Shingles GWAS identifies seven immune loci and effects on stroke and autoimmunity

Shingles (herpes zoster), caused by reactivation of varicella zoster virus (VZV), affects approximately one third of the global population. Besides environmental factors, host genetics play a role in determining susceptibility to shingles. Here, we performed a large-scale genome-wide association study (GWAS) meta-analysis of shingles across five cohorts comprising 72,935 cases and 1,644,597 controls of European ancestry. We identified seven genome-wide significant loci, including novel associations at IGHG1, IFNAR2, MPV17L2 (IL12RB1), BACH2, and RHOBTB1, implicating MHC class I antigen presentation, type I interferon signaling, humoral immunity, and T-cell memory maintenance as key genetic determinants of shingles susceptibility. HLA fine-mapping identified eight independently associated HLA alleles, mapping predominantly to HLA-B (HLA-B*44:02), with additional associations at HLA-C (HLA-C*02:02) and an independent association at HLA-DQB1 (HLA-DQB1*05:02). Gene set analysis and stratified LD score regression identified significant enrichment of shingles heritability in immune tissues and pathways. Phenome-wide association study, genetic correlation analysis, and bidirectional two-sample Mendelian randomization identified causal effects of shingles on stroke, herpes simplex infection, and systemic lupus erythematosus, and suggested pain conditions and arthrosis as risk factors for shingles. These findings advance understanding of the genetic architecture of VZV reactivation and its causal relationships with other diseases.