Genes and environment profoundly affect the human virome

Many viruses have adapted to persist in infected humans for life. Variable host control of their abundance (or load) can lead to clearance or disease. Here, we analyzed the viral load of 31 DNA viruses in human blood and saliva using whole-genome sequencing data from UK Biobank (n=490,401), SPARK (n=12,519), and All of Us (n=414,817). Viral load varied markedly with age, time of day, and season, and was higher in men than women for most viruses. Human genetic variation at dozens of genomic loci associated with load of seven viruses: Epstein-Barr virus (EBV, 45 loci), human herpesvirus 7 (HHV-7, 24 loci), HHV-6B, Merkel cell polyomavirus, and three anelloviruses. Variation at the human leukocyte antigen (HLA) complex generated the strongest associations ( p = 1.1×10 ^-8 to 9.1×10 ^-851 ). Effects of HLA alleles exhibited specificity to different viruses and varied by age and body site, and HLA-B*08:01 also exhibited a host-virus genetic interaction with EBV subtype ( p = 2.3×10 ^-44 ). Other human genetic effects involved genes encoding proteins that process peptides for antigen presentation, such as ERAP1 (HHV-7, p = 2.7×10 ^-78 ) and ERAP2 (EBV, p = 4.6×10 ^-111 ). Mendelian randomization analyses indicated that although EBV infection strongly increases risk of multiple sclerosis (MS), EBV DNA load is unlikely to further modulate risk of MS ( p = 0.52). In contrast, EBV viral load exhibited a strong causal effect on increased risk of Hodgkin lymphoma (OR = 19.81 [3.04–129] per s.d. increase in EBV load, p = 1.8×10 ^-3 ). This suggests that higher chronic EBV viral load increases lymphoma risk, whereas associations of EBV infection with autoimmune conditions reflect host immune responses to particular viral epitopes.