Evidence for genetic contribution to the increased risk of type 2 diabetes in schizophrenia

Abstract

The epidemiologic link between schizophrenia (SCZ) and type 2 diabetes (T2D) remains poorly understood. Here, we investigate the presence and extent of a shared genetic background between SCZ and T2D using genome-wide approaches. We performed a genome-wide association study (GWAS) and polygenic risk score analysis in a Greek sample collection (GOMAP) comprising three patient groups: SCZ only (n = 924), T2D only (n = 822), comorbid SCZ and T2D (n = 505); samples from two separate Greek cohorts were used as population-based controls (n = 1,125). We used genome-wide summary statistics from two large-scale GWAS of SCZ and T2D from the PGC and DIAGRAM consortia, respectively, to perform genetic overlap analyses, including a regional colocalisation test. We show for the first time that patients with comorbid SCZ and T2D have a higher genetic predisposition to both disorders compared to controls. We identify five genomic regions with evidence of colocalising SCZ and T2D signals, three of which contain known loci for both diseases. We also observe a significant excess of shared association signals between SCZ and T2D at nine out of ten investigated p value thresholds. Finally, we identify 29 genes associated with both T2D and SCZ, several of which have been implicated in biological processes relevant to these disorders. Together our results demonstrate that the observed comorbidity between SCZ and T2D is at least in part due to shared genetic mechanisms.

Integrated Analysis of Summary Statistics to Identify Pleiotropic Genes and Pathways for the Comorbidity of Schizophrenia and Cardiometabolic Disease

“…Similar to our results, genetic variants in NT5C2 were previously reported to be associated with the comorbidity of SCZ and BMI (6), and genetic variants in or around MPHOSPH9 were reported to be increased risk of T2D in SCZ (49). The remaining genes are considered as novel genes associated with the comorbidity of SCZ and CMD.…”

Pharmacological enrichment of polygenic risk for precision medicine in complex disorders

“…Enrichment in these actionable pathways is consistent with longstanding hypotheses of deficits in neurodevelopment contributing to the aetiology of schizophrenia 36 . There is also evidence for aetiological overlap between schizophrenia and diabetes beyond what is attributable to metabolic effects of antipsychotic treatment, which supports our identification of an insulin related pathway as a candidate PES [37][38][39] .…”

Evidence-based guidelines for the pharmacological treatment of schizophrenia: Updated recommendations from the British Association for Psychopharmacology

“…Two meta-analyses provide evidence for impaired glucose tolerance and insulin resistance in those with a first episode of schizophrenia (Perry et al, 2016;Pillinger et al, 2017), and there is also evidence that relatives of patients with schizophrenia have a higher than expected prevalence of diabetes (Mothi et al, 2015). However, analysis of data derived from genome-wide association studies has not provided consistent evidence regarding a possible genetic contribution to the risk of type-2 diabetes in individuals with schizophrenia (Padmanabhan et al, 2016;Hackinger et al, 2018).…”