The genetic overlap between mood disorders and cardiometabolic diseases: a systematic review of genome wide and candidate gene studies

Abstract

Meta-analyses of genome-wide association studies (meta-GWASs) and candidate gene studies have identified genetic variants associated with cardiovascular diseases, metabolic diseases and mood disorders. Although previous efforts were successful for individual disease conditions (single disease), limited information exists on shared genetic risk between these disorders. This article presents a detailed review and analysis of cardiometabolic diseases risk (CMD-R) genes that are also associated with mood disorders. First, we reviewed meta-GWASs published until January 2016, for the diseases 'type 2 diabetes, coronary artery disease, hypertension' and/or for the risk factors 'blood pressure, obesity, plasma lipid levels, insulin and glucose related traits'. We then searched the literature for published associations of these CMD-R genes with mood disorders. We considered studies that reported a significant association of at least one of the CMD-R genes and 'depression' or 'depressive disorder' or 'depressive symptoms' or 'bipolar disorder' or 'lithium treatment response in bipolar disorder', or 'serotonin reuptake inhibitors treatment response in major depression'. Our review revealed 24 potential pleiotropic genes that are likely to be shared between mood disorders and CMD-Rs. These genes include MTHFR, CACNA1D, CACNB2, GNAS, ADRB1, NCAN, REST, FTO, POMC, BDNF, CREB, ITIH4, LEP, GSK3B, SLC18A1, TLR4, PPP1R1B, APOE, CRY2, HTR1A, ADRA2A, TCF7L2, MTNR1B and IGF1. A pathway analysis of these genes revealed significant pathways: corticotrophin-releasing hormone signaling, AMPK signaling, cAMP-mediated or G-protein coupled receptor signaling, axonal guidance signaling, serotonin or dopamine receptors signaling, dopamine-DARPP32 feedback in cAMP signaling, circadian rhythm signaling and leptin signaling. Our review provides insights into the shared biological mechanisms of mood disorders and cardiometabolic diseases.

Figure 1

Schematic model for the potential pleiotropic effects of a shared gene locus that is associated with mood disorders and cardiometabolic diseases.^{, , , , ,} The distal and proximal factors are obtained from the literature, and the World Health Organization (WHO) often uses the classification. Distal factors refer to those factors that require an intermediate factor to cause diseases, while proximal factors can directly cause diseases. The red bold lines represent the pleiotropic effect of a genetic locus on cardiometabolic diseases and associated risk factors, psychiatric morbidity, i.e.mood disorders and pharmacological treatment response in MDD and BPD. The bi-directional arrows indicate bidirectional epidemiological relationships between the cardiometabolic diseases and mood disorders. BPD, bipolar disorder; MDD, major depressive disorder.

Figure 2

The flow chart shows the stages of literature search and evaluation of candidate pleiotropic genes for the CMD-Rs and mood disorders. CMD-R genes refers to the genes in which the CMD-R lead SNPs are located-in or nearby and their expression is influenced by the respective lead SNPs (cis-eQTL). CMD-R, Cardiometabolic Diseases and associated Risk factors; CMMDh, Cardiometabolic Mood Disorders hub genes; cis-eQTL, Cis (nearby) gene expression quantitative trait loci; GWAS, Genome Wide Assocation Study; Meta-GWA, meta-analysis of Genome Wide Association studies; MuTHER, Multiple Tissue Human Expression Resource; SNP, single nucleotide polymorphism.

Figure 3

The list of 24 CMMDh genes (left), genes enriched to the top canonical signaling pathways (middle) and the network of these genes with mood disorders and the CMD-Rs (right). In the right, it illustrates ingenuity IPA-generated network of the CMMDh genes with coronary artery diseases, hypertension, diabetes mellitus, obesity, depressive disorder and bipolar disorder. The coloured dotted lines highlights CMMDh genes that were related to bipolar disorder (orange) and depression (red). CMMDh, Cardiometabolic Mood Disorders hub genes; IPA, Ingenuity Pathway Analysis.