Evidence of bidirectional relationship between type 2 diabetes and depression; a Mendelian randomization study.

Major depressive disorder (MDD) and type 2 diabetes (T2D) represent two global health challenges with a high degree of co-occurrence. Here, we aim to investigate the causal relationship between MDD and T2D in diverse ancestries using Mendelian randomization (MR) in GWAS summary statistic and individual level (UK Biobank (UKB)) data. We assessed the bi-directional causal relationship between: (a) MDD and T2D and (b) MDD and glycaemic biomarkers (e.g. TG:HDL-C ratio, a measure of insulin resistance, fasting glucose) in non-diabetic individuals. In UKB we also tested the role of T2D on treatment resistant depression (TRD). We used multivariable MR (MVMR) to assess the role of body mass index (BMI) in the MDD to T2D relationship. Our results demonstrated that a doubling in MDD genetic liability was associated with 1.14 higher odds of T2D (95% CI:1.09, 1.19), whilst a doubling in T2D genetic liability associated with 1.02 higher odds of MDD (95% CI:1.01, 1.03). Consistent effect estimates were observed in the UKB when stratifying by sex and suggested a role for T2D in TRD. T2D GWAS derived clusters of genetic variants highlighted the importance of specific pathways in the MDD relationship, including variants raising T2D risk via body fat (OR:1.04; 95% CI:1.02, 1.06), obesity mediated insulin resistance (OR:1.06; 95% CI:1.04, 1.09) and residual glycaemic (OR: 1.02; 95% CI:1.00, 1.04) pathways. MVMR with BMI attenuated the bidirectional relationship between MDD and T2D, particularly from MDD to T2D. Genetic liability to MDD was also associated with higher TG:HDL-C ratio in individuals without T2D (β:0.11; 95% CI:0.08, 0.14). We provide evidence of bidirectional causal association between MDD and T2D, with MDD strongly predicting insulin resistance and T2D. T2D predicted both MDD and TRD and highlighted the importance of obesity and body fat pathways in the T2D to MDD relationship.