1/4 - The Autism Sequencing Consortium: Discovering autism risk genes and how they impact core features of the disorder

项目总结/摘要 在过去的十年里，自闭症谱系障碍（ASD）的遗传学取得了显著的进展。大部分 这一进展是通过研究自闭症患者罕见的遗传变异，特别是新生变异而取得的。 测序联盟（ASC）发挥着核心作用。ASC代表了一种协调的国际努力， 确定ASD风险基因。在我们最近未发表的对72，410名ASD家庭成员的分析中，我们 发现185个与风险相关的基因（FDR < 0.05）。其中一些基因与一种广泛的 一系列发育障碍，而其他人则没有。基于这些结果，我们认为，一些风险基因， 改变ASD的核心特征，同时减少对其他发展特征的干扰：发现 这些基因的研究将为ASD中被破坏的途径提供更深入的见解。我们将在这一进展的基础上， 分析来自三个资源的序列数据：ASD受试者和家庭;其他发育障碍受试者; 和神经精神障碍;以及来自人群样本的受试者。我们计划进行新的研究， 罕见变异的解释，包括单核苷酸变异（SNV）、插入缺失和拷贝数变异 （CNV）。我们的主要目标是遗传性变异，包括X连锁遗传性变异，迄今为止， 非常少的信号和错义变体，其信号已被限制于高度保守的取代。 我们预计通过增加家族的数量， 分析和完善的方法来解释遗传和错义变异。与此同时，我们希望 解决ASD遗传结构的关键方面，并揭示ASD及其核心的关键方面 特征-社会缺陷和限制性和重复性行为-不同于其他神经发育 紊乱为了发现对ASD有明显影响的ASD风险基因，我们有以下具体目标：1） 合并现有和新兴的全外显子组和全基因组序列数据; 2）开发新的 分析方法和分析积累的序列数据;和，3）对比ASD和其他 神经发育障碍风险基因，检查发育概况，涉及的细胞类型， 同一基因的变异在如何影响ASD和其他神经发育和精神疾病的风险方面存在差异。 紊乱通过这项新的研究，我们将加速我们的总体目标，即ASD的识别 基因，从而促进我们的长期目标，即建立ASD治疗靶点的基础。 出现。我们的基本原理是，确定基因赋予重大风险的ASD和相关的 神经发育障碍可以形成研究的基础，以了解发病机制，以及基础 新的治疗方法。我们的核心假设--基于过去十年的结果而形成--是罕见的 和常见的变异有助于增加ASD的风险，但只有某些罕见的变异赋予实质性的 风险在我们看来，这项研究是创新的，因为它使用了开创性和新颖的统计方法。 用于识别ASD的风险变体的方法。

Project Summary/Abstract The past decade has seen outstanding advances in the genetics of autism spectrum disorder (ASD). Most of this progress has occurred by the study of rare genetic variation, especially de novo variation, with the Autism Sequencing Consortium (ASC) playing a central role. The ASC represents a coordinated international effort to identify ASD risk genes. In our most recent, unpublished, analyses of 72,410 individuals from ASD families, we identified 185 genes associated with risk (FDR < 0.05). Some of these genes have been linked to a broad array of developmental disorders, while others have not. Based on these results, we posit that some risk genes alter the core features of ASD, while creating fewer perturbations to other features of development: discovery of such genes will provide deeper insights into pathways disrupted in ASD. We will build on this progress by analysis of sequence data from three resources: ASD subjects and families; subjects with other developmental and neuropsychiatric disorders; and subjects from population samples. We plan new research focusing on interpretation of rare variation, including single nucleotide variation (SNV), indels, and copy number variation (CNV). Our key targets are inherited variants, including X-linked inherited variants, which to date have shown very little signal, and missense variants, for which signal has been confined to highly conserved substitutions. We anticipate doubling the number of ASD genes discovered, ~ 400, by increasing the number of families analyzed and by refined methods to interpret inherited and missense variation. And, in parallel, we expect to resolve critical aspects of ASD genetic architecture and to unveil key aspects of what makes ASD and its core features – social deficits and restrictive and repetitive behaviors – different from other neurodevelopmental disorders. To discover ASD risk genes with a distinct effect on ASD, we have the following specific aims: 1) To amalgamate existing and emerging whole exome and whole genome sequence data; 2) To develop new analytical methods and analyze the accumulated sequence data; and, 3) To contrast ASD and other neurodevelopmental disorder risk genes, examining developmental profiles, cell types implicated, and whether variants in the same gene differ in how they affect risk for ASD and other neurodevelopmental and psychiatric disorders. With this new research we will accelerate our overall objective, which is the identification of ASD genes, thereby facilitating our long-term goal of building the foundation from which therapeutic targets for ASD emerge. Our rationale is that the identification of genes conferring significant risk to ASD and associated neurodevelopmental disorders can form the basis of studies to understand pathogenesis, as well as the basis for novel therapies. Our central hypothesis – formulated based on results over the past decade – is that rare and common variation contributes additively to risk for ASD, but only certain rare variants confer substantial risk. The research proposed is innovative, in our opinion, because it uses groundbreaking and novel statistical methods for identifying risk variants for ASD.