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][1]-[5][2] 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. ### Competing Interest Statement The authors declare competing financial interests authors affiliated with AncestryDNA are employed by Ancestry and may have equity in Ancestry. ### Funding Statement No external funding was received for this study. ### 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: All data for this research project were from subjects who provided prior informed consent to participate in AncestryDNAs Human Diversity Project, as reviewed and approved by our external institutional review board, Advarra (formerly Quorum). All data were de-identified prior to use. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.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 This study replicates findings by large consortia, for which full summary statistics can be found at https://rgc-covid19.regeneron.com and https://www.covid19hg.org/results/. [1]: #ref-1 [2]: #ref-5