We addressed the hypothesis that regions of E2-mediated epigenetic change may predict PPD risk. Numerous correlations linking E2-mediated epigenetic change with DNA methylation changes occurring in the PPD risk population were identified in both the original prepartum euthymic cohort as well as in the independent replication cohort of women depressed during pregnancy. Cumulatively, the results suggest a systematic increase in DNA methylation change occurs in the blood of the PPD group during a period where pregnancy hormones are at high levels. As gonadal hormone levels have been shown not to predict PPD risk, these data provide suggestive evidence that the underlying risk in this group may be related to an increased sensitivity for epigenetic change in response to normal levels of circulating hormones. It is important to consider that the sample sizes interrogated in the mouse experiments were small, and that higher powered experiments may identify additional genomic regions of E2-responsive DNA methylation change in the hippocampus. The findings of enriched SP-1 binding sites and increased evidence for hippocampal long-term potentiation-associated genes in E2-responsive DMRs is consistent with the known
