Introduction: Despite advances in psychotherapies and pharmacological treatments, the burden of severe mental illness (SMI) remains high. Prominent sex differences exist in 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, we computed genetic correlations using linkage disequilibrium score regression and bi-directional two-sample Mendelian Randomization (MR). A range of sensitivity methods was applied and potential mediators were investigated using multivariable MR. Sex-stratified summary-level data from genome-wide association studies (GWAS)s were used, further stratified on menopausal status when available. The main analysis focused on depressive disorder (N women=23,618 and N men=17,336), bipolar disorder (N women=26,573 and N men=22,381), schizophrenia (N women=54,513 and N men=68,287) as SMIs, and oestrogen (N women=229,966 and N men=206,927) and testosterone (N women=230,454 and N men=194,453) as the primary sex hormone traits. Exploratory analyses included other sex hormone traits (progesterone, sex hormone-binding globulin, prolactin, age of menarche, age of menopause). Potential mediators examined included levels of cortisol and CRP, smoking initiation, alcohol dependence, alcohol intake, BMI and body fat distribution. Only individuals of European ancestry were included. Results: We found a widespread pattern of significant genetic correlations between oestrogen/testosterone levels and depressive disorder/schizophrenia, in both positive and negative directions in both sexes (ranging between -0.22 and 0.13). There was no significant genetic correlation for bipolar disorder. In the MR analyses, evidence for causal effects was largely lacking; however, there was consistent evidence for a causal, increasing effect of testosterone levels on schizophrenia risk in men, completely mediated by CRP. Conversely, there was evidence for a causal, increasing effect of liability to schizophrenia 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.

The authors have declared no competing interest.

JLT is supported by a European Research Council (ERC) Starting grant (UNRAVEL-CAUSALITY, grant number 101076686) and a Senior Scientist Dekker Grant from the Dutch Heart Foundation (project number 03-004-2022-0055). KJHV is supported by the Foundation Volksbond Rotterdam. IECS received a grant from the Netherlands Organisation for Health Research and Development (ZonMw, project 91213009).

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Only summary statistics of genome-wide association studies were used. Data was available to download from https://www.ebi.ac.uk/gwas/, or upon request from the authors (please see references to the GWAS employed in the paper).

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All analyses in this study employed publicly available summary-level GWAS data