Analysis of the Correlation Between Circadian Rhythms and Immune Regulation Mechanisms in Vitiligo: Evidence From Summary Data–Based Mendelian Randomization Combined With Single‐Cell Analysis

Objective This study aimed to elucidate the regulatory role of circadian rhythm–related genes (CRGs) in immune cell function and their potential contribution to vitiligo pathogenesis. Characterizing the crosstalk between CRGs and immune cells may yield novel insights into the immune dysregulation underlying vitiligo development. Methods We integrated expression quantitative trait loci (eQTL) data from the eQTLGen and GTEx projects to analyze 2091 CRGs comprehensively. Summary data–based Mendelian randomization (SMR) and heterogeneity in dependent instruments (HEIDI) analyses were performed to identify key CRGs associated with vitiligo. Colocalization analysis and single‐cell RNA sequencing data were used to assess CRG expression in immune cells of vitiligo patients. Results Nine key CRGs were identified, showing significant associations with vitiligo in both eQTL datasets. USP40 , PEBP , NPM , FBXL1 , and GCLC exhibited negative correlations with vitiligo risk, while RPTO , FAM228B , DPH , and CHST1 were positively correlated. Single‐cell analysis revealed reduced CRG expression in vitiligo patients, particularly in natural killer (NK)/T cells, naive T cells, and monocytes. This CRG downregulation correlated with impaired immune cell functionality, implicating circadian dysregulation in the aberrant immune responses characteristic of vitiligo pathogenesis. Conclusion The results demonstrate that CRGs constitute potential regulatory components in vitiligo pathogenesis through their modulation of immune cell function. The identification of both protective and risk‐associated CRGs, coupled with evidence of circadian–immune crosstalk disruption in affected tissues, establishes a new mechanistic framework for understanding vitiligo etiology. These findings not only advance our knowledge of the circadian–immune axis in autoimmune skin disorders but also highlight CRGs as promising therapeutic targets for precision medicine approaches in vitiligo treatment.