Characterizing the genetic architecture of postpartum depression in populations of east Asian ancestry

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 mechanism triggered by significant fluctuations in steroid hormones. Here, we perform a genome-wide association study (GWAS) of PPD in the CONVERGE (China, Oxford and Virginia Commonwealth University Experimental Research on Genetic Epidemiology) cohort in order to determine whether genetic risk for PPD is reflecting more psychiatric- or reproductive-related processes. Methods: The CONVERGE 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 two or more episodes of MD meeting DSM-IV criteria 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. SNP-based heritability was estimated using Genome-wide Complex Trait Analysis (GCTA) genomic-relatedness-based restricted maximum-​likelihood (GREML). To assess whether genetic liability is shared between PPD, MD, and reproductive-related phenotypes, summary statistics from the PPD GWAS will be used to generate polygenic risk scores (PRS). The predictive ability of the PPD-PRS to identify risk for recurrent MD without onset in the postpartum will be tested in CONVERGE, and sex-stratified summary statistics from the BioBank Japan (BBJ) will be used to explore whether the PPD-PRS associates with reproductive-related phenotypes (e.g., endometriosis, age of menarche). Results: On average, initial onset of depressive episodes began within the first several weeks after delivery (mean = 3.05 weeks, standard deviation = 4.40). Approximately 6.1 million variants were tested for associations with PPD, however, no SNPs reached genome-wide significance. The most significant variant was rs1372053 (p = 1.1 × 10⁻⁶), located in the promoter of the HIBCH gene. Significant SNP-based heritability of PPD was estimated as 0.222 (SE = 0.09, p = 0.009, population prevalence k = 0.08). Discussion: A significant amount of variation in PPD liability was attributable to common genetic factors within a cohort of East Asian ancestry. Further analyses aim to outline genetic relationships between PPD, MD, and reproductive traits. Disclosure: Nothing to disclose.