Major depressive disorder and anti-depressant therapy markedly alters the human follicular niche DNA methylome

Generalized anxiety disorder, major depressive disorder and their treatment selective serotonin reuptake inhibitors (SSRIs) impact 4-17% of pregnancies worldwide and alter the epigenome of numerous tissues, but their effects on the ovarian follicle are unknown. This study profiles the methylome of granulosa cells, revealing novel epigenetic pathways and molecular mechanisms altered by mental health conditions and their treatments.

Generalized anxiety and major depressive disorders (GAD/MDD) impact 4-17% of pregnancies worldwide. GAD/MDD and SSRIs alter the epigenome of numerous tissues; however, their effect on the ovarian follicular niche is unknown. In this study, we determined SSRI concentrations in the follicular fluid and matched patients by clinical and stimulation characteristics, and then grouped them into three groups: i) treated GAD/MDD (n = 10), ii) untreated GAD/MDD (n = 4), and iii) control (n = 10). DNA methylation sequencing was performed on granulosa cells using the Illumina TruSeq Methyl Capture EPIC kit. For patients with untreated GAD/MDD, we identified 3,829 differentially methylated sites (DMSs). Pathway analysis revealed an enrichment in genes involved in catabolism and immune response for the hypomethylated DMSs and hypermethylated DMSs were associated with protein localization and cellular transport. When assessing the effect of SSRI treatment, we identified 3,690 DMSs. Hypomethylated DMSs were associated with genes involved in cytoskeleton organization and cellular transport, whereas hypermethylated DMSs were associated with apoptosis and cell cycle. This is the first study profiling the methylome of human granulosa cells from patients with treated or untreated GAD/MDD. This study provides a valuable dataset describing the effects of SSRI on cells in the ovarian follicular niche.