Identification and Validation of Epigenetic Biomarkers of PMDD

PROJECT SUMMARY Premenstrual dysphoric disorder (PMDD) is a reproductive affective disorder with impairing mood symptoms that emerge monthly in the premenstrual (luteal) phase of the menstrual cycle. Excitingly, in recent exploratory analyses by our team, epigenetic biomarkers of postpartum depression also distinguished PMDD cases from controls in the luteal phase of the menstrual cycle. Reproductive affective disorders, including PMDD and postpartum depression, can be conceptualized as disorders of hormone sensitivity - an abnormal brain response to ovarian hormone fluctuations. Epigenetic variations at the TTC9B and HP1BP3 loci identified by Co-Is Payne and Kaminsky were prospectively predictive of postpartum depression risk across multiple studies, with over 80% accuracy. Recently, in a cross-sectional cohort of 50 women with and without PMDD, this postpartum depression epigenetic biomarker linear model distinguished PMDD cases from controls in the luteal phase, suggesting our biomarkers may be markers of sensitivity to reproductive hormone change. The primary aim of this R01 is to explore whether the epigenetic biomarkers may represent a broad marker for hormone sensitivity, by assessing women (controls, PMDD) in both the follicular and luteal phases of their menstrual cycles, using a repeated measures approach instead of cross-sectional. A secondary aim is to examine whether our epigenetic biomarkers differ between women with PMDD who have responded to selective serotonin reuptake inhibitor (SSRI) treatment versus those who have failed SSRIs. SSRIs are the first-line treatment for PMDD, yet 40-50% of PMDD patients do not respond to SSRIs. Preliminary data from PI Hantsoo’s laboratory suggests that this epigenetic biomarker may distinguish between SSRI responders and nonresponders in PMDD. Importantly, SSRI treatment response prediction was validated in a prospective postpartum depression cohort, differentiating SSRI responders from non-responders with an AUC of 0.86 (95% CI: 0.63-1). These data suggest that these epigenetic biomarkers may represent a biology important for SSRI response in reproductive affective disorders, which are understudied and have limited effective treatment options. The proposed study will apply our published postpartum depression biomarker linear model to DNA methylation generated by targeted pyrosequencing at TTC9B and HP1BP3 in a cohort of women with PMDD and controls. We will compare the epigenetic biomarker between controls and PMDD in the follicular and luteal phases. Within the PMDD group, we will compare the biomarker between those who have responded to SSRI treatment and those who have not. Blood will be collected at home by participants using a dried blood spot collection system. DNA will be extracted from blood spots and subjected to sodium bisulfite modification and hybridized to a CLIA certified Illumina MethyEPIC Beadchip. Methylation patterns analyzed by Co-I Kaminsky who will use the published algorithm for postpartum depression to determine if the biomarkers predict PMDD.