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.
Highlights
Schizophrenia (SCZ) patients are 1.5–2 times more likely to develop type 2 diabetes (T2D) compared to the general population[1]
Data sets The GOMAP (Genetic Overlap between Metabolic and Psychiatric disorders) study comprises a collection of 2,747 DNA samples from four different patient categories: T2D patients, SCZ patients, individuals with both SCZ and T2D, and individuals with a different psychiatric diagnosis (Table 1)
In order to match the ancestry of the base data as closely to GOMAP as possible, we looked up summary statistics of all independent variants (76 in total) identified in the trans-ethnic study[15] in the DIAGRAMv3 stage 1 metaanalysis17(Supplementary Tables 4) based on samples of European descent
Summary
Schizophrenia (SCZ) patients are 1.5–2 times more likely to develop type 2 diabetes (T2D) compared to the general population[1]. Several explanations for this epidemiologic link have been proposed, including environmental factors, the use of antipsychotic medication, and/ or shared genetic aetiology[1,2,3,4]. Patients with severe mental illness often lead a more sedentary life and are more likely to smoke compared to the general. Several studies have found an association between psychotropic medication and T2D risk[6,7,8], but it is still unclear to what extent interactions between different medications, life-style and inter-patient variability affect this association[4]. Studies on the genetics of antipsychotic response have been small (n < 400) and unable to identify replicating associations[9,10]
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