A common genetic factor underlies genetic risk for gynaecological and reproductive disorders and is correlated with risk to depression

IntroductionSex steroid hormone fluctuations may underlie both reproductive disorders and sex difference in lifetime depression prevalence. Previous studies report high comorbidity among reproductive disorders and between reproductive disorders and depression. This study sought to assess the multivariate genetic architecture of reproductive disorders and their loading onto a common genetic factor, and investigated whether this latent factor shares a common genetic architecture with female depression, including perinatal depression (PND).MethodUsing UK Biobank and FinnGen data, genome-wide association meta-analyses were conducted for nine reproductive disorders, and genetic correlation between disorders estimated. Genomic Structural Equation Modelling identified a latent genetic factor underlying disorders, accounting for their significant genetic correlations. SNPs significantly associated with both latent factor and depression were identified. ResultsExcellent model fit existed between a latent factor underlying five reproductive disorders (2 (5)=6.4; AIC=26.4; CFI=1.00; SRMR=0.03) with high standardised loadings for menorrhagia (0.96, SE=0.05); ovarian cysts (0.94, SE=0.05); endometriosis (0.83, SE=0.05); menopausal symptoms (0.77, SE=0.10); and uterine fibroids (0.65, SE=0.05). This latent factor was genetically correlated with perinatal depression (PND) (rG = 0.37, SE=0.15, P=1.4e-03), depression in females only (rG=0.48, SE=0.06, P=7.2e-11) and depression in both males and females (MD) (rG=0.35, SE=0.03, P=1.8e-30), with its top locus associated with FSHB/ARL14EP (rs11031006; P=9.1e-33). SNPs intronic to ESR1, significantly associated with the latent factor, were also associated with PND, female depression, and MD. Discussion/ConclusionA common genetic factor, correlated with depression, underlies risk to reproductive disorders, with implications for etiology and treatment. Genetic variation in ESR1 is associated with reproductive disorders and depression, highlighting the importance of estrogen signalling to both reproductive and mental health.