Genetics of Autism Intermediate Phenotypes

本项目的目的是利用中间表型寻找自闭症的易感基因。我们将测试8-10个大型扩展犹他谱系，和50个较小的多重谱系（2-4个受影响的病例）。7个大型家系和57个较小的多重家系已经被确定，我们有初步证据表明，在这些家系中广泛的表型是可行的。谱系将用微卫星标记和Affymetrix 10k SNP芯片进行分型。我们选择在这些谱系上测量的表型显示了遗传变异的证据。新的家谱将通过确定800个三联家谱来确定（86个三联家谱已经完成，另有214个三联家谱将在犹他州完成，100个将来自我们在科罗拉多州的合作地点）。犹他州人口数据库，用于确定第一个扩展谱系，将用于寻找新的扩展/多重谱系。当这三个家庭进入研究时，采集他们的DNA血样和选定的表型。这种预先收集的DNA和表型不仅为家谱鉴定提供了直接的资源，也为后续的阳性连锁结果的追踪和通过连锁分析发现的最佳候选基因的研究提供了直接的资源。对三人组和谱系的中间表型的测量将使我们能够对样本进行分层，这在以前大规模的自闭症基因研究中是不可能的。犹他大学分子遗传学实验室将在基因分型、精细定位、候选基因选择、测序和结果解释方面为我们提供世界一流的专业知识。我们的具体目标是：1)确定550个以上的三联体，共800个，以发现新的多重/扩展家系，用于连锁随访，并在基因组扫描（目标2）完成后研究2个位置候选基因。2)对8-10个扩展自闭症家族和50个较小的多重自闭症家族进行额外的特异性表型分析。检测中间表型的遗传变异。使用全基因组扫描来搜索使用中间表型的联系。精细地图感兴趣的区域。用系谱法和三位一体法研究两个最佳位置候选基因。

The purpose of this project is to search for susceptibility genes for autism using intermediate phenotypes. We will test 8-10 large extended Utah pedigrees, and 50 smaller multiplex pedigrees (2-4 affected cases). Seven large pedigrees and 57 smaller multiplex pedigrees have already been identified, and we have preliminary evidence that extensive phenotyping in these pedigrees will be feasible. Pedigrees will be typed with microsatellite markers and the Affymetrix 10k SNP chip. The phenotypes we have chosen to measure on these pedigrees show evidence of heritable variation. New pedigrees will be identified through the ascertainment of 800 trio families (86 trios are already complete and 214 more waiting to be scheduled at Utah, and 100 will come from our collaborating site in Colorado). The Utah Population DataBase, used to identify the first extended pedigrees, will be used to find new extended/multiplex pedigrees. Blood for DNA and selected phenotypes is collected on the trio families as they enter the study. This up-front DNA and phenotype collection provides an immediate resource not only for pedigree identification but also for later follow-up of positive linkage results and for the study of the best positional candidate genes found through the linkage analyses. The measurement of intermediate phenotypes on the trios as well as the pedigrees will allow us to stratify our sample to a degree that has not before been possible in large-scale genetic studies of autism. University of Utah molecular genetics labs will give us world-class expertise in genotyping, fine mapping, candidate gene selection, sequencing, and interpretation of results. Our specific aims are: 1) Ascertain 550 more trios for a total of 800 to find new multiplex/extended pedigrees, to use for linkage follow-up, and to study 2 positional candidate genes once genome scanning (Aim 2) is complete. 2) Perform additional specific phenotyping in 8-10 extended autism families and 50 smaller multiplex families. Test intermediate phenotypes for heritable variation. Use a whole genome scan to search for linkage using intermediate phenotypes. Fine map regions of interest. Study the two best positional candidate genes using pedigrees and trios.