Replication of Epigenetic Postpartum Depression Biomarkers and Variation with Hormone Levels

Abstract

DNA methylation variation at HP1BP3 and TTC9B is modified by estrogen exposure in the rodent hippocampus and was previously shown to be prospectively predictive of postpartum depression (PPD) when modeled in antenatal blood. The objective of this study was to replicate the predictive efficacy of the previously established model in women with and without a previous psychiatric diagnosis and to understand the effects of changing hormone levels on PPD biomarker loci. Using a statistical model trained on DNA methylation data from N=51 high-risk women, we prospectively predicted PPD status in an independent N=51 women using first trimester antenatal gene expression levels of HP1BP3 and TTC9B, with an area under the receiver operator characteristic curve (AUC) of 0.81 (95% CI: 0.69-0.92, p<5 × 10(-4)). Modeling DNA methylation of these genes in N=240 women without a previous psychiatric diagnosis resulted in a cross-sectional prediction of PPD status with an AUC of 0.81 (95% CI: 0.68-0.93, p=0.01). TTC9B and HP1BP3 DNA methylation at early antenatal time points showed moderate evidence for association to the change in estradiol and allopregnanolone over the course of pregnancy, suggesting that epigenetic variation at these loci may be important for mediating hormonal sensitivity. In addition both loci showed PPD-specific trajectories with age, possibly mediated by age-associated hormonal changes. The data add to the growing body of evidence suggesting that PPD is mediated by differential gene expression and epigenetic sensitivity to pregnancy hormones and that modeling proxies of this sensitivity enable accurate prediction of PPD.

Figures

Figure 1

Receiver operator characteristic curves of prospective PPD prediction. Receiver Operator Characteristic (ROC) curves depicting the sensitivity (y axis) as a function of specificity (x axis) for prediction of PPD status in the Prospective Gene Expression cohort during the first (a) and third (b) trimesters.

Figure 2

PPD prediction in women without a psychiatric history. (a) Receiver operator characteristic (ROC) curves depicting the sensitivity (y axis) as a function of specificity (x axis) for prediction of 6–8 months HDRS scores ⩾14 status in the FRAMES cohort of women from the general population. (b) A plot of the performance of PPD model prediction as measured by AUC (y axis) as a function of the HDRS cutoff signifying affected individuals (x axis). The horizontal line denotes the threshold of a ‘good' biomarker at an AUC of 0.80, whereas the vertical dashed line denotes an HDRS cutoff of 14.

Figure 3

PPD biomarkers across the reproductive years. Plots of the mean DNA methylation (x axis) for PPD (triangles) and non-PPD (circles) cases for the HP1BP3 (a) and TTC9B (b) genes over a 10-year sliding window as a function of age (y axis) in the GenRED cohort. Plots of the mean DNA methylation (x axis) for PPD (triangles) and non-PPD (circles) cases for the HP1BP3 (c) and TTC9B (d) genes over a 10-year sliding window as a function of age (y axis) in the FRAMES cohort. The vertical dashed line represents an age of 35 years and denotes the approximate age in the female population when estrogen levels begin to decline.

Figure 4

PPD biomarkers and pregnancy hormone trajectories. (a) A scatterplot of the third trimester estradiol levels in (y axis) as a function of TTC9B DNA methylation (x axis) for women who did (triangles, dashed regression line) and did not (circles, solid regression line) develop PPD. (b) A scatterplot of the change in estradiol from second to third trimester (y axis) as a function of second trimester TTC9B DNA methylation levels (x axis) for women who did (triangles, dashed regression line) and did not (circles, solid regression line) develop PPD. (c) A scatterplot of the third trimester allopregnanolone levels in (y axis) as a function of HP1BP3 DNA methylation (x axis) for women who did (triangles, dashed regression line) and did not (circles, solid regression line) develop PPD. (d) A scatterplot of the change in allopregnanolone from second to third trimester (y axis) as a function of second trimester HP1BP3 DNA methylation levels (x axis) for women who did (triangles, dashed regression line) and did not (circles, solid regression line) develop PPD. All data derives from the Johns Hopkins Prospective cohort.