The Palmitoyltransferases ZDHHC6 and ABHD17A Modulate Type 2 Diabetes Risk via Genetic Causality and Molecular Interactions

Abstract Background: Type 2 diabetes mellitus is a multifactorial metabolic disorder caused by insulin resistance and pancreatic β-cell dysfunction. Its molecular mechanisms have not yet been fully explained despite intensive research. S-palmitoylation, a reversible posttranslational modification, regulates protein function and location, with new functions in metabolic diseases. This study addresses the causal link between S-palmitoylation-related genes and type 2 diabetes mellitus viaMendelian randomization (MR) and colocalization studies. Methods: We employed a two-step MR technique to assess causal effects, employing genetic variants as instrumental factors. Data were gathered from large-scale GWAS and eQTL datasets, including the UK Biobank and FinnGen datasets. Sensitivity analyses (e.g., MR‒Egger, Cochran's Q) corrected for pleiotropy and heterogeneity. Mediation analysis revealed hypothesized mechanistic pathways, whereas colocalization and molecular docking established genetic and protein-level relationships. Results: ZDHHC6 (OR = 0.957, 95% CI: 0.920–0.994) and ABHD17A (OR = 1.214, 95% CI: 1.027–1.434) exhibited significant causal correlations with type 2 diabetes mellitus. Colocalization linked ZDHHC6's cis-region to type 2 diabetes mellitus risk loci (PP.H3 > 0.8). Molecular docking revealedstable ZDHHC6-TYRO3 and ABHD17A-ANGPTL4 contacts, supporting palmitoylation-mediated metabolic regulatory functions. A mediation study implicated TYRO3 and ANGPTL4 as partial mediators. Conclusions: This study provides genetic evidence that S-palmitoylation enzymes, particularly ZDHHC6 and ABHD17A, alter type 2 diabetes mellitus etiology, presumably through immune‒metabolic interactions. These findings reveal that palmitoylation is a therapeutic target and demonstrate functional validation in distinct groups.