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

Abstract

Introduction: 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.

Methods: 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.

Results: 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 < 0.05). Additionally, genetic liability to higher body fat percentage and alcohol consumption were suggestively associated with an increased risk of ED (P < 0.05 and adjusted P > 0.05). Genetic predisposition to higher sex hormone-binding globulin (SHBG) levels could decrease the risk of ED (P < 0.05). No significant association was detected between lipid levels and ED. Multivariate MR identified type 2 diabetes, basal metabolic rate, cigarette consumption, hypertension, and coronary heart disease as risk factors for ED. The combined results confirmed that waist circumference, whole body fat mass, poor overall health rating, type 2 diabetes, basal metabolic rate, adiponectin, cigarette consumption, snoring, hypertension, ischemic stroke, coronary heart disease, myocardial infarction, heart failure, and major depressive disorder could increase the risk of ED (all P < 0.05), while higher SHBG decreased the risk of ED (P = 0.004). There were suggestive significances of BMI, insomnia, and stroke on ED (P < 0.05 and adjusted P > 0.05).

Conclusion: 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.

Keywords: Cardiovascular diseases; Erectile dysfunction; Lifestyle factors; Mendelian randomization; Mental disorder; Metabolic diseases.

Graphical abstract

Fig. 1

Overview of the study design and analysis strategy. (A): Overview of the study design. Exposures are from six domains including anthropometric traits, metabolic traits, lifestyle factors, hormones, cardiovascular diseases, and mental disorders. The MR framework is based on the three basic MR assumptions. (B): Analysis strategy of MR. Qualified SNPs are filtered as IVs and then subjected to sensitivity analyses and evaluation of heterogeneity and pleiotropy. The biases from sample overlap and statistic power are further evaluated. Results from the discovery and replication stages are combined. MR: Mendelian Randomization; SNP: single nucleotide polymorphism; BMI: body mass index; HbA1C: glycosylated hemoglobin type A1C; SHBG: sex hormone-binding globulin; SVMR: single variable MR; MVMR: multivariate MR.

Fig. 2

Analysis of 42 predominant risk factors on ED in the discovery ED GWAS. The analysis is performed in the discovery ED GWAS and the results of six approaches including IVW, MR-Egger, Weighted median, Maximum likelihood, MR.RAPS, and MR-PRESSO are summarized here. Detailed statistics are described in Supplemental Table 2 and Fig. 3. ED: erectile dysfunction; BMI: body mass index; SHBG: sex hormone-binding globulin; HbA1C: glycosylated hemoglobin type A1C; GWAS: genome-wide association study; MR: Mendelian Randomization; IVW: inverse variance weighting; MR-PRESSO: MR Pleiotropy Residual Sum and Outlier; MR.RAPS: robust adjusted profile score. High risk: P < 0.05 and FDR < 0.05; Potential risk: P < 0.05 and FDR > 0.05; Unclear: P > 0.05; Protective: P < 0.05 and FDR < 0.05.

Fig. 3

Forest plot of IVW estimator results in the discovery ED GWAS. GWAS: genome-wide association study; IVW: inverse variance weighting; BMI: body mass index; ED: erectile dysfunction; SHBG: sex hormone-binding globulin; HbA1C: glycosylated hemoglobin type A1C; OR: odds ratio; CI: confidence interval; FDR: false discovery rate.

Fig. 4

The association between modifiable factors and ED in multivariate MR. All the analyses were performed in the discovery ED GWAS. GWAS: genome-wide association study; MR: Mendelian Randomization; ED: erectile dysfunction; NSNP: number of single nucleotide polymorphisms; SHBG: sex hormone-binding globulin; M to V: moderate to vigorous; ADHD: attention deficit and hyperactivity disorder; OR: odds ratio; CI: confidence interval.

Fig. 5

Results of mediation MR results in the discovery ED GWAS. GWAS: genome-wide association study; ED: erectile dysfunction; SHBG: sex hormone-binding globulin; OR: odds ratio; CI: confidence interval.

Fig. 6

Combined results from the discovery and replication ED GWASs. GWASs: genome-wide association studies; BMI: body mass index; ED: erectile dysfunction; SHBG: sex hormone-binding globulin; HbA1C: glycosylated hemoglobin type A1C; M to V: moderate to vigorous; ADHD: attention deficit and hyperactivity disorder; OR: odds ratio; CI: confidence interval; FDR: false discovery rate.