Follistatin levels and endocrine disorders: A two-sample Mendelian randomization study

To investigate the causal relationship between follistatin (FST) levels and endocrine diseases such as polycystic ovary syndrome (PCOS), type 2 diabetes (T2DM), obesity, and osteoporosis (OP) using a 2-sample Mendelian randomization (MR) analysis. Instrumental variables closely associated with FST levels were obtained from large-scale genome-wide association study data in the IEU database. Summary-level data for 4 endocrine diseases were sourced from the latest version of the FinnGen database. Our primary method for MR analysis was the inverse-variance weighted (IVW) method, supplemented by the MR-Egger and Weighted Median methods. We conducted a series of sensitivity tests to assess the reliability of our MR results. The IVW analysis revealed a significant causal relationship between elevated levels of FST and both PCOS (odds ratio [OR] = 1.129, 95% confidence interval [CI]: 1.042-1.224, P = .003) and T2DM (OR = 1.103, 95% CI: 1.02-1.187, P = .01). However, the IVW model did not indicate a causal connection between FST levels and either OP (OR = 1.061, 95% CI: 0.909-1.238, P = .452) or obesity (OR = 1.082, 95% CI: 0.983-1.192, P = .108). The reverse MR analysis results indicated a causative association between T2DM (OR = 1.047, 95% CI: 1.006-1.089, P = .023) and an elevation in FST levels, as well as a causal link between OP (OR = 0.889, 95% CI: 0.804-0.982, P = .021) and a reduction in FST levels. There is no direct causality between PCOS (OR = 0.925, 95% CI: 0.778-1.098, P = .372), obesity (OR = 1.035, 95% CI: 0.968-1.107, P = .312), and FST levels. In addition, our sensitivity tests, which included a pleiotropy test, heterogeneity test, and "leave-one-out" analysis, consistently confirmed the reliability of our results. Genetically predicted high FST levels are causally associated with increased risks of PCOS and T2DM, indicating a potential role in endocrine disease pathogenesis. Moreover, reverse MR analysis revealed a significant causal link between OP and decreased FST levels, suggesting that FST may serve as a promising biomarker or therapeutic target in bone metabolism.