Duncan NRI Faculty and Staff Publications

Language

English

Publication Date

2-1-2026

Journal

Nature

DOI

10.1038/s41586-025-10020-2

PMID

41606327

PMCID

PMC12888827

PubMedCentral® Posted Date

1-28-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Epstein–Barr virus (EBV) is an endemic herpesvirus implicated in autoimmunity, cancer and neurological disorders. Although primary infection is often subclinical, persistent EBV infection can drive immune dysregulation and long-term complications. Despite the ubiquity of infection, the determinants of EBV persistence following primary exposure remain poorly understood, although human genetic variation partially contributes to this phenotypic spectrum1–3. Here we demonstrate that existing whole genome sequencing (WGS) data of human populations can be used to quantify persistent EBV DNA. Using WGS and health record data from the UK Biobank (n = 490,560) and All of Us (n = 245,394), we uncover reproducible associations between blood-derived EBV DNA quantifications and respiratory, autoimmune, neurological and cardiovascular diseases. We evaluate genetic determinants of persistent EBV DNA via genome association studies, revealing heritability enrichment in immune-associated regulatory regions and protein-altering variants in 148 genes. Single-cell and pathway level analyses of these loci implicate variable antigen processing as a primary determinant of EBV DNA persistence. Further, relevant gene programs were enriched in B cells and antigen-presenting cells, consistent with their roles in viral reservoir and clearance. Human leukocyte antigen genotyping and predicted viral epitope presentation affinities implicate major histocompatibility complex class II variation as a key modulator of EBV persistence. Together, our analyses demonstrate how re-analysis of human population-scale WGS data can elucidate the genetic architecture of viral DNA persistence, a framework generalizable to the broader human virome

Keywords

Humans, Herpesvirus 4, Human, Epstein-Barr Virus Infections, DNA, Viral, Genome-Wide Association Study, Whole Genome Sequencing, Male, Female, HLA Antigens, B-Lymphocytes, Persistent Infection, United Kingdom, Single-Cell Analysis, Population genetics, Viral infection, Pathogens, Genome-wide association studies, Immunogenetics

Published Open-Access

yes

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