Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism.

NDAR Data for this study consist of Whole Exome sequencing for the additional 56 families from SSC collection. Other Whole Exome sequencing data and results used in this study were originally published elsewhere. NDAR Studies 340, 320, and 317 describe the data published in Iossifov et al., 2012; Neale et al., 2012; O'Roak et al., 2012b, respectively, as cited in this publication. The RNA-Seq data from this publication are available from NCBI at the given BioProject accession.

Autism spectrum disorder (ASD) is a complex developmental syndrome of unknown etiology. Recent studies employing exome- and genome-wide sequencing have identified nine high-confidence ASD (hcASD) genes. Working from the hypothesis that ASD-associated mutations in these biologically pleiotropic genes will disrupt intersecting developmental processes to contribute to a common phenotype, we have attempted to identify time periods, brain regions, and cell types in which these genes converge. We have constructed coexpression networks based on the hcASD "seed" genes, leveraging a rich expression data set encompassing multiple human brain regions across human development and into adulthood. By assessing enrichment of an independent set of probable ASD (pASD) genes, derived from the same sequencing studies, we demonstrate a key point of convergence in midfetal layer 5/6 cortical projection neurons. This approach informs when, where, and in what cell types mutations in these specific genes may be productively studied to clarify ASD pathophysiology.

本研究使用的NDAR数据集包含源自SSC队列的额外56个家庭的全外显子组测序（Whole Exome Sequencing）数据。本研究中使用的其余全外显子组测序数据及分析结果，此前已在其他出版物中发表。NDAR研究340、320与317分别对应本研究引用的Iossifov等（2012）、Neale等（2012）以及O'Roak等（2012b）的已发表数据。本研究相关的RNA测序（RNA-Seq）数据可通过NCBI提供的BioProject登录号获取。

自闭症谱系障碍（Autism Spectrum Disorder, ASD）是一种病因未明的复杂发育综合征。近年来，通过全外显子组及全基因组测序技术开展的研究已确认9个高可信度自闭症谱系障碍（high-confidence ASD, hcASD）基因。基于“这些具有多效生物学功能的基因所携带的自闭症相关突变，会通过干扰相互交叉的发育进程，最终促成共同的表型”这一假说，本研究尝试明确这些基因产生汇聚作用的时间窗口、脑区及细胞类型。本研究以hcASD "seed" 基因为基础构建共表达网络，利用涵盖人类从发育阶段至成年期多个脑区的丰富表达数据集开展分析。通过评估源自同一测序研究的独立候选自闭症谱系障碍（probable ASD, pASD）基因集的富集情况，我们证实了妊娠中期皮层5/6层投射神经元存在关键的基因汇聚节点。该研究明确了可有效开展相关特异性基因突变研究的时间、脑区与细胞类型，有助于阐明自闭症谱系障碍的病理生理机制。