History of Peripartum Depression Moderates the Association Between Estradiol Polygenic Risk Scores and Basal Ganglia Volumes in Major Depressive Disorder

Background: The neurobiological differences between women who have experienced a peripartum episode and those who have only had episodes outside of this period are not well understood. Methods: Sixty-four parous female patients with major depressive disorder who had either a positive (n = 30) or negative (n = 34) history of peripartum depression (PPD) underwent magnetic resonance imaging acquisition to obtain structural brain images. An independent 2-sample t test comparing patients with and without a history of PPD was performed using voxel-based morphometry analysis. Additionally, polygenic risk scores for estradiol were calculated, and a moderation analysis was conducted between 3 estradiol polygenic risk scores and PPD history status on extracted cluster volumes using IBM SPSS PROCESS macro. Results: The voxel-based morphometry analysis identified larger gray matter volumes in bilateral clusters encompassing the putamen, pallidum, caudate, and thalamus in patients with a PPD history than in patients without a history. The moderation analysis identified a significant interaction effect between 2 estradiol polygenic risk scores and PPD history on gray matter cluster volumes, with a positive effect in women with PPD and a negative effect in women with no history of PPD. Conclusions: Our findings demonstrate that women who have experienced a peripartum episode are neurobiologically distinct from women who have no history of PPD in a cluster within the basal ganglia, an area important for motivation, decision making, and emotional processing. Furthermore, we show that the genetic load for estradiol has a differing effect in this area based on PPD status, which supports the claim that PPD is associated with sensitivity to sex steroid hormones.