点的DNA甲基化的影响。我们在4,203例患者和50,728例对照中发现了染色体16q24.2上的SVS相关性（比值比[OR; 95%置信区间{CI}] = 1.16 [1.10-1.22]; p = 3.2 × 10−9）。单核苷酸多态性（rs 12445022）也与脑白色物质高信号相关（OR [95% CI] = 1.10 [1.05-1.16]; p = 5.3 × 10−5; N = 3，670），但不是脑出血（OR [95% CI] = 0.97 [0.84-1.12]; p = 0.71; 1，545例病例，1，481例对照）。rs 12445022与动脉组织中ZCCHC 14的mRNA表达（p = 9.4 × 10−7）和全血中探针cg 16596957的DNA甲基化（p = 5.3 × 10−6）相关。16q24.2与SVS相关。该基因座与ZCCHC 14表达和DNA甲基化的关联表明该基因座通过调节元件的变化起作用。神经学年鉴2017;81：383-394
Genome‐wide association studies (GWAS) have been successful at identifying associations with stroke and stroke subtypes, but have not yet identified any associations solely with small vessel stroke (SVS). SVS comprises one quarter of all ischemic stroke and is a major manifestation of cerebral small vessel disease, the primary cause of vascular cognitive impairment. Studies across neurological traits have shown that younger‐onset cases have an increased genetic burden. We leveraged this increased genetic burden by performing an age‐at‐onset informed GWAS meta‐analysis, including a large younger‐onset SVS population, to identify novel associations with stroke. We used a three‐stage age‐at‐onset informed GWAS to identify novel genetic variants associated with stroke. On identifying a novel locus associated with SVS, we assessed its influence on other small vessel disease phenotypes, as well as on messenger RNA (mRNA) expression of nearby genes, and on DNA methylation of nearby CpG sites in whole blood and in the fetal brain. We identified an association with SVS in 4,203 cases and 50,728 controls on chromosome 16q24.2 (odds ratio [OR; 95% confidence interval {CI}] = 1.16 [1.10–1.22]; p = 3.2 × 10−9). The lead single‐nucleotide polymorphism (rs12445022) was also associated with cerebral white matter hyperintensities (OR [95% CI] = 1.10 [1.05–1.16]; p = 5.3 × 10−5; N = 3,670), but not intracerebral hemorrhage (OR [95% CI] = 0.97 [0.84–1.12]; p = 0.71; 1,545 cases, 1,481 controls). rs12445022 is associated with mRNA expression of ZCCHC14 in arterial tissues (p = 9.4 × 10−7) and DNA methylation at probe cg16596957 in whole blood (p = 5.3 × 10−6). 16q24.2 is associated with SVS. Associations of the locus with expression of ZCCHC14 and DNA methylation suggest the locus acts through changes to regulatory elements. Ann Neurol 2017;81:383–394