Investigating shared aetiology between type 2 diabetes and major depressive disorder in a population based cohort

Abstract

Type II diabetes (T2D) and major depressive disorder (MDD) are often co‐morbid. The reasons for this co‐morbidity are unclear. Some studies have highlighted the importance of environmental factors and a causal relationship between T2D and MDD has also been postulated. In the present study we set out to investigate the shared aetiology between T2D and MDD using Mendelian randomization in a population based sample, Generation Scotland: the Scottish Family Health Study (N = 21,516). Eleven SNPs found to be associated with T2D were tested for association with MDD and psychological distress (General Health Questionnaire scores). We also assessed causality and genetic overlap between T2D and MDD using polygenic risk scores (PRS) assembled from the largest available GWAS summary statistics to date. No single T2D risk SNP was associated with MDD in the MR analyses and we did not find consistent evidence of genetic overlap between MDD and T2D in the PRS analyses. Linkage disequilibrium score regression analyses supported these findings as no genetic correlation was observed between T2D and MDD (rG = 0.0278 (S.E. 0.11), P‐value = 0.79). As suggested by previous studies, T2D and MDD covariance may be better explained by environmental factors. Future studies would benefit from analyses in larger cohorts where stratifying by sex and looking more closely at MDD cases demonstrating metabolic dysregulation is possible. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

Genetic comorbidity between major depression and cardio-metabolic disease, stratified by age at onset of major depression

“…Twin studies have previously shown genetic overlap between MDD and type 2 diabetes, but evidence from genetic studies has been weaker. The current study, however, does show evidence for a shared genetic aetiology between MDD and type 2 diabetes based on both polygenic risk scores and genetic correlations (21)(22)(23).…”

“…Studies using twin data also showed that the phenotypic association between MDD and type 2 diabetes was partly due to genetic effects (21). This finding has been replicated using a polygenic risk score approach(22), but not using genetic correlations (22,23). The Brainstorm Consortium did not find a significant genetic correlation between MDD and stroke(24), while Wassentheil-Smoller et al(25) showed that higher polygenic risk for MDD was associated with increased risk for stroke, in particular small vessel disease.…”

How 25 years of psychosocial research has contributed to a better understanding of the links between depression and diabetes

“…No single type 2 diabetes risk SNP was associated with major depression in the MR analyses. In the same way, the results for the polygenic risk scores analyses and also the linkage disequilibrium score regression analyses showed no consistent evidence of genetic overlap between major depression and type 2 diabetes . However, the lack of genetic studies that explain the link between depression and diabetes does not reject the common ground hypothesis, as we know that the genetic predisposition of both diabetes and depression is modest.…”

“…Based on the common ground hypothesis, several biological mechanisms have been associated with poor diabetes outcomes in people with diabetes and depression [31][32][33][34][35][36][37]. This hypothesis assumes that diabetes and depression have common denominators, including genetic factors, overactivation of the innate immune system or dysregulation of the HPA axis.…”

The Bidirectional Relationship between Diabetes and Depression: A Literature Review

“…Furthermore, the study found no association between T2DM and depression at the phenotypic level (adjusted P≤0.65). Clarke et al [ 60 ] in 2017 used Mendelian randomization in a populationbased cohort of 21,516 individuals to test the association between MDD and 11 SNPs previously found to be associated with T2DM. In their analysis, only the A allele of rs6808574 was negatively associated with MDD.…”