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，估计影响大约1%的总人口。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，遗传率很高。分离分析未能明确支持单一的遗传模式，并提出了至少几个可能相互作用的易感基因座。我们之前已经在一组中等大小的加拿大家庭中发现了与1q22的强连锁信号(hlod=6.5，经验p小于0.0002)，之所以选择这些家庭进行研究，是因为有多个亲属被临床诊断为精神分裂症或分裂情感障碍。精细图谱连锁分析已经确定了大约1.3Mb的区间，该区间似乎非常可能含有易感基因，通过连锁确定的300kb亚区最有可能含有该基因。我们进一步确定了该亚区100kb范围内的显著连锁不平衡(LD)。Ld区包含在ICAPON基因超过300kb的基因组范围内，有证据表明在这个大基因的内含子中可能存在其他基因。我们计划在这个区域搜索额外的转录序列，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来确定该区域内保守的调控区域。这些也将被评估与精神分裂症易感性有关的变异。与该区域有较强连锁的样本将首先进行LD检测，NIMH-HGI收集和一名加拿大病例对照样本也将用在连锁样本中产生显著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Stanley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。我们希望以我们在这个样本中对该基因座的研究为基础，提炼出一种综合的易感基因鉴定方法，结合连锁和连锁不平衡作图，基于进化的序列比较方法，以及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额外易感基因。

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.