MOLECULAR GENETICS OF SCHIZOPHRENIA LOCUS ON 1Q21-22

2021-22 年 1 季度精神分裂症基因座的分子遗传学

• 批准号: 6629285
• 负责人: Linda M Brzustowicz
• 金额: $ 31.1万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6629285
• 关键词: clinical research; family genetics; gel electrophoresis; gene environment interaction; gene expression; gene mutation; genetic disorder; genetic markers; genetic regulatory element; genetic screening; genetic susceptibility; genotype; human data; human genetic material tag; linkage disequilibriums; schizophrenia

DESCRIPTION (Investigator's Abstract): Schizophrenia is a serious neuropsychiatric illness estimated to affect 1.3 percent of the adult population in the United States. Family, twin and adoption studies have demonstrated that schizophrenia is predominantly genetic, with a high heritability. The complex genetics, phenotypic uncertainty, and unclear role of environmental interactions have led to the discouraged view that significant genetic linkage will not be easily obtained. None of the linkage reports published to date detail a finding of significant magnitude to serve as a starting point for positional cloning. We have recently concluded a genome-wide search for loci contributing to risk for schizophrenia, and multipoint analysis with markers from 1q21-22 have produced a maximum LOD score of 6.50 between the markers D1S1653 and D1S1679, with an estimated 75 percent of families linked to this locus. Further mapping has reduced the interval containing this gene to less than 2 Mb. We propose a project to develop a dense map of polymorphic markers within this currently defined minimum genetic region, for use in crossover and linkage disequilibrium analyses to further narrow the region containing the gene. Using sequence data from the Human Genome Project, we then plan to identify a comprehensive list of gene in the new minimum genetic region and systematically screen them for mutations using temperature gradient gel electrophoresis on a sample of subjects with very high (greater than 95 percent) conditional probability of linkage to 1Q21-22. Simulation studies suggest that we will have sufficient power to identify the true susceptibility gene. We plan to screen this gene for mutations in the remainder of our linkage sample and in the schizophrenia subjects in the NIMH Center for Genetics Studies sample. The identification of a gene involved in schizophrenia susceptibility will allow insight into the earliest genesis of this debilitating illness. Screening for mutations in this gene in larger, unrelated samples will allow for an estimate of the prevalence of the effect of this locus in the general population. Controlling for the effects of this gene in genetic linkage studies should increase the power to identify other susceptibility loci. Unraveling the genetics of this complex disorder will also facilitate the investigation of the environmental triggers of disease expression, and could ultimately lead to strategies to prevent the onset of clinical symptoms.

描述(研究人员摘要)：精神分裂症是一种严重的 据估计，1.3%的成年人患有神经精神疾病 美国的人口。家庭、双胞胎和收养研究 表明精神分裂症主要是遗传的，有很高的 遗传力。复杂的遗传学，表型的不确定性，以及不清楚的作用 环境的相互作用导致了令人沮丧的观点，即 基因连锁不会轻易获得。没有任何链接报告 迄今为止公布的一项重大发现详细说明了这一点 位置克隆的起点。我们最近完成了一项全基因组 寻找导致精神分裂症风险的基因，并进行多点分析 与来自1q21-22的标记产生的最大LOD分数在 标记D1S1653和D1S1679，估计75%的家系与 这个轨迹。进一步的作图已经将包含该基因的间隔缩短到 小于2 Mb。我们提出了一个项目，以开发一个密集的多态地图 在当前定义的最小遗传区域内的标记，用于 交叉和连锁不平衡分析，以进一步缩小区域 含有这种基因。使用来自人类基因组计划的序列数据，我们随后 计划在新的最小遗传区确定一份全面的基因清单 并使用温度梯度凝胶系统地筛选它们的突变 非常高(大于95)的受试者样本的电泳法 百分比)链接到1Q21-22的条件概率。模拟研究 表明我们将有足够的力量来识别真正的易感性 吉恩。我们计划对该基因进行筛查，找出其剩余部分的突变。 样本和在NIMH遗传学中心的精神分裂症患者中 研究样本。精神分裂症相关基因的鉴定 易感性将使我们能够洞察这一现象的最早起源 使人虚弱的疾病。在较大的、无关的情况下筛查该基因的突变 样本将允许估计这种影响的流行程度。 一般人群中的基因座。控制该基因的作用 基因连锁研究应该增加识别其他基因的能力 易感基因座。解开这种复杂疾病的遗传学也将 促进对致病环境因素的调查 表达，并最终可能导致预防发病的策略 临床症状。