Novel Candidate gene analysis using the genome of Monozygotic twin discordant for Schizophrenia

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Paternally transmitted ε-sarcoglycan (SGCE) gene variants cause myoclonus-dystonia syndrome (MDS). SGCE is a candidate for roles in schizophrenia because a) MDS patients can show prominent psychiatric abnormalities and b) SGCE is localized to a Chr 7q21.3 region implicated in schizophrenia in several previous genome scans. We screened SGCE for missense and promoter variants. We did not detect any SNPs in the coding region and are still screening the promoter region through 16 schizophrenia trios by direct DNA sequencing. It may turn out that SGCE may be a highly conserved gene. Sixteen-locus transmission/disequilibrium testing (TDT) performed in 114 schizophrenia trio pedigrees revealed significant association between schizophrenia and markers defining a 100 kb haplotype block that includes the SGCE gene (p < 0.005). TDT tests for at some markers were positive in maternally-and some in paternally-inherited models. We evaluated the effects of SGCE haplotypes on expression to determine whether this gene or surrounding genes in this haplotype block harbor variants that contribute to susceptibility to schizophrenia. We examined the expression of SGCE gene in lymphoblasts of GATA allele 5 donors who have the same genotype and obtained evidence that the SGCE gene expression may be influenced by the polymorphic GATA repeat, specifically allele 5. These data were from single schizophrenia patient allele 5 transmitted from father that showed a 1.30-1.45 fold increase compared to that of GATA allele 5 donors from mother. This result supports my hypothesis that GATA allele 5 from father has a key role to maternal imprinting and that over expression of SGCE gene might be associated with schizophrenia.