Isolation of Autism susceptibility genes

自闭症易感基因的分离

• 批准号: 7096473
• 负责人: Kari Stefansson
• 金额: $ 56.06万
• 依托单位: DECODE GENETICS, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7096473
• 关键词: Asperger syndrome; Scandinavian country; autism; cell bank /registry; cell line; clinical research; epidemiology; family genetics; gene expression; gene targeting; genetic disorder diagnosis; genetic library; genetic screening; genetic susceptibility; genotype; information systems; international cooperation; linkage mapping; mass screening; patient oriented research; phenotype; psychometrics; quantitative trait loci; social behavior

DESCRIPTION (provided by applicant): Autism is a devastating neurodevelopmental condition whose biological basis is still poorly understood. Furthermore, there are no laboratory or radiological tests available to aid in diagnosis, and although early behavioral intervention is considered effective in some cases, there are few proven treatments currently available. Autism has a striking genetic component with first degree relative risk estimated in some studies higher than 50. Therefore, defining the genes with variants contributing to autism risk would theoretically define the key molecular pathways involved. A number of genome-wide linkage scans and association studies performed in the last decade have begun to show promise by identifying a few overlapping regions of interest, but, no clear autism gene has been isolated and confirmed in multiple populations. In Iceland we have recruited most of confirmed autism cases in Iceland and used the genealogy database to connect many of these cases into the extended families. In preliminary analyses, suggestive loci have been found, most of which overlap with previously reported suggestive loci in autism scans, including those from a large subset of the AGRE/UCLA cohort, which consists of mostly nuclear multiplex autism pedigrees. Both the Decode group and the UCLA group have been attempting to increase the power of their respective cohorts by increasing the number of affecteds in their studies through broadening of the autism- related phenotyping to include quantitative measures of autism-related impaired social interaction, using the Social Responsiveness Scale (SRS). The use of this scale also allows for a QTL analysis that may further increase the power to find significant linkage, and takes advantage of the critical dimension of social deficits as a core feature of autism spectrum disorders in genetic studies for the first time. Genome-wide linkage scans in the ACRE and Decode populations have revealed a number of suggestive loci for autism or autism-related endophenotypes. Several of the loci with highest statistical support identified in ACRE and ICELAND cohorts overlap with each other and with loci from other populations, including an AGRE locus enhanced by QTL analysis based on SRS data. We believe that collaborative efforts to isolate genes from the strongest overlapping loci provides an efficient way to leverage these already recruited and genotyped patient cohorts. This grant proposal leverages both of these large cohorts that have already been genotyped in initial genome scans. We propose to phenotype additional relatives both in Iceland and the US, and analyze the US and Decode cohorts in parallel, performing the same multipoint QTL analysis, followed by fine mapping and narrowing regions of shared linkage. We plan to focus on the isolation of genes within loci that are supported in both populations.

描述（由申请人提供）：自闭症是一种毁灭性的神经发育状况，其生物学基础仍然很少了解。此外，没有可用的实验室或放射学测试来帮助诊断，尽管在某些情况下认为早期行为干预被认为有效，但目前几乎没有可靠的治疗方法。自闭症具有惊人的遗传成分，在某些研究高于50的研究中估计的一级相对风险。因此，定义带有自闭症风险的变异的基因理论上将定义涉及的关键分子途径。过去十年中进行的许多全基因组链接扫描和关联研究已经开始通过识别一些重叠的关注区域来表现出希望，但是，在多个人群中尚未隔离和确认明确的自闭症基因。在冰岛，我们已经招募了冰岛确认的自闭症病例，并使用家谱数据库将其中许多案件连接到大家庭。在初步分析中，已经发现了暗示性的基因座，其中大多数与先前报道的自闭症扫描中有暗示性的基因座重叠，包括来自大部分Chare/UCLA队列的大部分，其中大多数由核多重自闭症分子组成。解释组和UCLA组一直试图通过使用社会响应量表（SRS）来扩大自闭症与自闭症相关的社交相互作用的定量测量，从而通过扩大自闭症与自闭症相关的社交相互作用的定量度量来增加其研究中受影响的人数的能力。该量表的使用还允许进行QTL分析，该分析可能会进一步提高找到显着联系的能力，并利用社会缺陷的临界维度作为遗传研究中自闭症谱系障碍的核心特征。在英亩和解码种群中，全基因组的连锁扫描显示出许多针对自闭症或自闭症相关的内表型的建议性基因座。在英亩和冰岛队列中鉴定出最高统计支持的几个基因座相互重叠，并与其他人群的基因座重叠，包括基于SRS数据的QTL分析增强的协议基因座。我们认为，将基因与最强的重叠基因座隔离的协作努力提供了一种有效的方法来利用这些已经招募和基因型的患者同伙。该赠款提案利用了在初始基因组扫描中已经进行了基因分型的这两个大型队列。我们建议在冰岛和美国进行表型的其他亲戚，并并行分析美国并分解同类群体，进行相同的多点QTL分析，然后进行精细的映射和共享链接的狭窄区域。我们计划专注于两个人群中支持的基因座基因的隔离。