Mapping the human genetic architecture of COVID-19

Mari E. K. Niemi, Juha Karjalainen, Rachel G. Liao, Benjamin M. Neale, Mark Daly, Andrea Ganna, Gita A. Pathak, Shea J. Andrews, Masahiro Kanai, Kumar Veerapen, Israel Fernandez-Cadenas, Eva C. Schulte, Pasquale Striano, Minttu Marttila, Camelia Minica, Eirini Marouli, Mohd Anisul Karim, Frank R. Wendt, Jeanne Savage, Laura SloofmanGuillaume Butler-Laporte, Han-Na Kim, Stavroula Kanoni, Yukinori Okada, Jinyoung Byun, Younghun Han, Mohammed Jashim Uddin, George Davey Smith, Cristen J. Willer, Joseph D. Buxbaum, Juha Karjalainen, Juha Mehtonen, Lasse Folkersen, Ida Moltke, Anke Hinney, Chen Wang, David Ellinghaus, Søren Brunak, Pedro Castro, Marta Guindo-Martinez, Ji Yeon Lee, Ruth J. F. Loos, Jing Hua Zhao, Yan V. Sun, Bo Wang, Robert Parker, Sara Mingo Garcia, Oliver Smith, Christopher Davis, COVID-19 Host Genetics Initiative, 23andMe COVID-19 Team, Norwegian SARS-CoV-2 Study Grp, Humanitas COVID-19 Task Force, Humanitas Gavazzeni COVID-19 Task, FHoGID, RegCOVID, P-PredictUs, SeroCOVID, CRiPSI, Genes & Hlth Res Team, UCLA Hlth ATLAS Data Mart Working

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Abstract

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19(1,2), host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases(3-7). They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

Original languageEnglish
JournalNature
Volume600
Pages (from-to)472-477
ISSN0028-0836
DOIs
Publication statusPublished - 2021

Keywords

  • GENOME-WIDE ASSOCIATION
  • SUSCEPTIBILITY LOCI
  • HERITABILITY
  • METAANALYSIS

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