GENETIC CONTRIBUTIONS TO ENDOPHENOTYPES OF AUTISM

整个UW ACE主题集中在风险，风险过程， 自闭症谱系障碍（ASD）的症状出现和适应。根据这一模式，早期 孤独症风险因素（遗传、家庭和环境）导致风险过程，即改变的 儿童与其环境之间的相互作用，反过来又会导致儿童的异常行为。 神经回路和非典型行为的发展。项目一有两个主要目标。首先，它将识别 自闭症易感基因及其基因组位置：基因变异影响ASD风险。 其次，它将寻求扩大一套组成特征（内表型），有证据表明， 遗传基础识别易感基因将导致识别潜在的生物学 机制，并提供了症状前诊断的承诺，并最终改变疾病 在疾病早期和症状前期使用的药物或其他疗法。 项目I的具体目标建立在我们以前由NICHD CPEA计划资助的工作基础上， 我们招募了一个大样本的多重核心自闭症家庭，对家庭成员进行基因分型， 多指标综合评价。在项目I中，我们建议扩展这项研究 该计划的目标是确定风险基因和风险基因的染色体位置， ASD内表型我们将从现有的家庭样本中招募更多的成年亲属， 收集这些亲属的表型和基因型数据。我们将利用这些大家庭和 我们以前收集的核心家族的剩余部分，以确定包含ASD风险的基因组区域 基因.我们的方法将使用来自所有家庭成员的这些新的内表型， ART统计遗传分析。我们还将研究新的表型，以扩大可能的面板， 通过确定父母的这些措施中哪些与自闭症相关， 孩子这个项目直接涉及NIH自闭症研究矩阵中概述的目标，包括（1） 确定自闭症和自闭症相关症状发展的生物风险指数 婴儿，如语言和社会障碍，（2）自闭症易感基因的鉴定。

The overall UW ACE theme centers on a comprehensive development model of risk, risk processes, symptom emergence, and adaptation in autism spectrum disorder (ASD). According to this model, early autism risk factors (genetics, familial, and environmental) lead to risk processes, namely altered patterns of interaction between the child and his/her environment, which, in turn, contribute to the abnormal development of neural circuitry and atypical behavior. Project I has two major goals. First, it will identify autism susceptibility genes and their genomic location(s): genes in which variation affects risk for ASD. Second, it will seek to expand the set of component traits (endophenotypes) for which there is evidence for a genetic basis. Identification of susceptibility genes will lead to identification of underlying biological mechanisms, and offers the promise of presymptomatic diagnosis and, ultimately, of disease-modifying medications or other therapies for use early in disease and during the presymptomatic period. The specific aims of Project I build on our previous work funded by the NICHD CPEA program in which we recruited a large sample of multiplex nuclear autism families, genotyped the family members, and comprehensively evaluated them with multiple measures. In Project I we propose to extend this research program with the goal of identifying risk genes and chromosomal locations of risk genes that contribute to ASD endophenotypes. We will recruit additional adult relatives from our existing sample of families, and will collect phenotype and genotype data on these relatives. We will use these extended families and the remainder of our previously-collected nuclear families to identify genomic regions that contain ASD risk genes. Our approach will use these novel endophenotypes from all family members coupled with state-of-the art statistical genetic analyses. We will also investigate new phenotypes to extend the possible panel of endophenotypes by determining which of these measures in parents are associated with autism in their children. This,project directly addresses goals outlined in the NIH Autism Research Matrix, including (1) identification of biological risk indices for the development of autism and autism-related symptoms in infants, such as language and social impairments, and (2) identification of autism susceptibility genes.