Whole-genome sequencing reveals host factors underlying critical COVID-19.
Whole-genome sequencing reveals host factors underlying critical COVID-19.
复制标题
全基因组测序揭示了关键COVID-19的宿主因素。
DOI：
10.1038/s41586-022-04576-6
复制
发表时间：
2022-07
期刊：
影响因子：
64.8
通讯作者：
中科院分区：
文献类型：
--
作者：
重症 COVID-19 是由免疫介导的炎症性肺损伤引起的。宿主遗传变异会影响感染 SARS-CoV-2 后需要重症监护或住院治疗的疾病的发展。 GenOMICC（重症监护死亡率遗传学）研究能够将重症患者的基因组与对照组的基因组进行比较，以发现潜在的疾病机制。在这里，我们对 7,491 名重症患者与 48,400 名对照者进行全基因组测序，发现并复制了 23 个显着易患重症 COVID-19 的独立变异。我们确定了 16 个新的独立关联，包括参与干扰素信号传导（IL10RB 和 PLSCR1）、白细胞分化（BCL11A）和血型抗原分泌状态（FUT2）的基因内的变异。利用全转录组关联和共定位来推断基因表达对疾病严重程度的影响，我们发现了与危重疾病有关的多个基因（包括膜翻转酶（ATP11A）表达减少和粘蛋白（MUC1）表达增加）的证据。孟德尔随机化提供了支持骨髓细胞粘附分子（SELE、ICAM5 和 CD209）和凝血因子 F8 因果作用的证据，所有这些都是潜在的药物靶标。我们的结果与 COVID-19 病理生理学的多成分模型大致一致，其中至少有两种不同的机制可能导致危及生命的疾病：无法控制病毒复制；或肺部炎症和血管内凝血的倾向增强。我们表明，危重疾病病例与人群对照之间的比较对于检测疾病的治疗相关机制非常有效。对 7,000 多名危重 COVID-19 患者进行全基因组测序、全转录组关联和精细定位分析，用于识别与 COVID-19 严重疾病相关的 16 个独立变异。
Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalization after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease. Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.
登录
查看更多内容
影响因子：
30.8
作者：
Bulik-Sullivan, Brendan K.;Loh, Po-Ru;Finucane, Hilary K.;Ripke, Stephan;Yang, Jian;Patterson, Nick;Daly, Mark J.;Price, Alkes L.;Neale, Benjamin M.
通讯作者：
Neale, Benjamin M.
XGR软件可增强对基因组摘要数据的解释，并通过应用于免疫特征说明。
影响因子：
12.3
作者：
Fang H;Knezevic B;Burnham KL;Knight JC
通讯作者：
Knight JC
影响因子：
16.6
作者：
Barbeira AN;Dickinson SP;Bonazzola R;Zheng J;Wheeler HE;Torres JM;Torstenson ES;Shah KP;Garcia T;Edwards TL;Stahl EA;Huckins LM;GTEx Consortium;Nicolae DL;Cox NJ;Im HK
通讯作者：
Im HK
影响因子：
30.8
作者：
Bernabeu, Elena;Canela-Xandri, Oriol;Tenesa, Albert
通讯作者：
Tenesa, Albert
影响因子：
5.2
作者：
Balduzzi, Sara;Ruecker, Gerta;Schwarzer, Guido
通讯作者：
Schwarzer, Guido