Antenatal prediction of postpartum depression with blood DNA methylation biomarkers

, JL Payne and ZA KaminskyPostpartum depression (PPD) affects B10–18% of women in the general population and results in serious consequences to boththe mother and offspring. We hypothesized that predisposition to PPD risk is due to an altered sensitivity to estrogen-mediatedepigenetic changes that act in a cell autonomous manner detectable in the blood. We investigated estrogen-mediated epigeneticreprogramming events in the hippocampus and risk to PPD using a cross-species translational design. DNA methylation profileswere generated using methylation microarrays in a prospective sample of the blood from the antenatal period of pregnant mooddisorder patients who would and would not develop depression postpartum. These profiles were cross-referenced with synteniclocations exhibiting hippocampal DNA methylation changes in the mouse responsive to long-term treatment with 17b-estradiol(E2). DNA methylation associated with PPD risk correlated significantly with E2-induced DNA methylation change, suggesting anenhanced sensitivity to estrogen-based DNA methylation reprogramming exists in those at risk for PPD. Using the combined mouseand human data, we identified two biomarker loci at the HP1BP3 and TTC9B genes that predicted PPD with an area under thereceiver operator characteristic (ROC) curve (area under the curve (AUC)) of 0.87 in antenatally euthymic women and 0.12 in areplication sample of antenatally depressed women. Incorporation of blood count data into the model accounted for thediscrepancy and produced an AUC of 0.96 across both prepartum depressed and euthymic women. Pathway analysesdemonstrated that DNA methylation patterns related to hippocampal synaptic plasticity may be of etiological importance to PPD.Molecular Psychiatry advance online publication, 21 May 2013; doi:10.1038/mp.2013.62Keywords: biomarker; DNA methylation; estrogen; HP1BP3; postpartum depression; TTC9BINTRODUCTIONPostpartum depression (PPD) occurs in approximately 10–18% ofwomen and results in significant morbidity in both mother andchild, with offspring risks including low self-esteem, low intellec-tual skills, child abuse and infanticide.