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

父系遗传的ε-肌聚糖(Sgce)基因变异会导致肌阵挛-肌张力障碍综合征(Mds)。SGCE是精神分裂症的候选角色，因为a)MDS患者可以表现出显著的精神异常，以及b)SGCE定位于之前几次基因组扫描中与精神分裂症有关的Chr 7q21.3区域。我们对SGCE进行了错义和启动子变异的筛查。我们没有在编码区检测到任何SNPs，目前仍在通过直接DNA测序对16个精神分裂症三联体的启动子区域进行筛选。这可能证明SGCE可能是一个高度保守的基因。对精神分裂症三个家系进行的16位点传递/不平衡测试显示，精神分裂症与定义包含sgce基因的100kb单倍型区块的标记显著相关(p&lt；0.005)。在母系遗传模型和父系遗传模型中，AT某些标志物的TDT检测呈阳性。我们评估了SGCE单倍型对表达的影响，以确定该基因或该单倍型中的周围基因是否阻止了导致精神分裂症易感性的变异。我们检测了GATA等位基因5号供者的淋巴组织中SGCE基因的表达，发现SGCE基因的表达可能受GATA重复序列的影响，特别是5号等位基因。这些数据来自父亲遗传的单个精神分裂症患者的5号等位基因，是母亲5号等位基因携带者的1.30~1.45倍。这一结果支持了我的假设，即父亲的GATA等位基因5对母亲的印记起关键作用，SGCE基因的过度表达可能与精神分裂症有关。

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.