Initial whole-genome sequencing and analysis of the host genetic contribution to COVID-19 severity and susceptibility.
Initial whole-genome sequencing and analysis of the host genetic contribution to COVID-19 severity and susceptibility.
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宿主遗传对 COVID-19 严重程度和易感性影响的初步全基因组测序和分析
DOI：
10.1038/s41421-020-00231-4
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发表时间：
2020-11-10
期刊：
影响因子：
33.5
通讯作者：
Liu L
中科院分区：
文献类型：
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作者：
Wang F;Huang S;Gao R;Zhou Y;Lai C;Li Z;Xian W;Qian X;Li Z;Huang Y;Tang Q;Liu P;Chen R;Liu R;Li X;Tong X;Zhou X;Bai Y;Duan G;Zhang T;Xu X;Wang J;Yang H;Liu S;He Q;Jin X;Liu L
COVID-19大流行在短时间内导致全球数百万人感染，数十万人死亡。患者在临床和实验室表现以及疾病严重程度方面表现出极大的多样性。尽管如此，很少有人知道宿主的遗传贡献所观察到的个体间表型变异。在这里，我们报告了第一个在中国人群中进行的宿主遗传学研究，通过对来自深圳市第三人民医院的332名按不同严重程度分类的COVID-19患者进行深度测序和分析。在总共2220万个遗传变异中，我们在校正潜在混杂因素后，在五个严重程度组（包括无症状、轻度、中度、重度和危重病患者）中进行了单变异和基于基因的关联检验。系谱分析表明，GOLGA 3和DPP 7中功能丧失变体的潜在单基因效应用于重症和无症状疾病的证明。全基因组关联研究表明，与严重程度相关的最显著基因位点位于参与IL-1信号通路的TMEM 189-UBE 2 V1。影响TMPRSS 2蛋白稳定性的p.Val197Met错义变体在重度患者中显示出与轻度和一般人群相比降低的等位基因频率。我们发现HLA-A*11：01、B*51：01和C*14：02等位基因显著倾向于患者的最差结果。这项对中国患者的初步基因组研究为COVID-19患者群体之间的表型差异提供了遗传学见解，并突出了可能有助于指导遏制疫情的有针对性的努力的基因和变异。该研究的局限性和优势也进行了审查，以指导未来的国际努力，阐明COVID-19和其他传染性和复杂疾病的宿主-病原体相互作用的遗传结构。
The COVID-19 pandemic has accounted for millions of infections and hundreds of thousand deaths worldwide in a short-time period. The patients demonstrate a great diversity in clinical and laboratory manifestations and disease severity. Nonetheless, little is known about the host genetic contribution to the observed interindividual phenotypic variability. Here, we report the first host genetic study in the Chinese population by deeply sequencing and analyzing 332 COVID-19 patients categorized by varying levels of severity from the Shenzhen Third People’s Hospital. Upon a total of 22.2 million genetic variants, we conducted both single-variant and gene-based association tests among five severity groups including asymptomatic, mild, moderate, severe, and critical ill patients after the correction of potential confounding factors. Pedigree analysis suggested a potential monogenic effect of loss of function variants in GOLGA3 and DPP7 for critically ill and asymptomatic disease demonstration. Genome-wide association study suggests the most significant gene locus associated with severity were located in TMEM189–UBE2V1 that involved in the IL-1 signaling pathway. The p.Val197Met missense variant that affects the stability of the TMPRSS2 protein displays a decreasing allele frequency among the severe patients compared to the mild and the general population. We identified that the HLA-A*11:01, B*51:01, and C*14:02 alleles significantly predispose the worst outcome of the patients. This initial genomic study of Chinese patients provides genetic insights into the phenotypic difference among the COVID-19 patient groups and highlighted genes and variants that may help guide targeted efforts in containing the outbreak. Limitations and advantages of the study were also reviewed to guide future international efforts on elucidating the genetic architecture of host–pathogen interaction for COVID-19 and other infectious and complex diseases.
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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.
影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
9.8
作者：
Hammer C;Begemann M;McLaren PJ;Bartha I;Michel A;Klose B;Schmitt C;Waterboer T;Pawlita M;Schulz TF;Ehrenreich H;Fellay J
通讯作者：
Fellay J
影响因子：
14.9
作者：
Buniello, Annalisa;MacArthur, Jacqueline A. L.;Parkinson, Helen
通讯作者：
Parkinson, Helen
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
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