Major depressive disorder but not bipolar disorder and schizophrenia is a causal factor for type 2 diabetes as determined by Mendelian randomization

Objective: In many epidemiologic studies, type 2 diabetes has been reported to be associated with severe mental illness (SMI) such as schizophrenia (SCZ), bipolar disorder (BPD), and major depressive disorder (MDD). However, the relationship between SMI and type 2 diabetes is bi-directional, and the causal relationship remains unclear due to various confounders. Therefore, a Mendelian randomization (MR) study is necessary to identify the causality between them. Research Design and Methods: We conducted a two-sample MR study to identify the causal effect of SMI on type 2 diabetes using the inverse-variance weighted (IVW), MR-Egger, MR- Egger with a simulation extrapolation, weighted median approach, and MR-Pleiotropy RESidual Sum and Outlier methods. The most appropriate method was selected according to the instrument variables assumption. Results: We found that MDD had a significant causal effect on type 2 diabetes from the results obtained using the IVW method (Odds ratio (OR): 1.191, 95% CI: 1.036-1.372, P = 0.014); however, this was not observed for BPD (IVW, OR: 1.006, 95% CI: 0.918-1.104, P = 0.892) or SCZ (IVW, OR: 1.016, 95% CI: 0.974-1.059, P = 0.463). The absence of reverse-causality between MDD and type 2 diabetes was also demonstrated from bidirectional MR studies. Conclusions: These results clearly reveal important knowledge on the causal role of MDD in the risk of type 2 diabetes without a residual confounding, whereas the causality of BPD and SCZ was not shown. Therefore, careful attention should be paid to MDD patients in type 2 diabetes prevention and treatment.