A Mendelian randomization study on causal relationship between metabolic factors and abnormal spermatozoa.

Background: Male infertility is a global health problem. There is an increasing attention on the association of metabolic status with spermatogenesis. However, the impacts of metabolic factors on semen parameters are still unclear. To provide evidence for developing appropriate interventions on disease screening and prevention, we performed a Mendelian randomization (MR) analysis to assess causality between various metabolic factors and abnormal spermatozoa.

Methods: We conducted a two-sample MR study to appraise the causal effects of 16 metabolic factors (including indexes of metabolic traits, glucose metabolism, lipid profile, adipokines, uric acid and metabolic diseases) on abnormal spermatozoa from genome-wide association studies (GWASs). Filtering with strict criteria, eligible genetic instruments closely associated with each of the factors were extracted. We employed inverse variance weighted for major analysis, with supplement MR methods including MR-Egger and weighted median. Heterogeneity and pleiotropy tests were further used to detect the reliability of analysis.

Results: After rigorous quality control in this MR framework, we identified that body fat percentage [odds ratio (OR) =1.49, 95% confidence interval (CI): 1.01-2.20, P=0.046] and resistin (OR =1.55, 95% CI: 1.11-2.19, P=0.01) were causally associated with a higher risk of abnormal spermatozoa. In terms of other indexes of metabolic traits, glucose metabolism, serum lipid profile and uric acid and metabolic diseases including type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD), no causal effects were observed (P>0.05).

Conclusions: Our MR analysis provides robust evidence that body fat percentage and resistin are risk factors for abnormal spermatozoa, suggesting implications of identifying them for potential interventions and clinical therapies in male infertility. Further investigation in larger-scale GWASs on subgroups of abnormal spermatozoa will verify impacts of metabolic factors on spermatogenesis.