MOLECULAR GENETICS OF AUTISM

自闭症的分子遗传学

• 批准号: 6480456
• 负责人: Edwin H Cook
• 金额: $ 18.66万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2002-09-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6480456
• 关键词: Asperger syndrome; autism; child behavior disorders; child mental disorders; family genetics; fragile X syndromes; genetic disorder diagnosis; genetic markers; genetic polymorphism; genotype; human genetic material tag; human subject; human tissue; linkage disequilibriums; molecular genetics; molecular pathology; neurobiology; polymerase chain reaction; Asperger syndrome; autism; child behavior disorders; child mental disorders; family genetics; fragile X syndromes; genetic disorder diagnosis; genetic markers; genetic polymorphism; genotype; human genetic material tag; human subject; human tissue; linkage disequilibriums; molecular genetics; molecular pathology; neurobiology; polymerase chain reaction

Autism is a severe developmental disorder afflicting about 2-10 per 10,000 individuals. While twin and family studies support significant gene involvement, the specific mode of genetic inheritance is unknown and multiplicative gene action, genetic heterogeneity, and variable expression of underlying susceptibility genes are probable. Given the unknown and complex mode of genetic inheritance in autism, success in localizing underlying disease genes in autism will require evaluation of hundreds of genetic markers spanning the genome and large sample sizes to obtain sufficient power to find underlying genes. In addition, candidate gene studies based on function or position are complementary strategies in a comprehensive approach to understanding the molecular genetic basis of autism. The goals of this project are to localize disease genes in autism through a systematic genome search and candidate gene analysis. In a multi-site international collaborative effort, 240 families with affected sibling pairs with autism will be collected and genotyped on highly polymorphic markers spanning the human genome at regular, close intervals. The U.S. collaborative group will identify and phenotype 120 families with affected siblings with autism and send blood from the families to U.K. for transformation of cell lines. The U.K.-European group of collaborators, through their own funding resources, will collect an additional set of 120 relative pairs and genotyping efforts will be conducted in an independent laboratory facility. Through this international effort susceptibility genes can be identified in approximately 240 pairs. In addition candidate genes will be studied using the transmission/disequilibrium test for serotonergic. dopaminergic. GABAergic and associated disease candidates (tuberculous sclerosis). Linkage disequilibrium studies, conducted in 350 families with only one child with autism and 80 families with a child with Asperger's disorder will allow determination of whether there arc different susceptibility genes involved in simplex autism, multiplex autism, or Asperger's disorder. Once susceptibility genes for autism are identified, their role in the clinical variability in autism and in the expression of putative milder variants in autism, including social functioning deficits, mood, and anxiety disorders may be identified. In addition, identification of the genetic determinants in autism would lay the groundwork for development of improved treatment interventions targeting the pathophysiology of autism.

自闭症是一种严重的发育障碍，每10,000大约2-10 个人。双胞胎和家庭研究支持重要基因 参与，遗传遗传的特定模式是未知的，并且 乘法基因作用，遗传异质性和可变表达 潜在的敏感性基因可能是可能的。鉴于未知和 自闭症中遗传遗传的复杂模式，在本地化方面的成功 自闭症中潜在的疾病基因将需要评估数百种 跨基因组和大样本量的遗传标记以获得 足够的能力找到基础基因。另外，候选基因 基于功能或位置的研究是互补的策略 理解分子遗传基础的综合方法 自闭症。 该项目的目标是通过 系统的基因组搜索和候选基因分析。在多站点中 国际合作努力，有240个家庭有影响的兄弟姐妹 将收集与自闭症的成对，并在高度多态性上进行基因分型 定期，紧密的间隔跨越人类基因组的标记。美国 协作小组将识别和表型120个家庭患有受影响的家庭 与自闭症的兄弟姐妹，并向英国献血。 细胞系的转化。英国 - 欧洲合作者团体， 通过他们自己的资金资源，将收集一组120 相对对和基因分型工作将在独立 实验室设施。通过这种国际努力敏感性 可以以大约240对鉴定基因。另外候选人 将使用传输/不平衡测试研究基因 血清素能。多巴胺能。 GABA能和相关疾病候选者 （结核性硬化）。在350中进行的连锁不平衡研究 只有一个孩子有自闭症的孩子和80个家庭有一个孩子的家庭 阿斯伯格（Asperger）的疾病将允许确定是否有弧度 单纯自闭症，多重敏感基因不同的敏感性基因 自闭症或阿斯伯格障碍。一旦自闭症的易感基因是 确定，它们在自闭症和 自闭症中推定的温和变体的表达，包括社会 可以确定功能缺陷，情绪和焦虑症。在 此外，自闭症中遗传决定因素的识别将是 改进治疗干预措施的发展的基础 靶向自闭症的病理生理学。