Genome-wide association study of early-onset and late-onset postpartum depression: the IGEDEPP prospective study

Abstract

Postpartum depression (PPD) appears at two peak periods: early-onset prior to 2 months after delivery and late-onset (2 months after delivery and beyond). The aim of our study is to evaluate the different genetic factors associated with early- and late-onset PPD. With the French multicenter interaction of gene and environment of depression during postpartum (IGEDEPP) cohort, we conducted a genome-wide association study (GWAS) on 234 women with early-onset PPD and 223 women with late-onset PPD, as well as 1,204 controls with no history of lifetime depression. We performed post-GWAS analyses: functional mapping and annotation of GWAS results using MAGMA thanks to Functional Mapping and Annotation of Genome-Wide Association Studies (FUMA), expression quantitative trait loci (QTL) analyses, mapping using data from the PsychENCODE and GTEx, and polygenic risk score (PRS) analysis based on published GWAS. We found two new significant candidate loci for early-onset PPD, rs6436132 in PTPRN gene on chromosome 2 and rs184644645 in RAD18 on chromosome 14, respectively, and one region of interest with five significant associated SNPs in chromosome 20 for late-onset PPD. Variant rs6436132 is the most significant associated with early-onset PPD, and it is a QTL that significantly modifies the expression and splicing of the PTPRN gene in different brain tissues. We also found an enrichment of uterus tissue in the early expression of PPD genes. PRS analysis showed a genetic overlap between both early and late-onset PPD and major depressive disorder, but only early-onset PPD overlaps with bipolar disorder. Our study presents two GWAS separately, highlighting two candidate loci for early-onset PPD and one different region of interest for late-onset PPD. These results have important consequences in our understanding of these disorders, especially since our data reinforce the hormonal pathophysiological hypotheses for early-onset PPD.