Disentangling Perinatal Depression from General Major Depression: A GWAS Meta-Analysis and Genetic Correlation Approach in European Datasets

Perinatal depression (PND), defined as depression occurring during the perinatal period, has a higher heritability than general major depressive disorder (MDD) yet remains understudied. This study aimed to increase power in PND GWAS and explore its genetic architecture. We meta-analysed an existing study by the Psychiatric Genomics Consortium (PGC) with data from the GLAD+ study and UK Biobank (UKB), yielding 25,452 PND cases and 72,131 controls. Linkage disequilibrium score (LDSC) regression was used to compare genetic correlation profiles of PND and general MDD across traits. Gene, gene-set, and tissue expression analyses were also performed. The genetic correlation between PGC PND and UKB-GLAD+ PND was high (0.93). No genome-wide significant loci emerged from the meta-analysis. The SNP-based heritability of PND on the liability scale was 0.089. PND and MDD displayed broadly similar genetic correlation patterns. Still, PND had a significantly higher genetic correlation with anxiety disorders, while MDD showed higher correlations with cannabis use disorder, bipolar disorder, and ADHD. Tissue expression analysis showed the highest enrichment in brain regions like the cortex and nucleus accumbens. The sample size was not large enough to detect genome-wide significant loci, and further analyses in ancestrally diverse datasets are needed. PND definitions were heterogeneous, and precise information on onset timing across studies was lacking. This study, the largest European ancestry meta-analysis of PND to date, suggests distinct genetic factors may differentiate PND from MDD in general. The findings highlight the need for larger and more ancestrally diverse studies to identify genome-wide significant loci.