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Its molecular mechanisms remain unclear due to significant clinical and immunological heterogeneity. In this study, we integrated multi\u2011omics genetic data to systematically screen for palmitoylation regulatory genes associated with MD risk. We first intersected 31 core palmitoylation genes with blood cis\u2011eQTL datasets to identify candidate expression\u2011related genes, then performed two\u2011sample Mendelian randomization (MR) to examine their genetic correlation with MD. Summary\u2011data\u2011based MR (SMR) using two independent peripheral blood eQTL cohorts (eQTLGen and GTEx) was further applied to validate robust candidate genes. Two\u2011sample inverse\u2011variance weighted (IVW) MR revealed nominally significant associations between PPT2, ZDHHC18, ZDHHC5 and MD risk. Independent SMR validation confirmed that peripheral ZDHHC5 expression was significantly correlated with MD (eQTLGen: PSMR\u2009=\u20090.023; GTEx: PSMR\u2009=\u20090.006), and a non\u2011significant HEIDI test ruled out strong linkage disequilibrium confounding. We further explored potential immune mediators using a two\u2011step MR screening framework covering 731 peripheral immune cell phenotypes. After Benjamini\u2013Hochberg false discovery rate (FDR) correction for all immune traits to control for multiple testing, no immune cell phenotype retained an FDR\u2009&lt;\u20090.05 association with MD; therefore, formal mediation analysis was not conducted. In summary, this MR\u2011based genetic analysis identifies ZDHHC5 as a gene associated with MD susceptibility. The potential immune regulatory axis involving NKT cells remains speculative and requires validation through large\u2011scale stratified immune cohort data and functional cellular\/animal experiments. No definitive causal or therapeutic conclusions can be drawn from the present genetic statistical evidence alone.<\/jats:p>","DOI":"10.1007\/s00335-026-10264-x","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T15:36:34Z","timestamp":1786635394000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["ZDHHC5 may regulate the function of NKT cells and the immune response in Meniere\u2019s disease"],"prefix":"10.1007","volume":"37","author":[{"given":"Ruilong","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keguang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"issue":"2","key":"10264_CR1","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1093\/ije\/dyv080","volume":"44","author":"J Bowden","year":"2015","unstructured":"Bowden J et al (2015) Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. 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