Multiple large COVID‑19 genome-wide association studies (GWAS) have identified reproducible genetic associations indicating a genetic component to susceptibility and severity risk. Many of these previous 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 expanded definitions that focus on susceptibility given exposure, mild clinical manifestations, and an aggregate score of symptom severity. We assessed replication of 12 previously identified COVID‑19 genetic associations with all eight phenotypes in a trans-ancestry meta-analysis of European (EUR), Admixed Amerindian (LAT), Admixed African-European ... (Show More)

Multiple large COVID‑19 genome-wide association studies (GWAS) have identified reproducible genetic associations indicating a genetic component to susceptibility and severity risk. Many of these previous 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 expanded definitions that focus on susceptibility given exposure, mild clinical manifestations, and an aggregate score of symptom severity. We assessed replication of 12 previously identified COVID‑19 genetic associations with all eight phenotypes in a trans-ancestry meta-analysis of European (EUR), Admixed Amerindian (LAT), Admixed African-European (AA) cohorts, and found distinct patterns of association, most notably related to the chr3/SLC6A20/LZTFL1 and chr9/ABO regions. Additionally, we performed a genome-wide analysis, which suggested certain expanded phenotypes may capture more protective associations than the established phenotypes.

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