Integrated proteomic, transcriptomic, and epigenomic profiling identifies SRA1 as a novel therapeutic target for postpartum depression

Postpartum depression (PPD) is one of the most common complications of childbirth, it is vital to identify novel treatments. We aimed to identify potential drug targets for PPD by integrating plasma proteome, transcriptome and epigenomic. We designed a comprehensive analysis pipeline involving two-sample Mendelian randomization (MR) (for proteins), colocalization (for coding genes), and summary-based MR (SMR) (for mRNA and DNA methylation), to identify potential therapeutic target for PPD. Genetic data on plasma proteome are obtained from 4907 aptamers in 35,559 Icelanders and 7596 proteins in 828 Fenland. GWAS data of PPD were sourced from Psychiatric Genomics Consortium (PGC) (Ncase = 17,339, Ncontrol = 53,426). A two-step MR approach assessed whether brain imaging-derived phenotypes (DIPs) and metabolites from blood, brain and cerebrospinal fluid mediated the observed effects. Across two proteome datasets, genetically predicted levels of 18 plasma proteins are nominally significant associated with PPD and SRA1 was significantly associated with PPD. SRA1, AGT, PGP have strong support for colocalization. The methylation of cg02434007 of SRA1 in brain was associated with higher expression of SRA1 and a high risk of PPD, which aligns with the positive effect of SRA1 gene expression on PPD risk. Isoleucine (mediation proportion: 5.8%, P = 0.042) from blood metabolites and the DIPs ICA100 edge 442 (mediation proportion: 7.6%, P = 0.044) may play mediating roles. This study reveals SRA1 as a novel therapeutic target for PPD, which enhances the understanding of molecular etiology and development of therapeutics.