A Genetic Analysis of the Relationship between Gluten Intolerance and Schizophrenia
relationship between schizophrenia and coeliac disease (CD) has long been postulated. However, despite the substantial genetic contribution defined for both conditions, the possibility of shared genetic risk factors has not previously been addressed. In this study, key CD-associated loci were tested in a schizophrenia cohort. Where association was found, functional studies were performed; including gene expression analysis, screening for functional variants, and correlation of alleles with antibody and cytokine levels. Two principle findings were drawn from the data produced. Firstly, there was no statistically significant association between schizophrenia, and the CD-associated loci; MYO9B, IL-2/21, or HLA-DQ2. Secondly, a robust association was found for 3 SNPs located in the 5‟ region of the gene encoding TGM2; the gluten-modifying enzyme targeted by autoantibodies in CD. Functional studies provided evidence of decreased serum IL-2, in correlation with a schizophrenia-associated SNP located in the TGM2 gene. In addition, cell culture work showed altered expression of the TGM2 gene, following treatment with 1 μg/ml of the neuroleptic drug clozapine. This study concludes that the major genetic factors underlying schizophrenia and CD are distinct, and that the gluten response observed in schizophrenia does not follow the classical CD pathway. Furthermore, this study provides evidence of a novel candidate gene for schizophrenia, TGM2, and explores how it may contribute to neurological aspects of the disease.
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