Whole genome sequence meta-analyses reveal common and rare genetic associations with critical COVID-19

In susceptible patients, COVID-19 causes life-threatening disease driven by immune-mediated inflammatory lung injury. We have previously shown that multiple common host genetic variants are significantly associated with susceptibility to critical Covid-19, ^1;2;3 and in one case, we demonstrated that such variants can inform development of new, effective drug treatment ^1;4 . Here we report an association analysis of whole-genome sequences (WGS) from 11,423 cases from the GenOMICC study and 60,628 controls, together with meta-analyses with available genome-wide data (Fig. 1). We identify a rare association signal at SLC50A1 , primarily driven by a missense variant rs147850817 (1:155138217:G:T, Arg201Leu) that may interfere with transport function, and we identify four common association signals near ARF1, ZNF462, KLF13 and MVP genes. Finally, we build a WGS-derived polygenic risk score (PRS) for critical Covid-19, which offers only marginal improvement in risk estimation for the general population but may provide clinically-valuable discrimination for extreme susceptibility.