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

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.

Genetic Determinants of Antibody-Mediated Immune Responses to Infectious Diseases Agents: A Genome-Wide and HLA Association Study

“…Our study used serology data, but others have used prospective patient enrollment [ 52 ] or electronic medical record data [ 50 , 51 ], and the biggest GWAS on infectious diseases to date used self-reported history using questionnaires [ 15 ]. A similar preprint using the same data as ours is currently accessible and found similar significant associations [ 53 ]. However, the authors performed a slightly different analysis that did not account for intrinsically limited serology testing specificity or UKB HLA quality control recommendations.…”

Common Genetic Variation in Humans Impacts In Vitro Susceptibility to SARS-CoV-2 Infection

“…Large-scale international consortia have assembled to identify host-genetic associations with COVID-19 clinical outcomes (Initiative, 2020;Shelton et al, 2020;Tanigawa and Rivas, 2020), although cohorts remain underpowered by genome-wide association study (GWAS) standards. To date, such studies have found only a handful of loci to be genome-wide significant (Initiative, 2020;Kachuri et al, 2020;Ramlall et al, 2020). The largest data freeze to date (https://www.covid19hg.org) does not include rs4702 within its summary statistics; however, we note an excess of nominally significant genetic variants within the FURIN cis-region (Table S1; binomial test p = 3.57 3 10 À31 ) comparing individuals hospitalized from COVID-19 with the general population (Initiative, 2020).…”

First flare of ACPA-positive rheumatoid arthritis after SARS-CoV-2 infection

“…Two studies of individuals positive for SARS‐CoV‐2 identified an association between HLA-DRB1*15:01 and HLA-DQB1*06:02 and an increased likelihood of testing positive for the virus, 8 suggesting the possibility of impaired presentation of viral peptides necessary to elicit a protective T‐cell response. 9 As such, the presence of homozygous HLA-DRB1*15:01 and HLA-DQB1 alleles in our patient could have had an effect on the quality of cellular immune responses generated in response to SARS-CoV-2 infection.…”