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

Abstract

INTRODUCTION PARAGRAPHMultiple 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.

Mapping the human genetic architecture of COVID-19 by worldwide meta-analysis

“…Our findings support the notion that some genetic variants, most notably at ABO and PPP1R15A loci, in addition to the aforementioned SLC6A20, might indeed impact susceptibility to infection rather than progression to a severe form of the disease once infected. Whilst our ability to draw definitive conclusions is impaired by incomplete capture of who has been infected with SARS-CoV-2, a recent study based on self-reported exposure to COVID-19 positive housemate and consequent development of the disease, support our findings 42 . Several of the loci reported here, as noted in previous publications 15,17 , intersect with well-known genetic variants that have established genetic associations.…”

Japan COVID-19 Task Force: a nation-wide consortium to elucidate host genetics of COVID-19 pandemic in Japan

“…We set the genome-wide association significance threshold of P < 5.0 × 10 -8 23 . We obtained the association of the DOCK2 variant (rs60200309) from the panancestry meta-analysis available at https://rgc-covid19.regeneron.com/ 24,25 . We obtained the meta-analysis results of the phenotype of “hospitalized COVID-19 vs COVID-19 negative or COVID-19 status unknown” with the largest case sample size.…”

“…We then looked up COVID-19 risk of the DOCK2 variant in different ancestries (3,138 hospitalized COVID-19 cases vs 891,375 controls from the pan-ancestry meta-analysis available at https://rgc-covid19.regeneron.com/) 24,25 . We observed the same directional effect with a marginal association signal (OR = 1.73, 95%CI = 0.95-3.15, P = 0.072, MAFCase = 0.0025, MAFControl = 0.0008; Supplementary Table 4).…”

The human genetic epidemiology of COVID-19

“…This is the most challenging phenotype to collect because viral exposure is difficult to trace. Roberts and colleagues from the AncestryDNA Science Team 37 have best attempted to capture susceptibility by comparing COVID-19 negative and positive individuals who had a housemate with a confirmed COVID-19 diagnosis. The COVID-19 Host Genetics Initiative (HGI) 38 used a simpler approach, comparing individuals who are COVID-19 positive versus population controls and named this phenotype ‘reported SARS-CoV-2 infection’.…”