Genetic Association of Sexual Behavior, Sildenafil, and Hormonal Contraceptives With Mental Disorders

The observational research indicates that risky sexual activities contribute to the development of mental disorders. However, the potential causal effects of sexual behaviors, sildenafil use, and hormonal contraceptive use on mental disorders remain unclear.

We applied two-sample Mendelian randomization (univariable and multivariable MR) to assess the effects of age at first sex (AFS) and number of sexual partners (NSP) on mental disorders and sex differences, using Genome-Wide Association Studies (GWAS) data from UK Biobank and FinnGen. An observational analysis using NHANES 2015-2016 was conducted for validation. We further used expression quantitative trait loci (eQTL) to proxy drug target genes and examined the impact of sildenafil and contraceptives on mental disorders using SMR and IVW-MR methods.

We found that an increased genetically predicted AFS was associated with decreasing anxiety disorders, bipolar affective disorders, depression, disturbance of activity and attention (DAA), and post-traumatic stress disorder. An increased genetically predicted NSP was associated with increasing anxiety disorders, bipolar affective disorders, depression, and post-traumatic stress disorder. SMR analysis found that PDE11A, instead of PDE5A, a drug target for sildenafil, causes DAA. Suggestive evidence was observed regarding the positive association between progesterone receptor expression and risk of depression. Notably, given the exploratory nature of the multiple analyses, these findings require replication in independent cohorts to confirm causal relationships.