No association observed between schizophrenia and non-HLA coeliac disease genes: integration with the initial MYO9B association with coeliac disease.

Schizophrenia is a severe psychotic illness with a heterogeneous presentation and a devastating impact on social and occupational function. Worldwide variations in schizophrenia incidence rates suggest that local conditions may modify disease risk. The human leukocyte antigen (HLA) region has been confirmed to be associated with schizophrenia by genome-wide association studies in populations across the world. While the presence of autoimmune processes in a subgroup of schizophrenia cases is contentious, the immune system could allow environmental exposures to lead to schizophrenia by generating improper immune response. To investigate this topic, we reviewed the current evidence of the relationship between schizophrenia and coeliac disease. Based on this review, we performed genetic analysis of the MYO9B gene and the IL-2/IL-21 locus by genotyping SNPs that have been previously associated with coeliac disease or schizophrenia in 223 families, 108 unrelated individuals with schizophrenia and 120 controls. Finding no evidence for association with these two loci in our study samples, we applied meta-analytic techniques to combine our findings with previous reports. This synthesis, in light of our review of previous reports, suggests a differing developmental trajectory for schizophrenia and coeliac disease. It is possible that these two conditions do not share any functional overlap.

The functional significance of the TGM2 gene in schizophrenia: a correlation of SNPs and circulating IL-2 levels.

The present study was undertaken to genotype four single nucleotide polymorphisms, which were previously found to be associated with schizophrenia, in 77 patients with schizophrenia and 52 control subjects in order to assess their genotypic association with plasma IL-2 levels. Kruskal-Wallis analysis revealed an association between rs4811528 and plasma IL-2 levels in the patient group (χ(2)=7.60, df=2, p=0.022) but not in the control group; binary logistic regression also confirmed the association of rs4811528 with altered IL-2 secretion (χ(2)=8.191, df=3, p=0.042) after adjustment for age and sex. TGM2 may be involved in dysfunction of the immune system in schizophrenia.

The TGM2 gene is associated with schizophrenia in a British population.

Several lines of evidence have suggested an interesting link between gluten ingestion and schizophrenia. Increased levels of gliadin antibodies have been observed in patients with schizophrenia. Tissue transglutaminase (transglutaminase 2, TGM2) is involved in the production of gliadin antibodies. To investigate genetic association of the TGM2 gene with schizophrenia, we detected eight single nucleotide polymorphisms (SNPs) present in the gene among 131 family trios composed of fathers, mothers and affected offspring with schizophrenia. Data analysis with the UNPHASED program showed allelic association for rs2076380 (chi(2) = 5.51, P = 0.019), rs7270785 (chi(2) = 8.13, P = 0.004), rs4811528 (chi(2) = 6.13, P = 0.013) and rs6023526 (chi(2) = 6.13, P = 0.013). The global P-value was 0.029 for 10,000 permutations with the TDT analysis. The strongest association was observed for the rs7270785-rs4811528 haplotypes (chi(2) = 16.18, df = 3, P = 0.001), and the global P-value was 0.008 for 10,000 permutations with the 2-SNP haplotype analysis. The 8-SNP haplotype analysis also revealed a strong haplotypic association (chi(2) = 44.82, df = 18, P = 0.0004) and the 1-df test showed that the A-T-A-A-T-G-A-G haplotype was excessively transmitted (chi(2) = 16.98, corrected P = 0.0007). The present results suggest that the TGM2 gene may be involved in the development of schizophrenia.