The role of sex hormones in severe mental illness: A genetic exploration

Introduction Prominent sex differences exist in severe mental illness (SMI), with increasing evidence pointing towards a pivotal role for sex hormones. Elucidation of these hormonal influences is crucial to tailor sex-specific prevention and treatment. Methods To investigate potential shared genetics and bi-directional causal effects between sex hormone traits and SMI (depressive disorder, bipolar disorder and schizophrenia-spectrum disorder), we computed genetic correlations using linkage disequilibrium score regression and bi-directional summary-level Mendelian Randomization (MR). A range of sensitivity methods was applied and potential mediators were investigated using multivariable MR. Sex-stratified data from genome-wide association studies were used, if available further stratified on menopausal status. We also incorporated other sex hormone traits (progesterone, sex hormone-binding globulin, prolactin, age of menarche, age of menopause) in exploratory analyses. Results We found a widespread pattern of statistically significant, modest genetic correlations between oestrogen/testosterone levels and depressive disorder/schizophrenia-spectrum disorder, in both positive and negative directions and in both sexes (ranging between −0.22 and 0.13). With MR, evidence for causal effects was largely lacking; apart from weak evidence for a causal, increasing effect of testosterone levels on schizophrenia-spectrum disorder risk in males, which was mediated by CRP. Conversely, there was very weak evidence for a causal, increasing effect of liability to schizophrenia-spectrum disorder on testosterone levels in both sexes. Conclusion This study offers new insights into the complex aetiology of SMI by comprehensively mapping genetic associations with sex hormone traits, emphasizing the need to further investigate sex hormones’ impact on SMI using larger and more precisely phenotyped samples to identify individuals particularly vulnerable to hormonal disturbances.