Genetic liability to major depressive syndrome (MDD) has demonstrated a significant positive causal association with type 2 diabetes and coronary artery disease (CAD), according to a study published in Diabetologia.

Epidemiological data and observational studies have shown an association between MDD and an increased risk of type 2 diabetes; whether this association is causal is unclear. Biological alterations and unhealthy behaviors associated with MDD may cause type 2 diabetes, and conversely, disability and comorbidity may cause MDD.

The researchers used Mendelian randomization to determine if there are bidirectional causal associations between MDD, type 2 diabetes, CAD, and heart failure. This method relies on genetic variants associated with increased risk of the examined health conditions, and therefore diminishes the role of environment or behavioral variables. The study relied on summary level data from meta-analyses of genome-wide association studies (GWAS) for which the vast majority of individuals were of European descent. 

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Data for MDD associated single-nucleotide polymorphisms (SNPs) came from a GWAS study of individuals with (n=246,363) and without (n=561,190) MDD, which was then replicated in a larger population (MDD, n=414,055; without MDD, n=892,299). Analyses for associations included the 96 significant variants from the studies. Additional GWAS data was collected from the UK Biobank and Psychiatric Genomic Consortium (MDD, n=107,756; without MDD, n=329,443). Data for cardiometabolic disease associated SNPs came from 32 GWASs (subjects with type 2 diabetes, n=74124; without type 2 diabetes, n=824,006) using 202 significant variants from the studies.

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The researchers used 1000 GWAS meta-analyses of 48 studies of individuals with (n=60801) and without (n=123,504) CAD using 44 significant SNPs. They also included data on individuals with (n=47309) and without (n=930,014) heart failure, analyzing 12 significant variants.

The results from the Mendelian randomization indicated a causal association of MDD with type 2 diabetes and CAD, as well as a trend for heart disease. Conversely the results showed no causation of type 2 diabetes, CAD, or heart failure with MDD. Genetic liability of MDD was significantly associated with type 2 diabetes (Odds Ratio [OR], 1.26; 95% CI, 1.10-1.43, P =.0006) and CAD (OR, 1.16; 95% CI, 1.05-1.29, P =.0047). While not statistically significant there was a trend for an association of MDD with heart failure (OR, 1.11; 95% CI, 1.01-1.21, P =.033). No significant association was found between genetic liability of type 2 diabetes, CAD, or heart failure with MDD.

The main limitations to the study are the possibility of pleiotropy, where genes may influence unrelated phenotypic traits causing a false association, and population stratification caused by inclusion of a minority of individuals (23%) that were not of European descent in the GWAS CAD data.

“A series of biological abnormalities related to depression, including increased counter-regulatory hormone release and activity, alterations in glucose transport function and increased immunoinflammatory activation, may influence the risk of type 2 diabetes,” the researchers noted, “in addition, lifestyle factors, such as smoking and alcohol consumption, may play a mediating role in the pathway from depression to type 2 diabetes.”


Tang B, Yuan S, Xiong Y, He Q, Larsson SC. Major depressive disorder and cardiometabolic diseases: a bidirectional Mendelian randomisation study [published online ahead of print, 2020 Apr 8]. Diabetologia. 2020;10.1007/s00125-020-05131-6.