PHENOTYPE DELINEATION AND GENETIC MODELING OF AUTISM

研究自闭症的遗传学提出了特殊的挑战（由于 到诸如有限的垂直传播和小家庭规模的特征）， 除了通常的建模困难之外， 异质性疾病 因此，表型的澄清 表达自闭症的遗传倾向是一个关键的第一步， 步 一种探索孤独症表型界限的方法， 确定自闭症先证者的亲属受广泛或 将使用来自巴尔的摩的数据开发多维表型 自闭症的家庭研究 该方法将被复制，在一个准- 验证步骤，使用来自另外两组自闭症家庭的数据 (one在爱荷华州收集的， 采取的类似或相同的手段和措施。 巴尔的摩的研究。 将测试识别受影响者的方法 因为它在提高遗传建模能力方面的效用，包括 分离和连锁分析。 将对两个数据集进行分离分析 上面描述 联系研究将进行模拟 数据;性状和标记基因型将被模拟的家系， 我们实际观察到的家庭的表型特征。 然后，基于似然和非参数的连锁分析将被 在各种模型下确定统计功效， 错误分类方案。 更一般地说，我希望这项工作将 有助于发展正确分类的方法 家族中受影响的亲属表达其他复杂疾病， 模糊的表型表达，并寻找其他基因 神经精神障碍

Investigating the genetics of autism presents particular challenges (due to features such as limited vertical transmission, and small family size), over and above the usual difficulties of modeling complex and heterogeneous disorders. Therefore, clarification of the phenotypic expression of the genetic liability underlying autism is a critical first step. A method for exploring the phenotypic boundaries of autism and identifying relatives of autistic probands affected with a broad or multidimensional phenotype will be developed using data from the Baltimore Family Study of Autism. The method will then be replicated, in a quasi- validation step, with data from two additional sets of autism families (one simplex and one multiplex) collected in Iowa with the use of instruments and measures similar or identical to those used in the Baltimore study. The method for identifying the affected will be tested for its utility in improving the power of genetic modeling, including segregation and linkage analyses. The segregation analyses will be carried out on the two data sets described above. The linkage studies will be carried out with simulated data; both trait and marker genotypes will be simulated for pedigrees with the phenotypic characteristics of the families we have actually observed. Then both likelihood-based and non-parametric linkage analysis will be carried out to determine statistical power under various models and misclassification schemes. More generally, I hope this work will contribute to the development of methods for correctly classifying affected relatives in families expressing other complex disorders with ambiguous phenotypic expression, and to the search for genes for other neuropsychiatric disorders.