| Summary: | Abstract Background Herpes simplex virus‐1 (HSV‐1) infection is reported to be associated with depression. But limited efforts were made to investigate the relationship between HSV‐1 infection and the risk of depression, especially from the genetic perspective. Methods In UK Biobank cohort, linear and logistic regression analyses were first performed to test the association of HSV‐1 seropositivity/antibody with depression, including depression status (N = 2951) and Patient Health Questionnaire (PHQ) score (N = 2839). Using individual genotypic and phenotypic data from the UK Biobank, genome‐wide environmental interaction study (GWEIS) was then conducted by PLINK2.0 to evaluate gene × HSV‐1 interacting effect on the risk of depression. Finally, gene set enrichment analysis was conducted to identify the biological pathways involved in the observed gene × HSV‐1 interaction for depression. Result In UK Biobank cohort, significant associations were observed between depression status and HSV‐1 (odds ratio [OR] = 1.09; 95% confidence interval [CI], 1.02‐1.16; P = 2.40 × 10−2 for HSV‐1 antibody and OR = 1.28; 95% CI, 1.12‐1.47, P = 2.59 × 10−3 for HSV‐1 seropositivity). GWEIS revealed four significant gene × HSV‐1 interaction signals for PHQ score (all P < 5.0 × 10−8) and the leading loci was SULF2 (rs6094791, P = 8.60 × 10−9). Pathway analyses identified 21 pathways for PHQ score and 19 for depression status, including multiple neural development‐ and immune‐related ones, such as KEGG_NEUROACTIVE_LIGAND_RECEPTOR_INTERACTION (false discovery rate [FDR] = 3.18 × 10−2) for depression and LU_AGING_BRAIN_UP (FDR = 4.21 × 10−2) for PHQ score. Conclusion Our results suggested that HSV‐1 was associated with the risk of depression, which was modulated by the several genes that were related to the nerve development or immune function.
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