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

Multiple large COVID-19 genome-wide association studies (GWAS) have identified reproducible genetic associations indicating that some infection susceptibility and severity risk is heritable. 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.

Common genetic variants identify therapeutic targets for COVID-19 and individuals at high risk of severe disease (preprint)

The need to identify and effectively treat COVID-19 cases at highest risk for severe disease is critical. We identified seven common genetic variants (three novel) that modulate COVID-19 susceptibility and severity, implicating IFNAR2, CCHCR1, TCF19, SLC6A20 and the hyaluronan pathway as potential therapeutic targets. A high genetic burden was strongly associated with increased risk of hospitalization and severe disease among COVID-19 cases, especially among individuals with few known risk factors.

COVID-19 Susceptibility and Severity Risks in a Survey of Over 500,000 People (preprint)

The growing toll of the COVID-19 pandemic has heightened the urgency of identifying individuals most at risk of infection and severe outcomes, underscoring the need to assess susceptibility and severity patterns in large datasets. The AncestryDNA COVID-19 Study collected self-reported survey data on symptoms, outcomes, risk factors, and exposures for over 563,000 adult individuals in the U.S., including over 4,700 COVID-19 cases as measured by a self-reported positive nasal swab test. We observed significant associations between several risk factors and COVID-19 susceptibility and severity outcomes. Many of the susceptibility associations were accounted for by differences in known exposures; a notable exception was elevated susceptibility odds for males after adjusting for known exposures and age. We also leveraged the dataset to build risk models to robustly predict individualized COVID-19 susceptibility (area under the curve [AUC]=0.84) and severity outcomes including hospitalization and life-threatening critical illness amongst COVID-19 cases (AUC=0.87 and 0.90, respectively). The results highlight the value of self-reported epidemiological data at scale to provide public health insights into the evolving COVID-19 pandemic.

AncestryDNA COVID-19 Host Genetic Study Identifies Three Novel Loci (preprint)

Human infection with SARS-CoV-2, the causative agent of COVID-19, leads to a remarkably diverse spectrum of outcomes, ranging from asymptomatic to fatal. Recent reports suggest that both clinical and genetic risk factors may contribute to COVID-19 susceptibility and severity. To investigate genetic risk factors, we collected over 500,000 COVID-19 survey responses between April and May 2020 with accompanying genetic data from the AncestryDNA database. We conducted sex-stratified and meta-analyzed genome-wide association studies (GWAS) for COVID-19 susceptibility (positive nasopharyngeal swab test, ncases=2,407) and severity (hospitalization, ncases=250). The severity GWAS replicated associations with severe COVID-19 near ABO and SLC6A20 (P<0.05). Furthermore, we identified three novel loci with P<5x10-8. The strongest association was near IVNS1ABP, a gene involved in influenza virus replication, and was associated only in males. The other two novel loci harbor genes with established roles in viral replication or immunity: SRRM1 and the immunoglobulin lambda locus. We thus present new evidence that host genetic variation likely contributes to COVID-19 outcomes and demonstrate the value of large-scale, self-reported data as a mechanism to rapidly address a health crisis.