Molecular Genetics of Schizophrenia Susceptibility

描述（由申请人提供）： 精神分裂症是一种严重的神经精神疾病，估计影响约1%的一般人群。家庭，双胞胎和收养研究表明，精神分裂症主要是一种遗传性疾病，具有很高的遗传性。分离分析未能明确支持一个单一的遗传模型，并建议至少有几个，可能相互作用，易感基因座。我们以前已经确定了一个强大的连锁信号（hlod=6.5，经验p小于0.0002），1 q22在一组中等规模的加拿大家庭，选择研究，因为多个亲属被临床诊断为精神分裂症或情感障碍。精细图谱连锁分析已经确定了一个大约1.3 Mb的区间，似乎很可能窝藏易感基因，与300 kb的亚区确定的连锁最有可能包含该基因。我们已经进一步确定了显着的连锁不平衡（LD）内的100 kb的部分，这个子区间。LD的区域包含在基因ICAPON的超过300 kb的基因组范围内，并且有证据表明在这个大基因的内含子内可能存在另外的基因。我们计划在这个区域寻找额外的转录序列，以筛选与精神分裂症易感性相关的变异。我们还计划使用比较基因组技术，以确定保守的调控区域在这一领域。还将评估这些与精神分裂症易感性相关的变异。与该区域具有强连锁的样品将首先进行LD检测，NIMH-HGI收集和加拿大病例对照样品也用在连锁样品中产生显著LD的标记进行基因分型。我们还计划进行蛋白质和RNA的表达研究，使用来自斯坦利阵列收集的RNA，来自哈佛脑库的死后大脑，以及来自我们的连锁样本和NIMH-HGI收集的淋巴母细胞系。我们希望利用我们的调查，在这个样本中的这个位点作为一个试验平台，完善一个全面的方法来易感基因的识别，结合连锁和连锁不平衡映射，基于进化的序列比较方法，互补基因表达的研究。我们预计，这些方法将在未来用于寻找精神分裂症和其他复杂疾病的易感基因。

DESCRIPTION (provided by applicant): Schizophrenia is a serious neuropsychiatric illness estimated to affect approximately 1% of the general population. Family, twin and adoption studies have demonstrated that schizophrenia is predominantly a genetic disorder, with a high heritability. Segregation analyses have failed to clearly support a single model of inheritance and suggest at least several, possibly interacting, susceptibility loci. We have previously identified a strong linkage signal (hlod=6.5, empirical p less than 0.0002) to 1q22 in a set of medium-sized Canadian families, selected for study because multiple relatives were clinically diagnosed with schizophrenia or schizoaffective disorder. Fine-map linkage analysis has identified an approximately 1.3 Mb interval that appears very likely to harbor the susceptibility gene, with a 300 kb sub-region identified by linkage as most likely to contain the gene. We have further identified significant linkage disequilibrium (LD) within a 100 kb portion of this sub-interval. The region of LD is contained within the over 300 kb genomic extent of the gene ICAPON, and there is evidence that additional genes may exist within the introns of this large gene. We plan to search this region for additional transcribed sequences to screen for variants associated with schizophrenia susceptibility. We also plan to use comparative genomic techniques to identify conserved regulatory regions within this area. These will also be assessed for variation that is associated with schizophrenia susceptibility. The sample with strong linkage to this region will first be tested for LD, with the NIMH-HGI collection and a Canadian case-control sample also genotyped with markers producing significant LD in the linkage sample. We also plan to conduct expression studies of protein and RNA, using RNA from the Stanley Array Collection, post-mortem brains from the Harvard Brain Bank, and lymphoblastoid cell lines from our linkage sample and the NIMH-HGI collection. We hope to use our investigations of this locus in this sample as a testbed for refining a comprehensive approach to susceptibility gene identification, combining linkage and linkage disequilibrium mapping, evolutionary based sequence comparison methods, and complementary gene expression studies. We anticipate that these methods will be of future use for finding additional susceptibility genes for schizophrenia and other complex disorders.