Novel COVID-19 phenotype definitions reveal phenotypically distinct patterns of genetic association and protective effects

Multiple large COVID-19 genome-wide association studies (GWAS) have identified reproducible genetic associations indicating that some infection susceptibility and severity risk is heritable.^1-5 Most of these studies ascertained COVID-19 cases in medical clinics and hospitals, which can lead to an overrepresentation of cases with severe outcomes, such as hospitalization, intensive care unit admission, or ventilation. Here, we demonstrate the utility and validity of deep phenotyping with self-reported outcomes in a population with a large proportion of mild and subclinical cases. Using these data, we defined eight different phenotypes related to COVID-19 outcomes: four that align with previously studied COVID-19 definitions and four novel definitions that focus on susceptibility given exposure, mild clinical manifestations, and an aggregate score of symptom severity. We assessed replication of 13 previously identified COVID-19 genetic associations with all eight phenotypes and found distinct patterns of association, most notably related to the chr3/SLC6A20/LZTFL1 and chr9/ABO regions. We then performed a discovery GWAS, which suggested some novel phenotypes may better capture protective associations and also identified a novel association in chr11/GALNT18 that reproduced in two fully independent populations.