PMID- 32511533 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240329 DP - 2020 Sep 5 TI - The landscape of host genetic factors involved in immune response to common viral infections. LID - 2020.05.01.20088054 [pii] LID - 10.1101/2020.05.01.20088054 [doi] AB - 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 DRbeta1 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.x10(-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=5.0x10(-15) (MCV), NTN5: P=1.1x10(-9) (BKV), and P2RY13: P=1.1x10(-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, USA. FAU - Francis, Stephen S AU - Francis SS AD - Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, USA. AD - Department of Neurological Surgery, University of California San Francisco, San Francisco, USA. AD - Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, USA. AD - Weill Institute for Neurosciences, University of California San Francisco, San Francisco, USA. FAU - Morrison, Maike AU - Morrison M AD - Summer Research Training Program, Graduate Division, University of California San Francisco, San Francisco, USA. AD - Department of Mathematics, The University of Texas at Austin, Austin, USA. FAU - Wendt, George A AU - Wendt GA AD - Department of Neurological Surgery, University of California San Francisco, San Francisco, USA. FAU - Bosse, Yohan AU - Bosse Y AD - Institut universitaire de cardiologie et de pneumologie de Quebec, Department of Molecular Medicine, Universite Laval, Quebec City, Canada. FAU - Cavazos, Taylor B AU - Cavazos TB AD - Program in Biological and Medical Informatics, University of California San Francisco, San Francisco, USA. FAU - Rashkin, Sara R AU - Rashkin SR AD - Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, USA. AD - Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, USA. FAU - Ziv, Elad AU - Ziv E AD - Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, USA. AD - Department of Medicine, University of California, San Francisco, San Francisco, USA. AD - Institute for Human Genetics, University of California San Francisco, San Francisco, USA. FAU - Witte, John S AU - Witte JS AD - Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, USA. AD - Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, USA. AD - Institute for Human Genetics, University of California San Francisco, San Francisco, USA. AD - Department of Urology, University of California San Francisco, San Francisco, USA. LA - eng GR - K24 CA169004/CA/NCI NIH HHS/United States GR - R01 CA201358/CA/NCI NIH HHS/United States GR - R25 CA112355/CA/NCI NIH HHS/United States GR - T32 GM067547/GM/NIGMS NIH HHS/United States PT - Preprint DEP - 20200905 PL - United States TA - medRxiv JT - medRxiv : the preprint server for health sciences JID - 101767986 UIN - Genome Med. 2020 Oct 27;12(1):93. PMID: 33109261 PMC - PMC7273301 OTO - NOTNLM OT - Infection OT - antibody OT - antigen OT - genome-wide association study (GWAS) OT - human leukocyte antigen (HLA) OT - immune response OT - immunoglobulin G OT - polyomavirus OT - serology OT - transcriptome-wide association study (TWAS) OT - virus COIS- COMPETING INTERESTS The authors declare no competing interests. EDAT- 2020/06/09 06:00 MHDA- 2020/06/09 06:01 PMCR- 2020/09/08 CRDT- 2020/06/09 06:00 PHST- 2020/06/09 06:00 [pubmed] PHST- 2020/06/09 06:01 [medline] PHST- 2020/06/09 06:00 [entrez] PHST- 2020/09/08 00:00 [pmc-release] AID - 2020.05.01.20088054 [pii] AID - 10.1101/2020.05.01.20088054 [doi] PST - epublish SO - medRxiv [Preprint]. 2020 Sep 5:2020.05.01.20088054. doi: 10.1101/2020.05.01.20088054.