Yuhan Zhang ^1,2,3 Liuxiang Fu ^1*

• ¹ Emergency Department, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, No.1 Minde Road, Nanchang 330006, China., Nanchang, China
• ² General Surgery Center, Department of Thyroid Surgery, The 1st Hospital of Jilin University, Chang Chun, China, Changchun, China
• ³ Department of General Surgery, Panzhihua Central Hospital, Panzhihua, Sichuan Province, China

Background: To investigate the causality between Grave's Disease (GD) and Diabetes mellitus (DM), we designed bidirectional two-sample Mendelian randomization (MR) and multivariable MR (MVMR) studies.Methods: Single-nucleotide polymorphisms (SNPs) associated with GD, thyroid peroxidase (TPO), thyroglobulin (Tg), thyroid-stimulating hormone (TSH), type 1 diabetes (T1D), and type 2 diabetes (T2D) were obtained from the IEU Open GWAS and FinnGen biobank databases. For the forward MR study, we used GD (sample size = 458,620) as the exposure and T1D (sample size = 520,580) and T2D (sample size = 211,766) as the outcomes. Next, high risk of T1D and T2D were used as exposure variables, and GD was used as the outcome variable for the reverse MR analysis. Finally, MVMR analysis was conducted to investigate the probable relationship between DM and indicators for thyroid function like TPO, Tg, and TSH. The inverse variance weighting (IVW) was used as the main method. Finally, the heterogeneity and sensitivity were assessed.Results: There were 27, 88, and 55 SNPs associated with GD, T1D, and T2D, respectively. A significant causal connection between higher genetic liability of GD and the risk of T1D (odds ratio [OR] [95% confidence interval, CI] = 1.411 [1.077-1.848], P = 0.012) and T2D (OR [95% CI] = 1.059 [1.025-1.095], P = 5.53e-04) was found in the forward MR analysis. However, reverse MR suggested that there was a genetic susceptibility to T1D that increased the likelihood of developing GD (OR [95% CI] = 1.059 [1.025-1.095], P = 5.53e-04), while T2D did not (OR [95% CI] = 0.963 [0.870-1.066], P = 0.468). Furthermore, there was inadequate evidence to suggest that abnormal TSH, TPO, and Tg levels increase the risk of incident T1D or T2D in individuals with GD. MVMR revealed no causal relationship among Tg, TSH, TPO, T1D, or T2D.There was no increased risk of T1D with an increase in genetic susceptibility to GD, although higher genetic susceptibility to T1D has been shown to be associated with increased risk of developing GD. A unidirectional causal relationship between the genetic liability for GD and increased risk of T2D was observed using MR analyses.