Human genomics of the humoral immune response against polyomaviruses

Abstract

Human polyomaviruses are widespread in humans and can cause severe disease in immunocompromised individuals. 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 responses against BK polyomavirus (BKPyV), JC polyomavirus (JCPyV), Merkel cellpolyomavirus (MCPyV), WU polyomavirus (WUPyV), and human polyomavirus 6 (HPyV6) in 15,660 individuals of European ancestry from three independent studies. We observed significant associations for all tested viruses: JCPyV, HPyV6, and MCPyV associated with human leukocyte antigen class II variation, BKPyV and JCPyV with variants in FUT2, responsible for secretor status, MCPyV with variants in STING1, involved in interferon induction, and WUPyV with a functional variant in MUC1, 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.

Keywords: GWAS; genomics; human; infection; meta-analysis; polyomavirus.

Figure 1.

Visual representation of study data. Diagram representing data availability for each human polyomavirus by cohort. Black dots indicate that serological data are available in the cohort, and white dots indicate that data are not available.

Figure 2.

Chicago plots of genome-wide association results of the meta-analyses of antibody levels (top) and serostatus (bottom) against BKPyV, HPyV6, JCPyV, MCPyV, and WUPyV. Chicago plots showing the significance of association of all SNPs across chromosomes 1–22. SNPs are plotted on the x-axis according to their physical position on each chromosome, and the strength of the association with antibody levels is indicated on the y-axis (as −log10 P-value for IgG response and as +log10 P-value for serostatus). The dashed line marks the Bonferroni-corrected genome-wide significance threshold of 5.6 × 10⁻⁰⁹. For each locus, the SNP with the most significant association is plotted in red and labeled. Serostatus was not tested for WUPyV due to very high seroprevalence. Chromosome X is not shown since data were not available for all studies.

Figure 3.

Serum IgG levels against BKPyV and JCPyV, by FUT2 genotype/secretor status. Violin plots show the log-transformed antibody levels (in MFI) against (A) BKPyV and (B) JCPyV. Antibody levels are categorized according to individuals, FUT2 secretor or non-secretor genotype. Red dots represent the mean. P-values based on t-test are shown.