Unraveling the genetic links between depression and type 2 diabetes

Background: Type 2 diabetes (T2D) is a chronic metabolic disorder that has high comorbidity with mental disorders. The genetic relationships between T2D and depression are far from being well understood. Methods: We performed genetic correlation, polygenic overlap, Mendelian randomization (MR) analyses, crosstrait meta-analysis, and Bayesian colocalization analysis to assess genetic relationships between T2D and depression, in the forms of major depressive disorder (MDD) and depressed affect (DAF). Then, the summary data-based MR (SMR) analysis was performed to prioritize genes contributing to MDD and to T2D from functional perspective. MDD-driven signaling pathways were constructed to understand the influence of MDD on T2D at the molecular level. Results: T2D has positive genetic correlations both with MDD (rg = 0.14) and with DAF (rg = 0.19). The polygenic overlap analysis showed that about 60 % of causal variants for T2D are shared with MDD and DAF. The MR analysis indicated that genetic liabilities to both MDD (OR: 1.24, 95 % CI: 1.11-1.38) and DAF (OR: 1.48, 95 % CI: 1.23-1.78) are associated with an increased risk for T2D, while genetic liability to T2D is not associated with the risk for MDD (OR: 1.00, 95 % CI: 0.99-1.01) or DAF (OR: 1.01, 95 % CI: 1.00-1.02). The cross-trait metaanalysis identified 271 genomic loci, of which 29 were novel. Genetic predisposition to MDD and T2D shares six overlapping loci, involving some well-characterized genes, such as TCF4 and NEGR1. Colocalization analysis revealed three shared chromosome regions between MDD and T2D, which covers mediator genes including SCYL1, DENND1A, and MAD1L1. Molecular pathway analysis suggests mechanisms that promote the development of T2D through inflammatory pathways overactive in patients with MDD. The SMR analysis and the metaanalysis highlighted seven genes with functional implications for both MDD and T2D, including TNKS2, CCDC92, FADS1, ERI1, THUMPD3, NUCKS1, and PM20D1. Conclusions: Our study points out that depression, in the forms of MDD and DAF, may increase the risk of T2D. Analysis of underlying genetic variation and the molecular pathways, connecting depression and T2D, indicate that the pathophysiological foundations of these two conditions have a notable overlap.