Integrative Genomics Analysis Reveals a Novel 21q22.11 Locus Contributing to Susceptibility of COVID-19

The systematic identification of host genetic risk factors is essential for the understanding and treatment of COVID-19. By performing a meta-analysis of two independent genome-wide association (GWAS) summary datasets (N = 680,128), a novel locus at 21q22.11 was identified to be associated with COVID-19 infection (rs9976829 in IFNAR2 and upstream of IL10RB , OR = 1.16, 95% CI = 1.09 - 1.23, P = 2.57×10−6). The rs9976829 represents a strong splicing quantitative trait locus (sQTL) for both IFNAR2 and IL10RB genes, especially in lung tissue (P 1.8×10−24). Gene-based association analysis also found IFNAR2 was significantly associated with COVID-19 infection (P = 2.58×10−7). Integrative genomics analysis of combining GWAS with eQTL data showed the expression variations of IFNAR2 and IL10RB have prominent effects on COVID-19 in various types of tissues, especially in lung tissue. The majority of IFNAR2 -expressing cells were dendritic cells (40%) and plasmacytoid dendritic cells (38.5%), and IL10RB -expressing cells were mainly nonclassical monocytes (29.6%). IFNAR2 and IL10RB are targeted by several interferons-related drugs. Together, our results uncover 21q22.11 as a novel susceptibility locus for COVID-19, in which individuals with G alleles of rs9976829 have a higher probability of COVID-19 susceptibility than those with non-G alleles. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by the National Natural Science Foundation of China (61871294 to J.S., 81501852 to N.W.), and Science Foundation of Zhejiang Province (LR19C060001 to J.S). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: GWAS summary data of all participants used in the current study were downloaded from the public databases, which have been approved by the relevant committees in the original articles All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All the GWAS summary statistics used in this study can be accessed in the official websites ([www.covid19hg.org/results][1] and [www.c19-genetics.eu][2]). The GTEx eQTL data (version 8) were downloaded from Zenodo repository (). All analysis code in the Methods is available in a publicly available GitHub repository at [https://github.com/YukuanHuang/Host\_genetics\_for_COVID-19][3]. [1]: https://www.covid19hg.org/results [2]: https://www.c19-genetics.eu [3]: https://github.com/YukuanHuang/Host_genetics_for_COVID-19