Human genomics of the humoral immune response against polyomaviruses

Human polyomaviruses are widespread in human populations and are able to cause severe disease in immunocompromised individuals. There remains an incomplete understanding of the potential impact of human genetic variation on inter-individual responses to polyomaviruses.

To identify human genetic determinants of the humoral immune response against polyomaviruses, we performed genome-wide association studies and meta-analyses of qualitative and quantitative immunoglobulin G (IgG) responses against the major capsid protein VP1 of Human polyomavirus 6 (HPyV6), BK virus (BKPyV), JC virus (JCPyV), Merkel Cell Polyomavirus (MCPyV) and WU polyomavirus (WUPyV), in a total of 15,660 individuals of European ancestry from CoLaus, UK Biobank and GRAS, three independent studies.

We observed significant associations for all tested viruses: JCPyV, HPyV6 and MCPyV associated with HLA class II variation; BKPyV and JCPyV with variants in the FUT2 gene, responsible for secretor status; MCPyV with variants in the STING1 gene, involved in interferon induction; and WUPyV with a functional variant in the MUC1 gene, previously associated with risk for gastric cancer.

These results provide insights into the genetic control of a family of very prevalent human viruses, highlighting genes and pathways that play a modulating role in human humoral immunity.