Autistic endophenotypes and their associations to oxytocin and cholesterol

描述(申请人提供)：这是一个为期两年的拨款申请，以回应PA-06-391：自闭症和自闭症谱系障碍研究R03。临床、动物和遗传证据表明，激素催产素在自闭症中起到了作用，并表明自闭症先证者的亲属中可能存在催产素相关的异常。挑衅性的线索给胆固醇带来了类似的可能性。在拟议的初步研究中，我们计划评估30个家庭(尽管其中15个家庭将通过其他方式提供资金)的样本中的催产素和胆固醇水平，每个家庭的孩子被诊断出患有自闭症或自闭症谱系障碍，以及20个没有自闭症家庭成员的家庭。从这个小项目中获得的初步数据将帮助我们设计一个更大的项目，最终旨在通过改进表型表达的描绘来寻找自闭症的易感基因。参与的自闭症先证者家庭也将有未受影响的孩子。这将使我们不仅能够比较患有自闭症的父母和对照父母，而且还可以比较患有自闭症的兄弟姐妹和对照兄弟姐妹。我们将对所有参与者进行自闭症筛查，并随后对可能受影响的儿童进行诊断评估。此外，我们将评估催产素和胆固醇之间的潜在关系，以及与自闭症的三个核心症状领域(社交缺陷、沟通和行为异常)以及执行功能相关的行为和神经心理学特征。虽然这些评估中的许多已经成功地用于自闭症家庭研究；但其他评估以前没有被用于自闭症家庭研究，因此是探索性的。除了它们与催产素和胆固醇的关系外，这些指标还将成为评估更具体的行为和神经心理特征，即所谓的内表型的工具。最后，使用一种新的统计学方法，多元距离矩阵回归方法，这是以前在自闭症或他们的亲属的研究中没有使用的方法，我们将试图识别家庭中的亚组，即可以通过独特的内部表型特征描述的家庭。阐明自闭症家族的内表型和亚群都是通过分子遗传学研究寻找相关基因的有用手段。因此，我们的研究将有助于提供必要的信息，以确定自闭症的病因。与公共卫生相关：由于自闭症和自闭症谱系障碍在遗传上是复杂的，这种疾病涉及的基因在很大程度上仍然未知。我们建议进行一项研究，旨在分离出不同的行为和认知特征及其与催产素和胆固醇的联系，这两种有机生物化学物质可以在血液中测量到，假设显示自闭症先证者及其家人存在异常。这将导致非常重要的新信息，这些信息可以提供信息并加强自闭症和自闭症的遗传学研究，从而有助于揭示这一严重发育障碍组的原因。

DESCRIPTION (provided by applicant): This is a 2-year grant application in response to PA-06-391: Research on Autism and Autism Spectrum Disorders R03. Clinical, animal, and genetic evidence points to a role for the hormone oxytocin in autism and suggests that oxytocin related abnormalities may be present in relatives of autism probands. Provocative clues raise a similar possibility for cholesterol. In the proposed pilot study, we plan to assess oxytocin and cholesterol levels in blood from a sample of 30 families (although 15 of these families will be financed through other means) each with a child diagnosed with autism or autism spectrum disorder and 20 families without autistic family members. The preliminary data obtained from this small project will help us design a larger one aimed ultimately at finding susceptibility genes for autism through the improved delineation of phenotypic expressions. Participating autism proband families will also have unaffected children. This will enable us to compare not only autism parents with control parents but also autism siblings with control siblings. We will screen all participants for autism and will subsequently use diagnostic assessments for potentially affected children. Furthermore, we will assess potential relationships between both oxytocin and cholesterol with behavioral and neuropsychological traits associated with the three core symptom domains of autism (social deficits, communication, and behavioral abnormalities), as well as executive functions. While many of these assessments have been used successfully in autism family studies; others have not been used in autism family studies before and are thus exploratory. Beyond their relationships with oxytocin and cholesterol, these measures will serve as a tool to evaluate more specific behavioral and neuropsychological traits, so called endophenotypes. Finally, using a new statistical method, multivariate distance matrix regression methodology, not previously employed in studies of autism or their relatives, we will try to identify subgroups within families, that is, families that can be described through a distinct endophenotypic profile. Clarifying endophenotypes and subgroups within autism families are both useful measures in the search for associated genes through molecular genetic studies. Accordingly, our study will contribute to the information necessary to define the causal factors of autism. PUBLIC HEALTH RELEVANCE: Because autism and autism spectrum disorder are genetically complex, the genes involved in this disorder are still largely unknown. We propose to conduct a study designed to isolate distinct behavioral and cognitive traits and their connections to oxytocin and cholesterol, two organic bio-chemicals that can be measured in the blood that are hypothesized to show abnormalities in autistic proband and their families. This will lead to very important new information that can inform and strengthen genetic studies of autism and ASD and thus help reveal the causes of this severe group of developmental disorders.