Isolation of Autism susceptibility genes

自闭症易感基因的分离

基本信息

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
项目类别：
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

项目摘要

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）：自闭症是一种破坏性的神经发育疾病，其生物学基础仍然知之甚少。此外，没有实验室或放射学测试可帮助诊断，尽管早期行为干预在某些情况下被认为是有效的，但目前几乎没有经过验证的治疗方法。自闭症具有显着的遗传成分，在一些研究中估计一级相对风险高于 50。因此，定义具有导致自闭症风险的变异的基因理论上将定义所涉及的关键分子途径。过去十年中进行的许多全基因组连锁扫描和关联研究已经开始通过识别一些重叠的感兴趣区域而显示出希望，但是，尚未在多个人群中分离和证实明确的自闭症基因。在冰岛，我们招募了冰岛大部分确诊的自闭症病例，并使用家谱数据库将其中许多病例与大家庭联系起来。在初步分析中，已经发现了暗示性位点，其中大部分与之前报道的自闭症扫描中的暗示性位点重叠，包括来自 AGRE/UCLA 队列的一个大子集的基因座，该群体主要由核多重自闭症谱系组成。解码小组和加州大学洛杉矶分校小组都一直在尝试通过扩大自闭症相关表型以包括与自闭症相关的社交互动受损的定量测量来增加研究中受影响的数量，从而提高各自队列的力量，使用社会反应量表（SRS）。该量表的使用还允许进行QTL分析，这可能会进一步增加发现显着关联的能力，并首次在遗传研究中利用社会缺陷的关键维度作为自闭症谱系障碍的核心特征。 ACRE 和 Decode 人群的全基因组连锁扫描揭示了许多自闭症或自闭症相关内表型的提示位点。在 ACRE 和 ICELAND 队列中确定的几个具有最高统计支持的基因座彼此重叠，并与其他种群的基因座重叠，包括通过基于 SRS 数据的 QTL 分析增强的 AGRE 基因座。我们相信，从最强的重叠位点中分离基因的合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分型的患者群体。该拨款提案利用了这两个已在初始基因组扫描中进行基因分型的大型群体。我们建议对冰岛和美国的其他亲属进行表型分析，并并行分析美国和解码群体，执行相同的多点 QTL 分析，然后进行精细绘图和缩小共享连锁区域。我们计划重点关注两个群体都支持的基因座内基因的分离。