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Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative.
Butler-Laporte, Guillaume; Povysil, Gundula; Kosmicki, Jack A; Cirulli, Elizabeth T; Drivas, Theodore; Furini, Simone; Saad, Chadi; Schmidt, Axel; Olszewski, Pawel; Korotko, Urszula; Quinodoz, Mathieu; Çelik, Elifnaz; Kundu, Kousik; Walter, Klaudia; Jung, Junghyun; Stockwell, Amy D; Sloofman, Laura G; Jordan, Daniel M; Thompson, Ryan C; Del Valle, Diane; Simons, Nicole; Cheng, Esther; Sebra, Robert; Schadt, Eric E; Kim-Schulze, Seunghee; Gnjatic, Sacha; Merad, Miriam; Buxbaum, Joseph D; Beckmann, Noam D; Charney, Alexander W; Przychodzen, Bartlomiej; Chang, Timothy; Pottinger, Tess D; Shang, Ning; Brand, Fabian; Fava, Francesca; Mari, Francesca; Chwialkowska, Karolina; Niemira, Magdalena; Pula, Szymon; Baillie, J Kenneth; Stuckey, Alex; Salas, Antonio; Bello, Xabier; Pardo-Seco, Jacobo; Gómez-Carballa, Alberto; Rivero-Calle, Irene; Martinón-Torres, Federico; Ganna, Andrea; Karczewski, Konrad J.
  • Butler-Laporte G; Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montréal, Québec, Canada.
  • Povysil G; Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada.
  • Kosmicki JA; Institute for Genomic Medicine, Columbia University, New York city, New York, United States of America.
  • Cirulli ET; Regeneron Genetics Center, Tarrytown, New York, United States of America.
  • Drivas T; Helix, San Mateo, California, United States of America.
  • Furini S; Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
  • Saad C; Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
  • Schmidt A; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
  • Olszewski P; Department of Medical Biotechnologies, Med Biotech Hub and Competence Center, University of Siena, Siena, Italy.
  • Korotko U; Qatar Genome Program, Qatar Foundation Research, Development and Innovation, Qatar Foundation, Doha, Qatar.
  • Quinodoz M; Institute of Human Genetics, School of Medicine and University Hospital Bonn, University of Bonn, Bonn, Germany.
  • Çelik E; IMAGENE.ME SA, Bialystok, Poland.
  • Kundu K; IMAGENE.ME SA, Bialystok, Poland.
  • Walter K; Centre for Bioinformatics and Data Analysis, Medical University of Bialystok, Bialystok, Poland.
  • Jung J; Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland.
  • Stockwell AD; Department of Genetics and Genome Biology, University of Leicester, Leicester, United Kingdom.
  • Sloofman LG; Department of Ophthalmology, University Hospital Basel, Basel, Switzerland.
  • Jordan DM; Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland.
  • Thompson RC; Department of Ophthalmology, University Hospital Basel, Basel, Switzerland.
  • Del Valle D; Department of Haematology, University of Cambridge, Cambridge, United Kingdom.
  • Simons N; Department of Human Genetics, Wellcome Sanger Institute, Hinxton, United Kingdom.
  • Cheng E; Department of Human Genetics, Wellcome Sanger Institute, Hinxton, United Kingdom.
  • Sebra R; Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, California, United States of America.
  • Schadt EE; Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
  • Kim-Schulze S; Genentech Inc, South San Francisco, California, United States of America.
  • Gnjatic S; Seaver Autism Center for Research and Treatment, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York city, New York, United States of America.
  • Merad M; Mount Sinai Clnical Intelligence Center, Charles Bronfman Institute for Personalized Medicine, Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York city, New York, United States of America.
  • Buxbaum JD; Icahn Institute of Data Science and Genomics Technology, New York city, New York, United States of America.
  • Beckmann ND; Icahn School of Medicine at Mount Sinai, New York city, New York, United States of America.
  • Charney AW; Icahn School of Medicine at Mount Sinai, New York city, New York, United States of America.
  • Przychodzen B; Icahn School of Medicine at Mount Sinai, New York city, New York, United States of America.
  • Chang T; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York city,New York, United States of America.
  • Pottinger TD; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York city,New York, United States of America.
  • Shang N; Department of Oncological Science, Human Immune Monitoring Center, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York city, New York, United States of America.
  • Brand F; Icahn School of Medicine at Mount Sinai, New York city, New York, United States of America.
  • Fava F; Precision Immunology Institute, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York city, New York, United States of America.
  • Mari F; Seaver Autism Center for Research and Treatment, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York city, New York, United States of America.
  • Chwialkowska K; Precision Immunology Institute, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York city, New York, United States of America.
  • Niemira M; Mount Sinai Clinical Intelligence Center; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York city, New York, United States of America.
  • Pula S; Vanda Pharmaceuticals, Washington, District of Columbia, United States of America.
  • Baillie JK; Department of Neurology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California, United States of America.
  • Stuckey A; Institute for Genomic Medicine, Columbia University, New York city, New York, United States of America.
  • Salas A; Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York city, New York, United States of America.
  • Bello X; Institute of Genomic Statistics and Bioinformatics, School of Medicine and University Hospital Bonn, University of Bonn, Bonn, Germany.
  • Pardo-Seco J; Department of Medical Biotechnologies, Med Biotech Hub and Competence Center, University of Siena, Siena, Italy.
  • Gómez-Carballa A; Genetica Medica, Azienda Ospedaliero-Universitaria Senese, Siena, Italy.
  • Rivero-Calle I; Medical Genetics, University of Siena, Siena, Italy.
  • Martinón-Torres F; Department of Medical Biotechnologies, Med Biotech Hub and Competence Center, University of Siena, Siena, Italy.
  • Ganna A; Genetica Medica, Azienda Ospedaliero-Universitaria Senese, Siena, Italy.
  • Karczewski KJ; Medical Genetics, University of Siena, Siena, Italy.
PLoS Genet ; 18(11): e1010367, 2022 11.
Article in English | MEDLINE | ID: covidwho-2098659
ABSTRACT
Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI 2.75-10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Exome / COVID-19 Type of study: Cohort study / Observational study / Prognostic study Topics: Variants Limits: Humans Language: English Journal: PLoS Genet Journal subject: Genetics Year: 2022 Document Type: Article Affiliation country: Journal.pgen.1010367

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Exome / COVID-19 Type of study: Cohort study / Observational study / Prognostic study Topics: Variants Limits: Humans Language: English Journal: PLoS Genet Journal subject: Genetics Year: 2022 Document Type: Article Affiliation country: Journal.pgen.1010367