Genetic overlap between depression and cardiometabolic disorders

Abstract

Depression and major cardiometabolic disorders (in this chapter, cardiometabolic disorders refer to the cardiovascular diseases, metabolic disorders, and associated risk factors) are highly heritable, i.e., they are caused by a combination of genetic and environmental factors. Moreover, there are genetic coheritabilities (genetic correlations) in these disorders suggesting the influence of common genes and shared biological pathways between them. Several candidate gene studies performed so far have identified risk-associated genes for depression, cardiovascular, and/or metabolic diseases. Besides, meta-analysis of genome-wide association (meta-GWA) studies reported a number of single nucleotide polymorphisms (SNPs) and candidate genes for the cardiometabolic disorders. Compared to the cardiometabolic disorders, the meta-GWA studies of depression have had limited success due to the heterogeneity of the disorder and lack of statistical power (sample size) to detect the associations. The first successfully replicated meta-GWA study for depression was published in July 2015. In this chapter, we present an appraisal and analysis of pleiotropic genes (pleiotropy occurs when a genetic region influences more than two phenotypes, disorders in this case) and shared biological pathways underlying the association of depression and the cardiometabolic diseases. These genes are shared between depression and (a) metabolic disorders (type 2 diabetes), (b) cardiovascular disorders (coronary artery diseases, hypertension), and (c) associated risk factors (blood pressure, obesity (body mass index), plasma lipid levels (high-density lipoprotein, low-density lipoprotein, triglycerides, total cholesterol), insulin and glucose-related traits (fasting glucose, fasting insulin, fasting proinsulin, insulin resistance-HOMA-IR, beta-cell function-HOMA-ß, and glycated hemoglobin A1C- HbA1C). Generally speaking, pleiotropic genes and shared biological mechanisms could explain part of the comorbidity between depression and cardiometabolic disorders. Genetic polymorphisms within the genes: MTHFR, CACNA1D, CACNB2, GNAS, ADRB1, NCAN, REST, FTO, POMC, BDNF, CREB, ITIH4, LEP, GSK3B, SLC18A1, TLR4, APOE, CRY2, HTR1A, ADRA2A, MTNR1B, and IGF1 are associated with both depression and cardiometabolic disorders. These genes belong to biologically relevant signaling pathways that are potentiality important in the relationship between depression and cardiometabolic diseases. The pathways include: corticotrophin - releasing hormone signaling, AMPK signaling, cAMP - mediated and G -p rotein- coupled receptor signaling, axonal guidance signaling, and serotonin and dopamine receptor signaling. A better understanding of these genes and related pathways will enhance knowledge as to why patients suffer from multiple diseases at a time and how multi-morbidities influence pharmacological treatment response.