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

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

doi:10.1101/2020.05.01.20088054

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

medRxiv [Preprint]. 2020 Sep 5:2020.05.01.20088054. doi: 10.1101/2020.05.01.20088054.

Authors

Linda Kachuri¹, Stephen S Francis^{1

2

3

4}, Maike Morrison^{5

6}, George A Wendt², Yohan Bossé⁷, Taylor B Cavazos⁸, Sara R Rashkin^{1

9}, Elad Ziv^{3

10

11}, John S Witte^{1

3

11

12}

Affiliations

¹ Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, USA.
² Department of Neurological Surgery, University of California San Francisco, San Francisco, USA.
³ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, USA.
⁴ Weill Institute for Neurosciences, University of California San Francisco, San Francisco, USA.
⁵ Summer Research Training Program, Graduate Division, University of California San Francisco, San Francisco, USA.
⁶ Department of Mathematics, The University of Texas at Austin, Austin, USA.
⁷ Institut universitaire de cardiologie et de pneumologie de Québec, Department of Molecular Medicine, Université Laval, Quebec City, Canada.
⁸ Program in Biological and Medical Informatics, University of California San Francisco, San Francisco, USA.
⁹ Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, USA.
¹⁰ Department of Medicine, University of California, San Francisco, San Francisco, USA.
¹¹ Institute for Human Genetics, University of California San Francisco, San Francisco, USA.
¹² Department of Urology, University of California San Francisco, San Francisco, USA.

Abstract

Introduction: 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 Herpes virus 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.×10^-8), including FUT2 (19q13.33) for human polyomavirus BK (BKV), STING1 (5q31.2) for MCV, as well as 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: Infection; antibody; antigen; genome-wide association study (GWAS); human leukocyte antigen (HLA); immune response; immunoglobulin G; polyomavirus; serology; transcriptome-wide association study (TWAS); virus.

Publication types

Preprint

Abstract

Publication types

Grants and funding