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A Phenome-Wide Association Study of genes associated with COVID-19 severity reveals shared genetics with complex diseases in the Million Veteran Program.
Verma, Anurag; Tsao, Noah L; Thomann, Lauren O; Ho, Yuk-Lam; Iyengar, Sudha K; Luoh, Shiuh-Wen; Carr, Rotonya; Crawford, Dana C; Efird, Jimmy T; Huffman, Jennifer E; Hung, Adriana; Ivey, Kerry L; Levin, Michael G; Lynch, Julie; Natarajan, Pradeep; Pyarajan, Saiju; Bick, Alexander G; Costa, Lauren; Genovese, Giulio; Hauger, Richard; Madduri, Ravi; Pathak, Gita A; Polimanti, Renato; Voight, Benjamin; Vujkovic, Marijana; Zekavat, Seyedeh Maryam; Zhao, Hongyu; Ritchie, Marylyn D; Chang, Kyong-Mi; Cho, Kelly; Casas, Juan P; Tsao, Philip S; Gaziano, J Michael; O'Donnell, Christopher; Damrauer, Scott M; Liao, Katherine P.
  • Verma A; Corporal Michael Crescenz VA Medical Center, Philadelphia, Pennsylvania, United States of America.
  • Tsao NL; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
  • Thomann LO; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
  • Ho YL; Corporal Michael Crescenz VA Medical Center, Philadelphia, Pennsylvania, United States of America.
  • Iyengar SK; Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
  • Luoh SW; VA Boston Healthcare System, Boston, Massachusetts, United States of America.
  • Carr R; Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, Massachusetts, United States of America.
  • Crawford DC; Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, United States of America.
  • Efird JT; Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, United States of America.
  • Huffman JE; VA Portland Health Care System, Portland, Oregon, United States of America.
  • Hung A; Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, United States of America.
  • Ivey KL; Corporal Michael Crescenz VA Medical Center, Philadelphia, Pennsylvania, United States of America.
  • Levin MG; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
  • Lynch J; University of Washington, Division of Gastroenterology, Seattle, Washington, United States of America.
  • Natarajan P; Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, United States of America.
  • Pyarajan S; Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, Ohio, United States of America.
  • Bick AG; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio, United States of America.
  • Costa L; Cooperative Studies Program Epidemiology Center, Health Services Research and Development, DVAHCS (Duke University Affiliate), Durham, North Carolina, United States of America.
  • Genovese G; VA Boston Healthcare System, Boston, Massachusetts, United States of America.
  • Hauger R; Tennessee Valley Healthcare System (Nashville VA) & Vanderbilt University, Nashville, Tennessee, United States of America.
  • Madduri R; Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, Massachusetts, United States of America.
  • Pathak GA; South Australian Health and Medical Research Institute, Infection and Immunity Theme, Adelaide, South Australia, Australia.
  • Polimanti R; Harvard T.H. Chan School of Public Health, Department of Nutrition, Cambridge, Massachusetts, United States of America.
  • Voight B; Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
  • Vujkovic M; VA Informatics and Computing Infrastructure, VA Salt Lake City Health Care System, Salt Lake City, Utah, United States of America.
  • Zekavat SM; VA Boston Healthcare System, Boston, Massachusetts, United States of America.
  • Zhao H; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
  • Ritchie MD; Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of Harvard & MIT, Cambridge, Massachusetts, United States of America.
  • Chang KM; Harvard Medical School, Boston, Massachusetts, United States of America.
  • Cho K; VA Boston Healthcare System, Boston, Massachusetts, United States of America.
  • Casas JP; Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America.
  • Tsao PS; Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, Massachusetts, United States of America.
  • Gaziano JM; Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of Harvard & MIT, Cambridge, Massachusetts, United States of America.
  • O'Donnell C; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
  • Damrauer SM; Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.
  • Liao KP; Department of Psychiatry, University of California, San Diego, La Jolla, California; Center of Excellence for Stress and Mental Health, VA San Diego Healthcare System, San Diego, California, United States of America.
PLoS Genet ; 18(4): e1010113, 2022 04.
Article in English | MEDLINE | ID: covidwho-1817364
ABSTRACT
The study aims to determine the shared genetic architecture between COVID-19 severity with existing medical conditions using electronic health record (EHR) data. We conducted a Phenome-Wide Association Study (PheWAS) of genetic variants associated with critical illness (n = 35) or hospitalization (n = 42) due to severe COVID-19 using genome-wide association summary data from the Host Genetics Initiative. PheWAS analysis was performed using genotype-phenotype data from the Veterans Affairs Million Veteran Program (MVP). Phenotypes were defined by International Classification of Diseases (ICD) codes mapped to clinically relevant groups using published PheWAS methods. Among 658,582 Veterans, variants associated with severe COVID-19 were tested for association across 1,559 phenotypes. Variants at the ABO locus (rs495828, rs505922) associated with the largest number of phenotypes (nrs495828 = 53 and nrs505922 = 59); strongest association with venous embolism, odds ratio (ORrs495828 1.33 (p = 1.32 x 10-199), and thrombosis ORrs505922 1.33, p = 2.2 x10-265. Among 67 respiratory conditions tested, 11 had significant associations including MUC5B locus (rs35705950) with increased risk of idiopathic fibrosing alveolitis OR 2.83, p = 4.12 × 10-191; CRHR1 (rs61667602) associated with reduced risk of pulmonary fibrosis, OR 0.84, p = 2.26× 10-12. The TYK2 locus (rs11085727) associated with reduced risk for autoimmune conditions, e.g., psoriasis OR 0.88, p = 6.48 x10-23, lupus OR 0.84, p = 3.97 x 10-06. PheWAS stratified by ancestry demonstrated differences in genotype-phenotype associations. LMNA (rs581342) associated with neutropenia OR 1.29 p = 4.1 x 10-13 among Veterans of African and Hispanic ancestry but not European. Overall, we observed a shared genetic architecture between COVID-19 severity and conditions related to underlying risk factors for severe and poor COVID-19 outcomes. Differing associations between genotype-phenotype across ancestries may inform heterogenous outcomes observed with COVID-19. Divergent associations between risk for severe COVID-19 with autoimmune inflammatory conditions both respiratory and non-respiratory highlights the shared pathways and fine balance of immune host response and autoimmunity and caution required when considering treatment targets.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Veterans / COVID-19 Type of study: Experimental Studies / Observational study / Prognostic study / Randomized controlled trials Topics: Variants Limits: Humans Language: English Journal: PLoS Genet Journal subject: Genetics Year: 2022 Document Type: Article Affiliation country: Journal.pgen.1010113

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Veterans / COVID-19 Type of study: Experimental Studies / Observational study / Prognostic study / Randomized controlled trials Topics: Variants Limits: Humans Language: English Journal: PLoS Genet Journal subject: Genetics Year: 2022 Document Type: Article Affiliation country: Journal.pgen.1010113