A Comprehensive Mendelian Randomization Study Investigating Multiple Exposures and Outcomes: Focusing on Nontoxic Goitre and Type 2 Diabetes Mellitus

Objective: Previous research suggests a correlation between nontoxic goitre and type 2 diabetes mellitus (T2DM). However, the causality was vulnerable to confounding variables. Therefore, there is an urgent need for a more rigorous research approach to examine the causal connection between nontoxic goitre and T2DM. Design: Multiple exposures and outcomes two-sample Mendelian randomization (MR) study was carried out in two stages: nontoxic goitre traits (including nontoxic diffuse goitre, NDG; nontoxic multinodular goitre, NMG; and other/unspecified nontoxic goitre, OUNG) were investigated as exposure while T2DM was investigated as an outcome in the first step, whereas the second step was reversed. The GWAS summary data for nontoxic goitre traits and T2DM were collected from the Finngen database. The summary data for fasting glucose, fasting insulin, and HbA1c were obtained from the open GWAS database established by the MRC Integrated Epidemiology Unit (IEU). The inverse-variance weighted (IVW) approach was used to obtain MR estimates, and various sensitivity analysis was also performed. Results: NDG had a potential protective causal relationship with T2DM (OR = 0.978; 95% CI: 0.957-0.998; p = 0.034) and fasting glucose (OR = 0.995; 95% CI: 0.990-0.999; p = 0.011), while NMG had a potential protective causal relationship with T2DM (OR = 0.941; 95% CI: 0.902-0.982; p = 0.008) and HbA1c (OR = 0.992; 95% CI: 0.986-0.998; p = 0.015). OUNG was found to decrease the odds of T2DM by 4.4% (OR = 0.966; 95% CI: 0.938-0.995, p = 0.023). T2DM had a potential causal relationship with NDG (OR = 1.239; 95% CI: 1.020-1.504; p = 0.031), and a potential protective effect against NMG (OR = 0.669; 95% CI: 0.566-0.792; p < 0.001) and OUNG (OR = 0.694; 95% CI: 0.545-0.883; p = 0.004). There was no evidence of a positive association between glycemic traits and nontoxic goitre traits (p > 0.05). Conclusions: Our findings indicate a potential causal relationship between nontoxic goitre traits and T2DM. Specifically, our study addresses that NMG and T2DM may have a significant causal effect on each other in both directions.