The landscape of host genetic factors involved in immune response to common viral infections

Linda Kachuri; Stephen S Francis; Maike L Morrison; George A Wendt; Yohan Bossé; Taylor B Cavazos; Sara R Rashkin; Elad Ziv; John S Witte

doi:10.1186/s13073-020-00790-x

The landscape of host genetic factors involved in immune response to common viral infections

Genome Med. 2020 Oct 27;12(1):93. doi: 10.1186/s13073-020-00790-x.

Authors

Linda Kachuri¹, Stephen S Francis^{2

3

4

5}, Maike L Morrison^{6

7

8}, George A Wendt⁹, Yohan Bossé¹⁰, Taylor B Cavazos¹¹, Sara R Rashkin^{1

12}, Elad Ziv^{13

14

15}, John S Witte^{16

17

18

19

20}

Affiliations

¹ Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA.
² Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA. stephen.francis@ucsf.edu.
³ Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA. stephen.francis@ucsf.edu.
⁴ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. stephen.francis@ucsf.edu.
⁵ Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA. stephen.francis@ucsf.edu.
⁶ Department of Biology, Stanford University, Stanford, CA, USA.
⁷ Summer Research Training Program, Graduate Division, University of California San Francisco, San Francisco, CA, USA.
⁸ Department of Mathematics, The University of Texas, Austin, TX, USA.
⁹ Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
¹⁰ Department of Molecular Medicine, Université Laval, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec City, QC, Canada.
¹¹ Program in Biological and Medical Informatics, University of California San Francisco, San Francisco, CA, USA.
¹² Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, USA.
¹³ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
¹⁴ Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
¹⁵ Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.
¹⁶ Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA. jwitte@ucsf.edu.
¹⁷ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. jwitte@ucsf.edu.
¹⁸ Department of Biology, Stanford University, Stanford, CA, USA. jwitte@ucsf.edu.
¹⁹ Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA. jwitte@ucsf.edu.
²⁰ Department of Urology, University of California San Francisco, San Francisco, CA, USA. jwitte@ucsf.edu.

Abstract

Background: Humans and viruses have co-evolved for millennia resulting in a complex host genetic architecture. Understanding the genetic mechanisms of immune response to viral infection provides insight into disease etiology and therapeutic opportunities.

Methods: We conducted a comprehensive study including genome-wide and transcriptome-wide association analyses to identify genetic loci associated with immunoglobulin G antibody response to 28 antigens for 16 viruses using serological data from 7924 European ancestry participants in the UK Biobank cohort.

Results: Signals in human leukocyte antigen (HLA) class II region dominated the landscape of viral antibody response, with 40 independent loci and 14 independent classical alleles, 7 of which exhibited pleiotropic effects across viral families. We identified specific amino acid (AA) residues that are associated with seroreactivity, the strongest associations presented in a range of AA positions within DRβ1 at positions 11, 13, 71, and 74 for Epstein-Barr virus (EBV), Varicella zoster virus (VZV), human herpesvirus 7, (HHV7), and Merkel cell polyomavirus (MCV). Genome-wide association analyses discovered 7 novel genetic loci outside the HLA associated with viral antibody response (P < 5.0 × 10^-8), including FUT2 (19q13.33) for human polyomavirus BK (BKV), STING1 (5q31.2) for MCV, and CXCR5 (11q23.3) and TBKBP1 (17q21.32) for HHV7. Transcriptome-wide association analyses identified 114 genes associated with response to viral infection, 12 outside of the HLA region, including ECSCR: P = 5.0 × 10^-15 (MCV), NTN5: P = 1.1 × 10^-9 (BKV), and P2RY13: P = 1.1 × 10^-8 EBV nuclear antigen. We also demonstrated pleiotropy between viral response genes and complex diseases, from autoimmune disorders to cancer to neurodegenerative and psychiatric conditions.

Conclusions: Our study confirms the importance of the HLA region in host response to viral infection and elucidates novel genetic determinants beyond the HLA that contribute to host-virus interaction.

Keywords: Antibody; Antigen; Genome-wide association study (GWAS); Human leukocyte antigen (HLA); Immune response; Immunoglobulin G; Infection; Polyomavirus; Serology; Transcriptome-wide association study (TWAS); Virus.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antibody Formation / genetics
Disease Susceptibility* / immunology
Gene Expression Profiling
Genetic Predisposition to Disease*
Genome-Wide Association Study
HLA Antigens / genetics
HLA Antigens / immunology
Host-Pathogen Interactions / genetics*
Humans
Immunity
Immunoglobulin G / immunology
Quantitative Trait, Heritable
Virus Diseases / etiology*

Substances

HLA Antigens
Immunoglobulin G

Abstract

Publication types

MeSH terms

Substances

Grants and funding