A Family-Genetic Study of Language in Autism

项目摘要 语用(即社交)语言缺陷是自闭症谱系障碍(ASD)的一个明显特征，它可以 在人的一生中对个人造成重大负担。强有力的证据也表明，这种临床上 在未受影响的亲属中，区域受ASD遗传易感性的影响，构成了 广泛的自闭症表型(BAP)，并与未受影响的亲属患ASD的多基因风险增加有关。 ASD的语用语言特征也与FMR1携带者的表型有显著重叠 突变，暗示这个高度渗透的ASD风险基因在ASD的语用语言表型中 很特别。因此，语用语言领域不仅在ASD中具有很高的临床意义，而且 对潜在的ASD遗传易感性敏感，使这项技能成为了解生物学 ASD的起源及其成分特征，具有潜在的重要临床应用。在这场竞争中 更新，我们将应用创新的深层表型方法和补充分析的工具 分析ASD语用语言障碍的因素及其生物学基础的平台。vbl.使用 一项家庭研究设计，并包括一个具有代表性的ASD队列，丰富了女孩、ASD父母和各自 控制组，我们将描述与ASD相关的语用特征，这些特征超越了传统的、明确的- 明确的诊断界限，可能与不同的神经特征和分子遗传学有关 变种。目标1将同时应用假设驱动和数据驱动的分析方法来分析 评估ASD中导致语用障碍的组件技能和亚临床语用 父母间的BAP存在差异。Aim 2将采用一系列有针对性的电生理措施来 检查ASD和BAP中语用障碍的潜在神经关联。最后，目标3将评估 分别在目标1和2中获得的行为和神经表型特征之间的关系， 和FMR1相关的遗传变异。我们的初步研究显示了一个复杂的技能网络 有助于ASD中的语用障碍，这些障碍可以用高级细粒度 本项目中提出的基于计算和机器学习的方法，与 神经生理学和分子遗传学的相关性将在这个项目中被测量。在一起，富人和 产生的大量数据将有助于理解细粒度技能，这些技能有助于 ASD的异质性，以及这一重要临床领域的机制和生物学起源。我们的发现 将使我们更接近于实现我们的长期翻译目标：增进我们对 ASD患者的语用语言障碍，以提高对临床结果的预测并帮助指导 ASD的未来干预和治疗。

Project Summary Pragmatic (i.e., social) language deficits are a defining feature of autism spectrum disorder (ASD), which can impose significant burden on individuals throughout the lifespan. Strong evidence also suggests that this clinical domain is influenced by genetic liability to ASD in unaffected relatives, constituting a principal component of the broad autism phenotype (BAP) and linked with increased polygenic risk for ASD in unaffected relatives. Pragmatic language features of ASD also show significant overlap with phenotypes observed in carriers of FMR1 mutations, implicating this highly penetrant ASD risk gene in the pragmatic language phenotype of ASD in particular. The pragmatic language domain is therefore not only highly clinically significant in ASD, but also sensitive to underlying ASD genetic liability, making this skill an important target for understanding the biological origins of ASD and its component features, with potentially important clinical applications. In this competing renewal, we will apply innovative deep phenotyping methods and an armamentarium of complementary analytic platforms to dissect the contributors to pragmatic language impairments in ASD and their biological basis. Using a family-study design and including a representative ASD cohort enriched for girls, ASD parents, and respective control groups, we will characterize ASD-related pragmatic profiles that extend beyond traditional, categorically- defined diagnostic boundaries, which may be linked with distinct neural signatures and molecular genetic variation. Aim 1 will apply both hypothesis- and data-driven analytic approaches to analyze a comprehensive battery assessing component skills contributing to pragmatic impairments in ASD, and subclinical pragmatic differences in the BAP among parents. Aim 2 will employ a battery of targeted electrophysiological measures to examine potential neural correlates of pragmatic impairment in ASD and the BAP. Finally, Aim 3 will evaluate the relationship between behavioral and neural phenotypic signatures obtained in Aims 1 and 2, respectively, and FMR1-related genetic variation. Our preliminary studies demonstrated a complex network of skills contributing to pragmatic impairments in ASD that may be sensitively measured with the advanced fine-grained computational- and machine-learning-based approaches proposed in this project, with compelling ties to neurophysiological and molecular genetic correlates that will be measured in this project. Together, the rich and extensive data produced will contribute to the understanding of the fine-grained skills that contribute to the heterogeneity in ASD, and the mechanistic and biological origins of this important clinical domain. Our findings will move us closer to achieving our long-term translational goal: to advance our understanding of the causes of the pragmatic language impairment in ASD in order to improve prediction of clinical outcomes and help guide future interventions and treatment in ASD.