DNA Methylation at cg18095732 Modulates ZDHHC20 Expression and Decreases Acne Vulgaris Risk.

Background: Acne vulgaris is a common chronic inflammatory skin disorder involving lipid metabolism and immune dysregulation. Protein S-palmitoylation regulates lipid homeostasis, while DNA methylation has emerged as a potential contributor to acne pathogenesis. Yet, how DNA methylation and palmitoylation intersect in acne remains unclear. Methods: The objective of this study was to investigate whether palmitoylation-related genes are causally linked to acne by integrating large-scale genetic and epigenetic datasets through Mendelian randomization and complementary analyses. Results: Our MR and SMR analyses identified ZDHHC20, a gene encoding a palmitoyltransferase, as significantly and negatively associated with acne risk. Further mediation analysis revealed that hypermethylation at the CpG site cg18095732 was positively associated with ZDHHC20 expression and indirectly contributed to a reduced risk of acne. This methylation site accounted for 61.90% of the total effect via mediation. Robustness of the findings was confirmed through sensitivity analyses, which indicated no evidence of horizontal pleiotropy or heterogeneity. Conclusion: This study provides supportive evidence for a regulatory pathway in which DNA methylation at cg18095732 up-regulates ZDHHC20 and is associated with lower acne susceptibility. Our findings highlight epigenetic regulation as a potential biomarker or intervention point for inflammatory skin disorders.