Genetic interrelationships between depression occurring in the postpartum period and reproductive-related phenotypes

Abstract

Background: Postpartum depression (PPD) is associated with negative outcomes for both mother (e.g., suicide) and child (e.g., delayed cognitive development), and is the most common complication of childbirth. Family studies have estimated the heritability of PPD at approximately 40%, however, PPD remains an understudied disorder in the psychiatric genetics field. The degree of etiological distinction between PPD and major depression (MD) is currently unknown, with some researchers speculating that an increased genetic risk for PPD actually reflects an underlying vulnerability to psychiatric illness in general, rather than PPD-specific genetic factors. Other reproductive-related phenotypes, such as endometriosis, have also been identified as risk factors for PPD, and these phenotypes could be connected through a common biological mechanism. Here, we outline polygenic relationships between PPD, MD, other psychiatric disorders, and reproductive-related outcomes within a cohort of East Asian ancestry to determine whether genetic risk for PPD is reflecting more psychiatric- or reproductive-related processes. Methods: The CONVERGE (China, Oxford and Virginia Commonwealth University Experimental Research on Genetic Epidemiology) consortium recruited 11,670 Han Chinese women with the primary aim of investigating recurrent MD. DNA was extracted from saliva and low-pass sequencing methods were used to genotype samples. PPD cases (n = 895) consisted of women who screened positive for DSM-IV-defined MD and reported “yes” to at least one of these episodes occurring within the postpartum period, defined as up to six months after giving birth. PPD controls (n = 3,383) included women aged 40+ years who reported at least one child and no lifetime history of psychiatric illness. PRS-CS was applied to summary statistics obtained from BioBank Japan (BBJ) and the Psychiatric Genomics Consortium (PGC) to generate polygenic risk scores (PRS). Logistic models tested relationships between PRS, PPD, and MD, while adjusting for those ancestry PCs significantly associated with the outcomes. A Bonferroni correction adjusted for multiple tests (p < 0.0063). Results: PRS were constructed from six reproductive-related BBJ GWAS: age at menarche, age at menopause, uterine fibroids, breast cancer, cervical cancer, and endometrial cancer. The PRS for age at menarche was significantly associated with an increased risk of PPD (r-squared= 0.0127; p= ​​0.0012), with an earlier age at menarche conferring risk, but not with general lifetime depression risk (r-squared= 0.0028; p= 0.0589). Higher genetic risk for cervical cancer was similarly associated with PPD only (r-squared= 0.0142; p= 0.001). Polygenic risk for psychiatric outcomes were associated with lifetime MD (r-squared= 0.0072 and 0.0048; p= 5.11 × 10-5 and 3.33 × 10-9 for bipolar disorder and schizophrenia, respectively) but not PPD (r-squared= 0.0094 and 0.0091; p= 0.9694 and 0.3800). Discussion: These results suggest that a specific genetic interrelationship exists between reproductive-related phenotypes and depression occurring in the postpartum period. This finding, combined with the genetic overlap observed between psychiatric disorders and MD, may indicate that partially distinct biological pathways are contributing to the etiology of PPD and MD occurring outside of the postpartum period. Disclosure: Nothing to disclose.