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Reviews of "Genetic association analysis of SARS-CoV-2 infection in 455,838 UK Biobank participants"

Reviewers: Jonathan Fischer (University of Florida) | 📗📗📗📗◻️ • Giuseppe Novelli (University of Rome Tor Vergata) | 📗📗📗📗◻️

Published onDec 09, 2020
Reviews of "Genetic association analysis of SARS-CoV-2 infection in 455,838 UK Biobank participants"
key-enterThis Pub is a Review of
Genetic association analysis of SARS-CoV-2 infection in 455,838 UK Biobank participants
Description

ABSTRACT Background Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes Coronavirus disease-19 (COVID-19), a respiratory illness with influenza-like symptoms that can result in hospitalization or death. We investigated human genetic determinants of COVID-19 risk and severity in 455,838 UK Biobank participants, including 2,003 with COVID-19.Methods We defined eight COVID-19 phenotypes (including risks of infection, hospitalization and severe disease) and tested these for association with imputed and exome sequencing variants.Results We replicated prior COVID-19 genetic associations with common variants in the 3p21.31 (in LZTFL1) and 9q34.2 (in ABO) loci. The 3p21.31 locus (rs11385942) was associated with disease severity amongst COVID-19 cases (OR=2.2, P=3×10−5), but not risk of SARS-CoV-2 infection without hospitalization (OR=0.89, P=0.25). We identified two loci associated with risk of infection at P<5×10−8, including a missense variant that tags the ε4 haplotype in APOE (rs429358; OR=1.29, P=9×10−9). The association with rs429358 was attenuated after adjusting for cardiovascular disease and Alzheimer’s disease status (OR=1.15, P=0.005). Analyses of rare coding variants identified no significant associations overall, either exome-wide or with (i) 14 genes related to interferon signaling and reported to contain rare deleterious variants in severe COVID-19 patients; (ii) 36 genes located in the 3p21.31 and 9q34.2 GWAS risk loci; and (iii) 31 additional genes of immunologic relevance and/or therapeutic potential.Conclusions Our analyses corroborate the association with the 3p21.31 locus and highlight that there are no rare protein-coding variant associations with effect sizes detectable at current sample sizes. Our full analysis results are publicly available, providing a substrate for meta-analysis with results from other sequenced COVID-19 cases as they become available. Association results are available at https://rgc-covid19.regeneron.com.

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Summary of Reviews: The authors looked for the genetic loci of COVID-19 risk and severity in the UK biobank. Further studies are needed to pinpoint bona fide loci associated with COVID19 severity and susceptibility, though this study method is deemed reliable by reviewers.

Reviewer 1 (Jonathan Fischer) | 📗📗📗📗◻️

Reviewer 2 (Giuseppe Novelli) | 📗📗📗📗◻️

RR:C19 Strength of Evidence Scale Key

📕 ◻️◻️◻️◻️ = Misleading

📙📙 ◻️◻️◻️ = Not Informative

📒📒📒 ◻️◻️ = Potentially Informative

📗📗📗📗◻️ = Reliable

📘📘📘📘📘 = Strong

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