Causal Associations Between Immune Cell‐Specific Gene Expression and Major Depressive Disorder: A Single‐Cell Transcriptome‐Wide Mendelian Randomization Study

ABSTRACT Major depressive disorder (MDD) is a prevalent psychiatric disorder, and its pathophysiology is related to immune dysregulation. The use of genetic evidence to identify molecular targets of specific immune cell types will provide new directions for the development of precision immunotherapy. We integrated single‐cell cis‐eQTL data for 14 immune cell subtypes from the OneK1K cohort with MDD GWAS summary statistics. We assessed the causal effect of genetically predicted immune cell‐specific gene expression on depression using single‐cell transcriptome‐wide Mendelian randomization (scTWMR), followed by Bayesian colocalization. Functional analyses included enrichment, protein–protein interaction, phenome‐wide association, and druggability assessment. We identified six significant gene–cell associations across CD4 + T cells, immature B cells, and plasma cells. Three genes showed strong colocalization evidence (PPH 4 > 80%): PTCH1 (CD4 NC, OR = 1.17, P‐FDR = 3.78 × 10 −4 ), MTHFD1L (plasma cells, OR = 1.11, P‐FDR = 5.20 × 10 −7 ), and RP11‐293M10.2 (CD4 NC, OR = 0.91, P‐FDR = 7.96 × 10 −8 ). Enrichment implicated Hedgehog signaling and folate metabolism. Drug repurposing highlighted metabolites targeting MTHFD1L and approved drugs targeting PTCH1 warranting further investigation. This study provides evidence for a genetically predicted causal relationship between immune cell‐specific gene expression and MDD, which not only constructs a screening framework for candidate gene drug targets but also validates and finds potential drug targets.