Initial Study of Human Genetic Contribution to COVID-19 Severity and Susceptibility

Wang, F.; Huang, S.; Gao, H.; Zhou, Y.; Lai, C.; Li, Z.; Xian, W.; Qian, X.; Huang, Y.; Tang, Q.; Liu, P.; Chen, R.; Liu, R.; Li, X.; Xin, T.; Xuan, Z.; Bai, Y.; Duan, G.; Zhang, T.; Xu, X.; Wang, J.; Yang, H.; Liu, S.; He, Q.; Jin, X.; Liu, L.

The COVID-19 pandemic has accounted for more than five million infections and hundreds of thousand deaths worldwide in the past six months. 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 inter-individual phenotypic variability. Here, we report the first host genetic study in China by deeply sequencing and analyzing the 332 COVID-19 patients categorized by varying levels of severity from the Shenzhen Third People's Hospital. Based on a total of 22.2 million genetic variants, we conducted both single-variant and gene-based association tests among the five severity groups including asymptomatic, mild, moderate, severe and critical ill patients after the correction of potential confounding factors. The most significant gene loci associated with severity is located in TMEM189-UBE2V1 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 also 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 study of Chinese patients provides a comprehensive view of the genetic 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 was 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.