PMID- 33109261 OWN - NLM STAT- MEDLINE DCOM- 20210803 LR - 20240330 IS - 1756-994X (Electronic) IS - 1756-994X (Linking) VI - 12 IP - 1 DP - 2020 Oct 27 TI - The landscape of host genetic factors involved in immune response to common viral infections. PG - 93 LID - 10.1186/s13073-020-00790-x [doi] LID - 93 AB - 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 DRbeta1 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 x 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 x 10(-15) (MCV), NTN5: P = 1.1 x 10(-9) (BKV), and P2RY13: P = 1.1 x 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. FAU - Kachuri, Linda AU - Kachuri L AD - Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA. FAU - Francis, Stephen S AU - Francis SS AD - Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA. stephen.francis@ucsf.edu. AD - Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA. stephen.francis@ucsf.edu. AD - Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. stephen.francis@ucsf.edu. AD - Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA. stephen.francis@ucsf.edu. FAU - Morrison, Maike L AU - Morrison ML AD - Department of Biology, Stanford University, Stanford, CA, USA. AD - Summer Research Training Program, Graduate Division, University of California San Francisco, San Francisco, CA, USA. AD - Department of Mathematics, The University of Texas, Austin, TX, USA. FAU - Wendt, George A AU - Wendt GA AD - Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA. FAU - Bosse, Yohan AU - Bosse Y AD - Department of Molecular Medicine, Universite Laval, Institut Universitaire de Cardiologie et de Pneumologie de Quebec, Quebec City, QC, Canada. FAU - Cavazos, Taylor B AU - Cavazos TB AD - Program in Biological and Medical Informatics, University of California San Francisco, San Francisco, CA, USA. FAU - Rashkin, Sara R AU - Rashkin SR AD - Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA. AD - Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, USA. FAU - Ziv, Elad AU - Ziv E AD - Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. AD - Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. AD - Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA. FAU - Witte, John S AU - Witte JS AD - Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA. jwitte@ucsf.edu. AD - Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. jwitte@ucsf.edu. AD - Department of Biology, Stanford University, Stanford, CA, USA. jwitte@ucsf.edu. AD - Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA. jwitte@ucsf.edu. AD - Department of Urology, University of California San Francisco, San Francisco, CA, USA. jwitte@ucsf.edu. LA - eng GR - MC_PC_17228/MRC_/Medical Research Council/United Kingdom GR - T32 GM067547/GM/NIGMS NIH HHS/United States GR - R01 CA201358/CA/NCI NIH HHS/United States GR - R25T CA112355/US National Institutes of Health/International GR - K99 CA246076/CA/NCI NIH HHS/United States GR - MC_QA137853/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20201027 PL - England TA - Genome Med JT - Genome medicine JID - 101475844 RN - 0 (HLA Antigens) RN - 0 (Immunoglobulin G) SB - IM UOF - medRxiv. 2020 May 30;:. PMID: 32511533 MH - Antibody Formation/genetics MH - *Disease Susceptibility/immunology MH - Gene Expression Profiling MH - *Genetic Predisposition to Disease MH - Genome-Wide Association Study MH - HLA Antigens/genetics/immunology MH - Host-Pathogen Interactions/*genetics MH - Humans MH - Immunity MH - Immunoglobulin G/immunology MH - Quantitative Trait, Heritable MH - Virus Diseases/*etiology PMC - PMC7590248 OTO - NOTNLM OT - Antibody OT - Antigen OT - Genome-wide association study (GWAS) OT - Human leukocyte antigen (HLA) OT - Immune response OT - Immunoglobulin G OT - Infection OT - Polyomavirus OT - Serology OT - Transcriptome-wide association study (TWAS) OT - Virus COIS- J.S.W. is a non-employee co-founder of Avail.bio and serves as an expert witness for Pfizer and Sanofi. The remaining authors declare that they have no competing interests. EDAT- 2020/10/29 06:00 MHDA- 2021/08/04 06:00 PMCR- 2020/10/27 CRDT- 2020/10/28 05:29 PHST- 2020/05/29 00:00 [received] PHST- 2020/10/07 00:00 [accepted] PHST- 2020/10/28 05:29 [entrez] PHST- 2020/10/29 06:00 [pubmed] PHST- 2021/08/04 06:00 [medline] PHST- 2020/10/27 00:00 [pmc-release] AID - 10.1186/s13073-020-00790-x [pii] AID - 790 [pii] AID - 10.1186/s13073-020-00790-x [doi] PST - epublish SO - Genome Med. 2020 Oct 27;12(1):93. doi: 10.1186/s13073-020-00790-x.