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Pan-ancestry exome-wide association analyses of COVID-19 outcomes in 586,157 individuals.

ABSTRACT: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a respiratory illness that can result in hospitalization or death. We used exome sequence data to investigate associations between rare genetic variants and seven COVID-19 outcomes in 586,157 individuals, including 20,952 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome wide or when specifically focusing on (1) 13 interferon pathway genes in which rare deleterious variants have been reported in individuals with severe COVID-19, (2) 281 genes located in susceptibility loci identified by the COVID-19 Host Genetics Initiative, or (3) 32 additional genes of immunologic relevance and/or therapeutic potential. Our analyses indicate there are no significant associations with rare protein-coding variants with detectable effect sizes at our current sample sizes. Analyses will be updated as additional data become available, and results are publicly available through the Regeneron Genetics Center COVID-19 Results Browser.

SUBMITTER: Kosmicki JA

PROVIDER: S-EPMC8173480 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Pan-ancestry exome-wide association analyses of COVID-19 outcomes in 586,157 individuals.

Kosmicki Jack A JA Horowitz Julie E JE Banerjee Nilanjana N Lanche Rouel R Marcketta Anthony A Maxwell Evan E Bai Xiaodong X Sun Dylan D Backman Joshua D JD Sharma Deepika D Kury Fabricio S P FSP Kang Hyun M HM O'Dushlaine Colm C Yadav Ashish A Mansfield Adam J AJ Li Alexander H AH Watanabe Kyoko K Gurski Lauren L McCarthy Shane E SE Locke Adam E AE Khalid Shareef S O'Keeffe Sean S Mbatchou Joelle J Chazara Olympe O Huang Yunfeng Y Kvikstad Erika E O'Neill Amanda A Nioi Paul P Parker Meg M MM Petrovski Slavé S Runz Heiko H Szustakowski Joseph D JD Wang Quanli Q Wong Emily E Cordova-Palomera Aldo A Smith Erin N EN Szalma Sandor S Zheng Xiuwen X Esmaeeli Sahar S Davis Justin W JW Lai Yi-Pin YP Chen Xing X Justice Anne E AE Leader Joseph B JB Mirshahi Tooraj T Carey David J DJ Verma Anurag A Sirugo Giorgio G Ritchie Marylyn D MD Rader Daniel J DJ Povysil Gundula G Goldstein David B DB Kiryluk Krzysztof K Pairo-Castineira Erola E Rawlik Konrad K Pasko Dorota D Walker Susan S Meynert Alison A Kousathanas Athanasios A Moutsianas Loukas L Tenesa Albert A Caulfield Mark M Scott Richard R Wilson James F JF Baillie J Kenneth JK Butler-Laporte Guillaume G Nakanishi Tomoko T Lathrop Mark M Richards J Brent JB Jones Marcus M Balasubramanian Suganthi S Salerno William W Shuldiner Alan R AR Marchini Jonathan J Overton John D JD Habegger Lukas L Cantor Michael N MN Reid Jeffrey G JG Baras Aris A Abecasis Goncalo R GR Ferreira Manuel A R MAR

American journal of human genetics 20210603 7

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a respiratory illness that can result in hospitalization or death. We used exome sequence data to investigate associations between rare genetic variants and seven COVID-19 outcomes in 586,157 individuals, including 20,952 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome wide or when specifically focusing on (1) 13 ...[more]

PMID: 34115965

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Project description:BackgroundVitamin D deficiency is more common among African-ancestry individuals and may be associated with adverse health outcomes. Vitamin D binding protein (VDBP) regulates concentrations of biologically active vitamin D.ObjectiveWe conducted genome-wide association study (GWAS) of VDBP and 25-hydroxyvitamin D among African-ancestry individuals.MethodsData were collected from 2,602 African American adults from the Southern Community Cohort Study (SCCS) and 6,934 African- or Caribbean-ancestry adults from the UK Biobank. Serum VDBP concentrations were available only in the SCCS and were measured by using the Polyclonal Human VDBP ELISA kit. Serum 25-hydroxyvitamin D concentrations for both study samples were measured by using Diasorin Liason, a chemiluminescent immunoassay. Participants were genotyped for single nucleotide polymorphisms (SNPs) with genome-wide coverage by using Illumina or Affymetrix platforms. Fine-mapping analysis was performed by using forward stepwise linear regression models including all variants with P value < 5 × 10-8 and within 250 kbps of a lead SNP.ResultsWe identified 4 loci notably associated with VDBP concentrations in the SCCS population: rs7041 (per allele β = 0.61 μg/mL, SE = 0.05, P = 1.4 × 10-48) and rs842998 (per allele β = 0.39 μg/mL, SE = 0.03, P = 4.0 × 10-31) in GC, rs8427873 (per allele β = 0.31 μg/mL, SE = 0.04, P = 3.0 × 10-14) near GC and rs11731496 (per allele β = 0.21 μg/mL, SE = 0.03, P = 3.6 × 10-11) in between GC and NPFFR2. In conditional analyses, which included the above-mentioned SNPs, only rs7041 remained notable (P = 4.1 × 10-21). SNP rs4588 in GC was the only GWAS-identified SNP associated with 25-hydroxyvitamin D concentration. Among UK Biobank participants: per allele β = -0.11 μg/mL, SE = 0.01, P = 1.5 × 10-13; in the SCCS: per allele β = -0.12 μg/mL, SE = 0.06, P = 2.8 × 10-02). rs7041 and rs4588 are functional SNPs that influence the binding affinity of VDBP to 25-hydroxyvitamin D.ConclusionsOur results were in line with previous studies conducted in European-ancestry populations, showing that GC, the gene that directly encodes for VDBP, would be important for VDBP and 25-hydroxyvitamin D concentrations. The current study extends our knowledge of the genetics of vitamin D in diverse populations.

Dataset Information

Pan-ancestry exome-wide association analyses of COVID-19 outcomes in 586,157 individuals.

Publications

Pan-ancestry exome-wide association analyses of COVID-19 outcomes in 586,157 individuals.

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