Abstract
Aims/hypothesisObservational studies have shown a bidirectional association between major depressive disorder (MDD) and cardiometabolic diseases. We conducted a two-sample bidirectional Mendelian randomisation (MR) study to assess the causal associations of MDD with type 2 diabetes, coronary artery disease (CAD) and heart failure and vice versa.MethodsWe extracted summary-level data for MDD, type 2 diabetes, CAD and heart failure from corresponding published large genome-wide association studies of individuals mainly of European-descent. In total, 96 SNPs for MDD, 202 SNPs for type 2 diabetes, 44 SNPs for CAD and 12 SNPs for heart failure were proposed as instrumental variables at the genome-wide significance level (p < 5 × 10−8). The random-effects inverse-variance weighted method was used for the main analyses.ResultsGenetic liability to MDD was significantly associated with type 2 diabetes and CAD at the Bonferroni-corrected significance level. The ORs of type 2 diabetes and CAD were respectively 1.26 (95% CI 1.10, 1.43; p = 6 × 10−4) and 1.16 (95% CI 1.05, 1.29; p = 0.0047) per one-unit increase in loge odds of MDD. There was a suggestive association between MDD and heart failure (OR 1.11 [95% CI 1.01, 1.21]; p = 0.033). We found limited evidence supporting causal effects of cardiometabolic diseases on MDD risk in the reverse MR analyses.Conclusions/interpretationThe present study strengthened the evidence that MDD is a potential risk factor for type 2 diabetes and CAD. Whether MDD is causally related to heart failure needs further study.Data availabilityAll data included in this study were uploaded as supplements and are also publicly available through published GWASs and open GWAS datasets (UK Biobank, 23andMe and Psychiatric Genomics: https://datashare.is.ed.ac.uk/handle/10283/3203; DIAGRAM: http://diagram-consortium.org/downloads.html; CARDIoGRAMplusCD4: www.cardiogramplusc4d.org/; HERMES: http://www.kp4cd.org/datasets/mi).Graphical abstract
Highlights
Major depressive disorder (MDD) and type 2 diabetes are both important public health issues globally
The association was slightly weaker and borderline significant in a sensitivity analysis using SNPs associated with type 2 diabetes in the BMI-adjusted model (ESM Fig. 2)
The reverse Mendelian randomisation (MR) analysis provided no evidence that liability to type 2 diabetes, coronary artery disease (CAD) or heart failure was related to MDD
Summary
Major depressive disorder (MDD) and type 2 diabetes are both important public health issues globally. Epidemiological data showed that the prevalence of MDD among individuals with type 2 diabetes was twice that in those without diabetes [3], which indicated a potential link between these two prevailing diseases. Observational studies have reported that MDD is associated with an increased risk of type 2 diabetes through several biological alterations and unhealthy behaviours [4, 5]. It has further been suggested that type 2 diabetes may play a role in the development of MDD, possibly by causing disability and comorbidity [6]. Whether the mutual association between MDD and type 2 diabetes is causal remains unclear due to potential residual confounding and reverse causation bias in observational studies [7]
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