Investigating sex-specific associations of Parkinson's disease with sex hormones and sex hormones-related phenotypes using Mendelian randomization.

BACKGROUND

It has been reported that the incidence of Parkinson's disease (PD) in men is 1.5 times that of women, which is easily associated with the protective effect of estrogens on the dopaminergic system. However, the exact direction and magnitude of the effect of sex hormones on PD risk have not been clarified. This study aimed to evaluate the sex-specific association between PD and sex hormones and their related phenotypes using Mendelian randomization (MR).

METHOD: We utilized summary statistics from seven sex-specific genome-wide association studies (GWAS), including the UK Biobank, FinnGen, the INTERVAL Study, and the International Parkinson's Disease Genomics Consortium. Using univariable MR (UVMR) and multivariable MR (MVMR), we investigated causal relationships between genetically predicted sex hormone levels and PD, as well as sex hormone-related traits.

RESULT: We found a negative genetic correlation between PD and total testosterone levels (rg = -0.019, p = 0.046) and bioavailable testosterone levels (rg = -0.028, p = 0.019) among the entire population. UVMR results suggested that genetically predicted elevated bioavailable and total testosterone levels were associated with a reduced risk of PD in the entire population. When evaluating reverse causation, we found that genetically predicted female PD was associated with lower levels of sex hormone-binding globulin. Using MVMR, we further identified a suggestive association between genetically predicted total testosterone levels and a lower risk of PD.

CONCLUSION

Based on our findings, we believe that there may be a potential association between genetically determined testosterone levels and the risk of PD.