The overlap of genetic susceptibility to schizophrenia and cardiometabolic disease can be used to identify metabolically different groups of individuals

Abstract

Understanding why individuals with severe mental illness (Schizophrenia, Bipolar Disorder and Major Depressive Disorder) have increased risk of cardiometabolic disease (including obesity, type 2 diabetes and cardiovascular disease), and identifying those at highest risk of cardiometabolic disease are important priority areas for researchers. For individuals with European ancestry we explored whether genetic variation could identify sub-groups with different metabolic profiles. Loci associated with schizophrenia, bipolar disorder and major depressive disorder from previous genome-wide association studies and loci that were also implicated in cardiometabolic processes and diseases were selected. In the IMPROVE study (a high cardiovascular risk sample) and UK Biobank (general population sample) multidimensional scaling was applied to genetic variants implicated in both psychiatric and cardiometabolic disorders. Visual inspection of the resulting plots used to identify distinct clusters. Differences between these clusters were assessed using chi-squared and Kruskall-Wallis tests. In IMPROVE, genetic loci associated with both schizophrenia and cardiometabolic disease (but not bipolar disorder or major depressive disorder) identified three groups of individuals with distinct metabolic profiles. This grouping was replicated within UK Biobank, with somewhat less distinction between metabolic profiles. This work focused on individuals of European ancestry and is unlikely to apply to more genetically diverse populations. Overall, this study provides proof of concept that common biology underlying mental and physical illness may help to stratify subsets of individuals with different cardiometabolic profiles.

Implication of Melanocortin Receptor Genes in the Familial Comorbidity of Type 2 Diabetes and Depression

“…As we and others have described [ 74 , 75 ], MDD, schizophrenia, bipolar disorder, and T2D share genetic comorbidity, but mental–metabolic comorbidity studies have begun in recent years [ 76 , 77 ]. Of equal interest, the globally recognized T2D risk gene TCF7L2 [ 78 ] has been found via a linkage study to contribute to schizophrenia [ 79 ], further supporting the existence of comorbid genetic pathogenesis of metabolic–mental disorders.…”

“…Our study suggests that the melanocortin receptors risk variants, detected as contributing to familial risk for MDD and/or T2D, might be part of a more complex pathway implicated in the shared comorbidity of metabolic and mental disorders [ 76 , 77 ]. While it is hard to disentangle the genes’ direct roles in the phenotypes tested from the possible underlying biological effect(s), the genes reported appear implicated in the investigated phenotypes, but only MC2R shows pleiotropic effects within our familial dataset.…”

Prenatal and Childhood Immuno-Metabolic Risk Factors for Adult Depression and Psychosis

“…147 Results have also suggested that distinct subgroups of schizophrenia patients could have unique metabolic risk loci and that leveraging pleiotropy with cardiovascular risk factors can aid in the discovery of schizophrenia risk variants. 147,148 Second, genetic predisposition to immuno-metabolic diseases has been associated with depression and psychosis. For instance, recent work from ALSPAC has found that genetic predisposition to type 2 diabetes was associated with an increased risk of psychosis at age 18 years, and vice versa; genetic predisposition to schizophrenia was associated with an increased risk of insulin resistance at age 18 years.…”

“…In addition, analyses of schizophrenia GWAS data have shown an enrichment of genetic risk for cardiovascular risk factors in common schizophrenia risk variants 147 . Results have also suggested that distinct subgroups of schizophrenia patients could have unique metabolic risk loci and that leveraging pleiotropy with cardiovascular risk factors can aid in the discovery of schizophrenia risk variants 147,148 …”

A network of transcriptomic signatures identifies novel comorbidity mechanisms between schizophrenia and somatic disorders

“…Conversely, the risk of somatic disease is approximately twice as high for persons with severe mental illnesses than for people without mental disorders 3 . Studies on genetic susceptibility have suggested a potential overlap of molecular mechanisms between psychotic disorders and somatic comorbidities 4,5 , such as shared gene risk loci that were demonstrated in several genotype studies 6 , biomarkers that were dysregulated across psychosis and comorbid diseases in transcriptomic analysis 7,8 , and shared molecular pathways that were identified in integrated analysis 7 .…”