Druggable Targets for Postpartum Depression: A Mendelian Randomization and Colocalization Study.

Abstract

Postpartum depression (PPD) remains a complex disorder with poorly understood genetic underpinnings. This study systematically evaluated the genetic susceptibility of PPD and identified potential therapeutic targets using Mendelian Randomization (MR) approach. Using a two-sample MR approach, the study assessed the causal effects of expression quantitative trait loci (eQTLs) of druggable genes in blood on PPD, which was sourced from the FinnGen. The primary analytical method was the inverse variance weighted, supplemented by a series sensitivity analyses. Summary-data-based Mendelian Randomization (SMR) analysis was used to validate the identified genes, and Bayesian colocalization analysis evaluated shared causal variants and colocalization probabilities between significant targets and PPD. A Phenome-Wide Association Study (PheWAS) was conducted to assess the associations of established PPD markers with other traits to exclude potential side effects. The results showed that the eQTLs of 12 druggable genes were significantly associated with PPD susceptibility. Seven genes were identified as risk factors, and the expression levels of five genes significantly reduced PPD susceptibility. Colocalization analysis supported the hypothesis that PPD may be associated with shared causal variants of ALDH16A1 (OR = 1.09, 95% CI 1.05-1.13, PP.H4 = 0.78) and SLC29A4 (OR = 1.36, 95% CI 1.23-1.50, PP.H4 = 0.76). The PheWAS did not indicate potential side effects for these two therapeutic targets. This study identified new genetic susceptibilities and potential therapeutic targets associated with PPD, providing novel insights for clinical diagnosis and treatment, and offering new research directions for understanding the molecular mechanisms of PPD.