Variation in early motor function in autism, cerebellar injury and normal twins

项目摘要 自闭症谱系障碍(ASD)是所有发育障碍中最常见和高度遗传的疾病之一， 遗传力超过0.80。尽管遗传学的显著进步已经确定了罕见的从头开始 根据定义，部分大脑基因的突变与自闭症的明显遗传性无关 与人口中的绝大多数病例有关。鉴于遗传性已被证明是一个函数 加性遗传风险，推断出不切实际的大量遗传目标进行干预，这是一个重要的 策略是通过阐明中间表型来确定多基因风险因素的汇聚机制 (即，内表型)，它们通过这些表型发挥其因果影响。我们的小组已经确定了两个这样的 看起来对ASD有很大贡献但不充分的候选人：(I)索引的社会行为表型 通过父母的数量(亚临床)自闭症特征(QAT-p)；以及(Ii)社交视觉参与(SVE)的变化， 一种基于动态社交场景观看的眼球跟踪测量。两者都可以在第一年确定 使用寿命的快速采集方法不到20分钟。我们团队之前的工作有力地支持了 自闭症是由这些因素和其他因素的共同相加遗传效应引起的发育模型 神经发育责任，表明以一组离散的早期贡献责任为目标 自闭症的发展为患有自闭症的儿童提供了最大的机会进行高影响力的个性化干预 常见的多基因形式的自闭症。 该研究计划的主要目标是验证可穿戴传感器方法(双侧、手腕佩戴 用于量化另外两种内表型的加速计)：多动(HYP，作为 易患注意力缺陷多动障碍，与自闭症强烈共存)和 运动协调障碍(MOT)。我们将在三个不同的样本中检查HYP和MOT。目标I 将研究120对婴儿双胞胎，首先在6个月大时进行评估，然后在18个月和36个月大时进行跟踪 评估HYP、MOT、QAT和SVE之间的早期关联以及它们的遗传性和能力 预测这对双胞胎中自闭症特征的数量差异。AIM II将对50名确诊为幼儿的儿童进行研究 使用特发性ASD来确定HYP和MOT基于传感器的新指标是否显示出差异 双胞胎和患有自闭症的孩子之间。AIM III将对120名高危婴儿进行研究 早产儿和/或小脑损伤所致的自闭症，我们将在其中探索小脑与 出生第一年的结构和功能以及a)基于传感器的HYP和MOT指数，b)定量自闭症 C)三岁时基于表现的运动能力指数。该项目预计将产生一个 丰富、全面地了解婴儿和儿童的运动内表型及其对 自闭症，最终目标是为未来的筛查和早期干预研究提供一个起点 在高危儿童中。

Project Summary Autism spectrum disorder (ASD) is one of the most common and highly inherited of all developmental disorders, with heritability exceeding 0.80. Although remarkable advances in genetics have identified rare de novo mutations in select brain genes, by definition, none of these relate to the pronounced heritability of autism relevant to the vast proportion of cases in the population. Given that heritability has been shown to be a function of additive genetic risk, inferring an impractically large number of genetic targets for intervention, an important strategy is to identify convergent mechanisms of polygenic risk factors by elucidating intermediate phenotypes (i.e., endophenotypes) through which they exert their causal influence. Our group has identified two such candidates that appear highly contributory but not sufficient for ASD: (i) the social behavioral phenotype indexed by quantitative (subclinical) autistic traits in parents (QAT-p); and (ii) variation in social visual engagement (SVE), an eye-tracking measure based on viewing of dynamic social scenes. Both can be ascertained in the first year of life using rapid acquisition methods of less than 20 minutes. Our team’s prior work strongly supports a developmental model in which autism arises from joint additive genetic effects of these and other neurodevelopmental liabilities, suggesting that targeting a discrete group of early-contributing liabilities before autism develops offers the greatest opportunity for high-impact, personalized intervention for children at risk for common, polygenic forms of ASD. The primary objective of this research program is to validate wearable-sensor methodology (bilateral, wrist-worn accelerometers) for quantifying two additional endophenotypes: hyperactivity (HYP, as an early marker of liability to Attention Deficit Hyperactivity Disorder, which is strongly comorbid with autism) and impairment in motor coordination (MOT). We will examine HYP and MOT in three distinct samples. Aim I will study 120 pairs of infant twins first assessed at 6 months of age and then followed at ages 18 and 36 months to evaluate early associations between HYP, MOT, QAT, and SVE, as well as their heritability and ability to predict quantitative variation in autistic traits among the twins. Aim II will study a cohort of 50 toddlers diagnosed with idiopathic ASD to determine whether novel sensor-based metrics of HYP and MOT show differences between the twins and children with ASD. Aim III will study a legacy cohort of 120 infants at elevated risk for autism due to prematurity and/or cerebellar injury, in whom we will explore relationships between cerebellar structure and function in the first year of life and a) sensor-based indices of HYP and MOT, b) quantitative autistic traits, and c) performance-based indices of motor ability at age three years. This project is expected to yield a rich, comprehensive understanding of motor endophenotypes in infants and children and their contributions to autism, with the eventual goal of providing a launching point for future screening and early intervention studies in high-risk children.