Fetal sex-specific epigenetic associations with prenatal maternal depressive symptoms

Prenatal maternal mental health is a global health challenge with poorly defined biological mechanisms. We used maternal blood samples collected during the second trimester from a Singaporean longitudinal birth cohort study to examine the association between inter-individual genome-wide DNA methylation and prenatal maternal depressive symptoms. We found that (1) the maternal methylome was significantly associated with prenatal maternal depressive symptoms only in mothers with a female fetus; and (2) this sex-dependent association was observed in a comparable, UK-based birth cohort study. Qualitative analyses showed fetal sex-specific differences in genomic features of depression-related CpGs and genes mapped from these CpGs in mothers with female fetuses implicated in a depression-associated WNT/β-catenin signaling pathway. These same genes also showed enriched expression in brain regions linked to major depressive disorder. We also found similar female-specific associations with fetal-facing placenta methylome. Our fetal sex-specific findings provide evidence for maternal-fetal interactions as a mechanism for intergenerational transmission.