Insights into modifiable risk factors of erectile dysfunction, a wide-angled Mendelian Randomization study

[Display omitted] •Our study explored the causal association between 42 predominant risk factors and erectile dysfunction (ED) under a two-sample MR framework.•This comprehensive MR study supported the causal role of obesity, type 2 diabetes, basal metabolic rate, poor self-health rating, cigarette and alcohol consumption, insomnia and snoring, depression, hypertension, stroke, ischemic stroke, coronary heart disease, myocardial infarction, heart failure, SHBG and adiponectin in the onset and development of ED. A clear causal link may be beneficial to early identification and target intervention in patients with ED.•No significant association was detected between lipid levels and ED.•Genetic predisposition to higher sex hormone-binding globulin (SHBG) levels can decrease the risk of ED.•Identifying reversible risk factors is the first-line evaluation for ED patients as per the diagnostic work-up of the European Association of Urology Guidelines. This study provides a better understanding of the risk factors of ED and is conducive to early identification and intervention of ED. The causal association between modifiable risk factors and erectile dysfunction (ED) remains unclear, which hinders the early identification and intervention of patients with ED. The present study aimed to clarify the causal association between 42 predominant risk factors and ED. Univariate Mendelian Randomization (MR), multivariate MR, and mediation MR analyses were used to investigate the causal association between 42 modifiable risk factors and ED. Combined results were pooled from two independent ED genome-wide association studies to verify the findings. Genetically predicted body mass index (BMI), waist circumference, trunk fat mass, whole body fat mass, poor overall health rating, type 2 diabetes, basal metabolic rate, adiponectin, cigarette consumption, insomnia, snoring, hypertension, stroke, ischemic stroke, coronary heart disease, myocardial infarction, heart failure, and major depressive disorder were found to increase the risk of ED (all P