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

项目摘要/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罕见的遗传变异，特别是自闭症患者的从头变异来实现的。 测序联盟(ASC)发挥着核心作用。ASC代表了一项协调一致的国际努力，以 确定ASD风险基因。在我们最近对72,410名来自ASD家庭的个体进行的未发表的分析中，我们 确定了185个与风险相关的基因(FDR&lt；0.05)。这些基因中的一些已经与广泛的 一系列发育障碍，而其他人则没有。基于这些结果，我们假设一些风险基因 改变ASD的核心功能，同时减少对其他开发功能的干扰：发现 对这类基因的研究将为ASD中中断的通路提供更深层次的见解。我们将在这一进展的基础上， 来自三个来源的序列数据分析：自闭症受试者和家系；有其他发育障碍的受试者 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，重点放在 罕见变异的解释，包括单核苷酸变异(SNV)、INDELS和拷贝数变异 (CNV)。我们的主要目标是遗传变异，包括X连锁的遗传变异，到目前为止已经表明 非常少的信号和错义变体，其信号被限制在高度保守的替换。 我们预计，通过增加家系数量，发现的ASD基因数量将翻一番，约400 分析并用精炼的方法解释遗传变异和错义变异。同时，我们预计 解决ASD遗传架构的关键方面，并揭示ASD及其核心的关键方面 特征--社交缺陷和限制性和重复行为--不同于其他神经发育 精神错乱。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) 融合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，并对累积的序列数据进行分析；3)对比ASD和其他 神经发育障碍风险基因，检查发育概况，所涉及的细胞类型，以及 同一基因中的变异在如何影响ASD和其他神经发育和精神疾病的风险方面有所不同 精神错乱。有了这项新的研究，我们将加速我们的总体目标，即ASD的鉴定 基因，从而促进了我们的长期目标，即建立ASD治疗靶点的基础 浮出水面。我们的理论基础是，识别出与自闭症和相关疾病相关的重大风险基因 神经发育障碍可以形成研究的基础，以了解发病机制，以及 寻找新的疗法。我们的中心假设--基于过去十年的研究结果--是罕见的吗？ 常见的变异增加了ASD的风险，但只有某些罕见的变异才能带来实质性的风险 风险。在我们看来，提出的研究是创新的，因为它使用了突破性的和新颖的统计方法 识别ASD风险变量的方法。

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 In our most recent, unpublished, analyses of 72,410 individuals from ASD families, we identified 185 genes associated with risk (FDR 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.