Rare Missense Functional Variants at COL4A1 and COL4A2 in Sporadic Intracerebral Hemorrhage.
Rare Missense Functional Variants at COL4A1 and COL4A2 in Sporadic Intracerebral Hemorrhage.
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DOI：
10.1212/wnl.0000000000012227
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发表时间：
2021-07-19
期刊：
影响因子：
9.9
通讯作者：
Anderson CD
中科院分区：
文献类型：
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作者：
Chung J;Hamilton G;Kim M;Marini S;Montgomery B;Henry J;Cho AE;Brown DL;Worrall BB;Meschia JF;Silliman SL;Selim M;Tirschwell DL;Kidwell CS;Kissela B;Greenberg SM;Viswanathan A;Goldstein JN;Langefeld CD;Rannikmae K;Sudlow CLM;Samarasekera N;Rodrigues M;Al-Shahi Salman R;Prendergast JGD;Harris SE;Deary I;Woo D;Rosand J;Van Agtmael T;Anderson CD
为了检测COL 4A 1和COL 4A 2中罕见错义变异的遗传贡献，其中常见变异与散发性脑出血（ICH）遗传相关，我们对散发性ICH风险的多个测序数据进行了罕见变异分析。我们在2,133名个体中进行了13 q34处559 Kbp的测序，包括COL 4A 1和COL 4A 2（1，055例ICH病例; 1，078例对照），美国和1，381例个体脑出血192例; 1，189名对照），随后进行序列注释、功能影响预测、遗传关联测试，和计算机热力学建模。我们在散发性ICH中鉴定了107种罕见的非同义变异，其中2种错义变异rs 138269346（COL 4A 1 I110 T）和rs 201716258（COL 4A 2 H203 L）被预测为高度功能性的，并且发生在多个ICH病例中，但不在基于美国队列的对照中。在苏格兰ICH患者中也存在rs 201716258的次要等位基因，在2名有高血压和心肌梗死病史的无ICH对照中观察到rs 138269346。Rs 138269346与非脑叶性ICH风险名义上相关（p = 0.05），但与脑叶性ICH无关（p = 0.08），而rs 201716258与ICH亚型之间的相关性不显著（p > 0.12）。基于次要等位基因频率（欧洲人群中<0.00035）、预测的功能影响（有害或可能具有损伤性）和计算机模拟研究（胶原蛋白的物理长度和热稳定性显著改变），认为这两种变体具有致病性。我们鉴定了与散发性ICH相关的COL 4A 1/A2中罕见的错义变体。我们的注释和模拟研究表明，这些变体是高度功能性的，并可能代表翻译后续的目标。
To test the genetic contribution of rare missense variants in COL4A1 and COL4A2 in which common variants are genetically associated with sporadic intracerebral hemorrhage (ICH), we performed rare variant analysis in multiple sequencing data for the risk for sporadic ICH. We performed sequencing across 559 Kbp at 13q34 including COL4A1 and COL4A2 among 2,133 individuals (1,055 ICH cases; 1,078 controls) in United States–based and 1,381 individuals (192 ICH cases; 1,189 controls) from Scotland-based cohorts, followed by sequence annotation, functional impact prediction, genetic association testing, and in silico thermodynamic modeling. We identified 107 rare nonsynonymous variants in sporadic ICH, of which 2 missense variants, rs138269346 (COL4A1I110T) and rs201716258 (COL4A2H203L), were predicted to be highly functional and occurred in multiple ICH cases but not in controls from the United States–based cohort. The minor allele of rs201716258 was also present in Scottish patients with ICH, and rs138269346 was observed in 2 ICH-free controls with a history of hypertension and myocardial infarction. Rs138269346 was nominally associated with nonlobar ICH risk (p = 0.05), but not with lobar ICH (p = 0.08), while associations between rs201716258 and ICH subtypes were nonsignificant (p > 0.12). Both variants were considered pathogenic based on minor allele frequency (<0.00035 in European populations), predicted functional impact (deleterious or probably damaging), and in silico modeling studies (substantially altered physical length and thermal stability of collagen). We identified rare missense variants in COL4A1/A2 in association with sporadic ICH. Our annotation and simulation studies suggest that these variants are highly functional and may represent targets for translational follow-up.