Bayesian-based analysis of the causality between 731 immune cells and erectile dysfunction: a two-sample, bidirectional, and multivariable Mendelian randomization study

Abstract

Background: The causal relationship between certain immune cells and erectile dysfunction (ED) is still uncertain.

Aim: The study sought to investigate the causal effect of 731 types of immune cells on ED through Mendelian randomization (MR) using genome-wide association studies (GWAS).

Methods: Genetic instruments for 731 immune cells were identified through GWAS, and ED data were obtained from the FinnGen database. Univariable and multivariable bidirectional MR studies were conducted to explore potential causal relationships between these immune cells and ED. The inverse-variance weighted method was primarily used, with Cochran's Q test and MR-Egger intercept test assessing pleiotropy and heterogeneity. Bayesian weighted Mendelian randomization (BWMR) was also employed.

Outcomes: Six immune cells were identified as related to ED. CD45 on Natural Killer (NK) cells, CD33dim HLA DR+ CD11b + Absolute Count, CD19 on IgD- CD38dim B cells, and CD3 on CD39+ resting CD4 regulatory T cells were identified as risk factors, whereas CD20 on IgD+ CD38dim B cells and Activated & resting CD4 regulatory T cell %CD4+ T cells were protective factors. Further multivariable MR analysis confirmed that 5 of these immune cells independently impacted ED, except for CD45 on NK cells. Reverse MR analysis indicated that ED occurrence decreases certain immune cell counts, but BWMR found no causal relationship for CD20 on IgD+ CD38dim B cells.

Results: Our MR analysis confirmed a potential bidirectional causal relationship between immune cells and ED, providing new insights into potential mechanisms and therapeutic strategies.

Clinical translation: This study provides evidence for the impact of certain immune cells on the development of ED and suggests potential therapeutic targets.

Strengths and limitations: We performed both univariable and multivariable MR to strengthen the causal relationship between exposures and outcomes. However, the population in this study was limited to European ancestry.

Conclusion: Our MR analysis confirmed a potential bidirectional causal relationship between immune cells and ED. This provides new insights into potential mechanisms of pathogenesis and subsequent therapeutic strategies.

Keywords: Mendelian randomization; erectile dysfunction; immune cells.

Figure 1

Causal relationship model between immune cells and erectile dysfunction (ED).This figure illustrates the framework for investigating the causal relationship between 731 immune cell types and ED using Mendelian randomization. SNPs were extracted with P < 1 × 10⁻⁵ and r² < 0.001 (left side) and P < 5 × 10⁻⁶ and r² < 0.001 (right side) within a 10 000 kb clumping window. The model includes assumptions that SNPs directly influence immune cells (assumption 1), confounders may affect both immune cells and ED (assumption 2), and SNPs indirectly influence ED through immune cells (assumption 3). Three Mendelian randomization methods are applied: 2-sample, multivariate, and Bayesian weighted.

Figure 2

Mendelian randomization analysis of immune cell types and erectile dysfunction (ED). This figure shows the results of Mendelian randomization (MR) analyses investigating the association between various immune cell types and ED. Each row represents a specific immune cell type, analyzed using different MR methods (MR Egger, weighted median, inverse-variance weighted, simple mode, weighted mode, MVMR). The columns include the number of SNPs used (nSNP), P-values, odds ratios (OR) with 95% confidence intervals (CIs), and heterogeneity and pleiotropy test P-values. The forest plots illustrate the effect sizes, with statistically significant results (P < .05) indicating potential causal relationships.