Bidirectional causal relationship between depression and Type 2 diabetes: a multi-ancestry and sex stratified Mendelian Randomization analysis.

Background: Observational studies have demonstrated a strong correlation between depression and type 2 diabetes (T2D). However, the causal relationships remain poorly understood, particularly in non-European and sex-stratified populations.

Methods: A two-sample bidirectional Mendelian randomization (MR) analysis was performed to evaluate the causal relationship between broadly defined depression and T2D across five ancestry groups (European, African, East Asian, South Asian, and Hispanic/Latin American), using the largest available multi-ancestry genome-wide association study (GWAS) data. Additionally, sex-stratified MR analysis was conducted to determine if these causal relationships were sex-specific. Potential mediators of the depression-T2D relationship were further explored through two-step MR analysis.

Results: Genetic predisposition to depression was significantly associated with an increased risk of T2D in the European population, but not in other ancestry groups, although the analyses in some non-European cohorts had limited statistical power. Conversely, genetically predicted T2D showed no causal association with depression across any populations. Sex-stratified analysis revealed that the depression-T2D relationship existed in both males and females, while being more significant in females. Mediation analysis suggested that body mass index (BMI) and smoking behavior explained a significant portion of the causal pathway linking depression to T2D.

Conclusion: These findings underscore the importance of early screening for depressive symptoms and the promotion of healthy lifestyle interventions, such as weight management and smoking cessation, as preventive strategies for T2D in people with depression. Further research is needed to validate these ancestry- and sex-specific causal effects, especially in populations with limited statistical power.