Integrative genomic analyses identify susceptibility genes underlying COVID-19 hospitalization

Gita A Pathak; Kritika Singh; Tyne W Miller-Fleming; Frank R Wendt; Nava Ehsan; Kangcheng Hou; Ruth Johnson; Zeyun Lu; Shyamalika Gopalan; Loic Yengo; Pejman Mohammadi; Bogdan Pasaniuc; Renato Polimanti; Lea K Davis; Nicholas Mancuso

doi:10.1038/s41467-021-24824-z

Integrative genomic analyses identify susceptibility genes underlying COVID-19 hospitalization

Nat Commun. 2021 Jul 27;12(1):4569. doi: 10.1038/s41467-021-24824-z.

Authors

Gita A Pathak^#^{1

2}, Kritika Singh^#^{3

4}, Tyne W Miller-Fleming^{3

4}, Frank R Wendt^{1

2}, Nava Ehsan⁵, Kangcheng Hou⁶, Ruth Johnson⁷, Zeyun Lu⁸, Shyamalika Gopalan⁸, Loic Yengo⁹, Pejman Mohammadi^{5

10}, Bogdan Pasaniuc¹¹, Renato Polimanti^{1

2}, Lea K Davis^{3

4}, Nicholas Mancuso^{12

13}

Affiliations

¹ Yale School of Medicine, Department of Psychiatry, Division of Human Genetics, New Haven, CT, USA.
² Veteran Affairs Connecticut Healthcare System, West Haven, CT, USA.
³ Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁴ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
⁵ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA.
⁶ Bioinformatics Interdepartmental Program, University of California Los Angeles, Los Angeles, CA, USA.
⁷ Department of Computer Science, University of California Los Angeles, Los Angeles, CA, USA.
⁸ Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁹ Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
¹⁰ Scripps Translational Science Institute, The Scripps Research Institute, La Jolla, CA, USA.
¹¹ Departments of Computational Medicine, Human Genetics, Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
¹² Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. nicholas.mancuso@med.usc.edu.
¹³ Center for Genetic Epidemiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. nicholas.mancuso@med.usc.edu.

^# Contributed equally.

Abstract

Despite rapid progress in characterizing the role of host genetics in SARS-Cov-2 infection, there is limited understanding of genes and pathways that contribute to COVID-19. Here, we integrate a genome-wide association study of COVID-19 hospitalization (7,885 cases and 961,804 controls from COVID-19 Host Genetics Initiative) with mRNA expression, splicing, and protein levels (n = 18,502). We identify 27 genes related to inflammation and coagulation pathways whose genetically predicted expression was associated with COVID-19 hospitalization. We functionally characterize the 27 genes using phenome- and laboratory-wide association scans in Vanderbilt Biobank (n = 85,460) and identified coagulation-related clinical symptoms, immunologic, and blood-cell-related biomarkers. We replicate these findings across trans-ethnic studies and observed consistent effects in individuals of diverse ancestral backgrounds in Vanderbilt Biobank, pan-UK Biobank, and Biobank Japan. Our study highlights and reconfirms putative causal genes impacting COVID-19 severity and symptomology through the host inflammatory response.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

COVID-19 / genetics
COVID-19 / metabolism*
Genetic Predisposition to Disease / genetics
Genome-Wide Association Study
Hospitalization
Humans
Polymorphism, Single Nucleotide / genetics
Risk Factors

Abstract

Publication types

MeSH terms

Grants and funding