Shared genetic architecture between anxiety, depression and erectile dysfunction: a genome-wide cross-trait analysis

The epidemiological association between erectile dysfunction (ED) and anxiety/depression has been extensively studied; however, the underlying genetic mechanisms remain elusive. This study aimed to investigate the shared genetic architecture linking ED with depression and anxiety disorders, and to identify common risk loci, associated genes, and underlying genetic mechanisms.

Based on a large-scale genome-wide association study (GWAS) summary-level, genetic overlaps were identified between two common mental health problems (anxiety and depression) and ED (223,805 participants). Depression-related phenotypes: depression (finngen_R12_F5_DEPRESSIO, 494,164 participants), major depression (ieu-b-102, 500,199 participants), mental health problemsever diagnosed by a professional: depression (ukb-d-20544_11, 117,782 participants), depression or dysthymia (finngen_R12_F5_DEPRESSION_DYSTHYMIA, 326,981 participants), psychotic depression (finngen_R12_F5_DEPRESSION_PSYCHOTIC, 257,015 participants), recurrent or chronic depression (F5_DEPRESSION_RECURRENT, 280,487 participants). Anxiety-related phenotypes: all anxiety disorders (finngen_R12_F5_ALLANXIOUS, 480,289 participants), anxious personality disorder (finngen_R12_F5_ANXPER, 487,194 participants), generalized anxiety disorder (finngen_R12_F5_GAD, 451,562 participants), mental health problems ever diagnosed by a professional: anxiety, nerves or generalized anxiety disorder (ukb-d-20544_15, 117,751 participants). Cross-trait pleiotropic analysis was conducted to pinpoint shared pleiotropic loci and genes. Additionally, functional annotation and tissue-specific analyses were executed to assess the influence of pleiotropic genes. Subsequently, Mendelian randomization methods were applied to explore causal associations.

Our study uncovered complex genetic and causal connections between anxiety, depression, and ED. We identified shared pleiotropic risk loci (16p13.3, 6q16.3, 6q25.1, 1p35.1, 8q22.1, and so on) and genes (TOX4, PTCH1, RERE, SLC45A and so on) across these conditions. Furthermore, we found that genetic risk loci may impact both mental health issues and ED through the involvement of the pituitary gland, cerebellum, and cerebellar hemispheres.

Our research demonstrates a shared genetic architecture between mental health problems (anxiety and depression) and ED, shedding light on potential underlying mechanisms.