Genes and environment profoundly affect the human virome

Many viruses have adapted to persist in infected humans for life1,2. Variable host control of their ongoing abundance ("load") can lead to clearance or disease3-5. We analyzed the viral DNA load of 31 common viruses in human blood and saliva using whole-genome sequencing data from UK Biobank (n=490,401), All of Us (n=414,817), and SPARK (n=12,519). Viral DNA load varied markedly with age, time of day, and season; most viruses were also present at greater abundance in men than in women. Human genetic variation at dozens of loci associated with DNA load of seven viruses: Epstein-Barr virus (EBV, 45 loci), human herpesvirus 7 (HHV-7, 37 loci), HHV-6B, Merkel cell polyomavirus, and three anelloviruses. Variation at the major histocompatibility complex (MHC) locus generated the strongest associations (p = 5.8x10-9 to 2.5x10-1459), which were specific to each virus. The HLA-B*08:01 allele also exhibited a host-virus genetic interaction with EBV subtype (p = 7.4x10-70). Other human genetic effects implicated genes encoding proteins that process peptides for antigen presentation, such as ERAP1 (HHV-7, p = 2.7x10-78) and ERAP2 (EBV, p = 4.6x10-111). Mendelian randomization analyses supported a strong causal effect of EBV DNA load on increased risk of Hodgkin lymphoma (p = 1.8x10-3) but not multiple sclerosis (p = 0.52). This suggests that higher chronic EBV load increases lymphoma risk, whereas associations of EBV infection with autoimmune conditions reflect host immune responses to particular viral epitopes.