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

Genome Medicine

Maike L. Morrison¹  Linda Kachuri²  Sara R. Rashkin³  Stephen S. Francis⁴  John S. Witte⁵  Yohan Bossé⁶  George A. Wendt⁷  Elad Ziv⁸  Taylor B. Cavazos⁹ 

[1] Department of Biology, Stanford University, Stanford, CA, USA;Summer Research Training Program, Graduate Division, University of California San Francisco, San Francisco, CA, USA;Department of Mathematics, The University of Texas, Austin, TX, USA;Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA;Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA;Center for Applied Bioinformatics, St. Jude Children’s Research Hospital, Memphis, TN, USA;Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA;Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA;Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA;Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA;Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA;Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA;Department of Biology, Stanford University, Stanford, CA, USA;Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA;Department of Urology, University of California San Francisco, San Francisco, CA, USA;Department of Molecular Medicine, Université Laval, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec City, QC, Canada;Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA;Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA;Department of Medicine, University of California, San Francisco, San Francisco, CA, USA;Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA;Program in Biological and Medical Informatics, University of California San Francisco, San Francisco, CA, USA;

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

DOI  :  10.1186/s13073-020-00790-x

来源: Springer

【 摘 要 】

BackgroundHumans 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.MethodsWe 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.ResultsSignals 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.ConclusionsOur 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.

【 授权许可】

CC BY