Cell-type-specific genetic architecture of postpartum depression: A single-cell Mendelian randomization framework for...

Postpartum depression (PPD) is a severe psychiatric disorder with complex and multifactorial origins. Although genetic factors have been implicated, the cell-type-specific mechanisms linking genetic variation to disease susceptibility remain largely unexplored.

We conducted a transcriptome-wide Mendelian randomization (MR) analysis integrating bulk and single-nucleus brain eQTL data across eight major brain cell types. Bayesian colocalization was used to assess whether gene expression and disease-associated variants share a common genetic basis. To evaluate potential safety concerns, phenome-wide MR screening was applied to prioritize genes with minimal pleiotropic effects.

Among 1746 independent eGenes tested, PTBP1 expression in pericytes showed a significant and specific causal association with PPD. Colocalization analysis supported a shared genetic signal between PTBP1 expression and PPD risk, strengthening its biological relevance. Notably, PTBP1 showed no evidence of widespread pleiotropy in phenome-wide screening.

These findings identify PTBP1 as a novel pericyte-specific gene implicated in the pathogenesis of PPD. By combining cell-type-resolved transcriptomic data with genetic causality frameworks, this study highlights a promising target for future therapeutic intervention in postpartum psychiatric disorders.