Trans-ethnic genome-wide association study of severe COVID-19

Wu, Peng; Ding, Lin; Li, Xiaodong; Liu, Siyang; Cheng, Fanjun; He, Qing; Xiao, Mingzhong; Wu, Ping; Hou, Hongyan; Jiang, Minghui; Long, Pinpin; Wang, Hao; Liu, Linlin; Qu, Minghan; Shi, Xian; Jiang, Qin; Mo, Tingting; Ding, Wencheng; Fu, Yu; Han, Shi; Huo, Xixiang; Zeng, Yingchun; Zhou, Yana; Zhang, Qing; Ke, Jia; Xu, Xi; Ni, Wei; Shao, Zuoyu; Wang, Jingzhi; Liu, Panhong; Li, Zilong; Jin, Yan; Zheng, Fang; Wang, Fang; Liu, Lei; Li, Wending; Liu, Kang; Peng, Rong; Xu, Xuedan; Lin, Yuhui; Gao, Hui; Shi, Limei; Geng, Ziyue; Mu, Xuanwen; Yan, Yu; Wang, Kai; Wu, Degang; Hao, Xingjie; Cheng, Shanshan; Qiu, Gaokun; Guo, Huan; Li, Kezhen; Chen, Gang; Sun, Ziyong; Lin, Xihong; Jin, Xin; Wang, Feng; Sun, Chaoyang; Wang, Chaolong

COVID-19 has caused numerous infections with diverse clinical symptoms. To identify human genetic variants contributing to the clinical development of COVID-19, we genotyped 1457 (598/859 with severe/mild symptoms) and sequenced 1141 (severe/mild: 474/667) patients of Chinese ancestry. We further incorporated 1401 genotyped and 948 sequenced ancestry-matched population controls, and tested genome-wide association on 1072 severe cases versus 3875 mild or population controls, followed by trans-ethnic meta-analysis with summary statistics of 3199 hospitalized cases and 897,488 population controls from the COVID-19 Host Genetics Initiative. We identified three significant signals outside the well-established 3p21.31 locus: an intronic variant in FOXP4-AS1 (rs1853837, odds ratio OR = 1.28, P = 2.51 × 10(−10), allele frequencies in Chinese/European AF = 0.345/0.105), a frameshift insertion in ABO (rs8176719, OR = 1.19, P = 8.98 × 10(−9), AF = 0.422/0.395) and a Chinese-specific intronic variant in MEF2B (rs74490654, OR = 8.73, P = 1.22 × 10(−8), AF = 0.004/0). These findings highlight an important role of the adaptive immunity and the ABO blood-group system in protection from developing severe COVID-19.