PsychENCODE: Autism Transcriptional and Epigenetic Profiling

Our current understanding of autism spectrum disorders (ASD) delineates a highly heritable, yet etiologically heterogeneous disease. Forward genetic approaches to find disease associated mutations or common variation have been successful and continue to offer considerable power. Yet, given the accumulating evidence for very significant heterogeneity and environmental influences, complementary approaches to classic forward genetics become necessary. Genetic polymorphism and mutation data to date have identified dozens of causal or contributory variants, yet our preliminary data from autism brain suggest that common molecular pathways are involved in a significant subset of cases. This convergence at the tissue level suggests that other mechanisms, specifically epigenetic changes, combined with genetic background, are contributing to such final common pathways. We further tested this hypothesis by taking a comprehensive and integrative genome-wide approach to assessing brain gene-expression, miRNA levels and the related, causal epigenetic mechanisms in ASD etiology. We performed RNA-seq analyses of four cerebral cortical regions and cerebellum from ASD cases and controls, to assess mRNA, miRNA, and splicing isoform regulation. In parallel, we identified key differences in chromatin state and DNA methylation across multiple brain regions in the same ASD and control individuals used in the expression analyses using ChIP-Seq and MeDIP. We assessed the mechanisms by which changes in DNA methylation, histone modification, and DNA sequence contribute to the observed differences in gene expression. This work, which represents an unprecedented effort to unify these often disparate data (usually produced without integration in mind), delineates potential shared molecular pathways in ASD and the underlying mechanism of these differences at the level of miRNA, the chromatin regulatory apparatus, and DNA methylation. The following substudies are part of the PsychENCODE release at dbGaP and offer additional molecular data: PsychENCODE: RNA-Sequencing - SRRM4 Splicing Study phs000872 PsychENCODE: Global Changes in Patterning, Splicing and lncRNAs phs001061 PsychENCODE: Chromatin Contact Map in Fetal Cortical Laminae phs001190 PsychENCODE: Epigenetic Dysregulation in Autism Spectrum Disorder phs001220 ]]> As many tissue samples from the Autism Tissue Program brain bank at the Harvard Brain and Tissue Bank and the National Institute for Child Health and Human Development Eunice Kennedy Shriver Brain and Tissue Bank for Developmental Disorders were used as could be acquired and balanced between cases and controls.]]> This is the first data release for this study, and remaining samples across additional individuals and brain regions, and additional epigenetic datasets along with complete differential gene expression, differential splicing, and co-expression analysis will be released in the coming future.]]>我们目前对自闭症谱系障碍（ASD）的认知将其界定为一类高可遗传性但病因异质性极强的疾病。用于筛选疾病相关突变或常见变异的正向遗传学方法已取得显著成效，且仍具备可观的研究潜力。然而，随着日益积累的证据表明该病存在显著的异质性与环境影响因素，经典正向遗传学的互补研究策略已成为必要之举。迄今为止，遗传多态性与突变数据已鉴定出数十种致病或促病变异，但我们针对自闭症患者脑组织的初步研究数据显示，常见分子通路参与了相当一部分病例的发病过程。这种组织层面的通路汇聚现象提示，其他机制——尤其是表观遗传改变结合遗传背景——正参与促成此类最终共同通路的形成。我们通过全面整合的全基因组研究策略，评估自闭症谱系障碍病因学中的脑组织基因表达、miRNA水平及相关致病表观遗传机制，以此验证这一假说。我们对自闭症病例与对照个体的四个大脑皮层区域及小脑开展RNA测序（RNA-seq）分析，以解析mRNA、miRNA及剪接异构体的调控模式。与此同时，我们利用染色质免疫沉淀测序（ChIP-Seq）与甲基化DNA免疫沉淀测序（MeDIP），对上述表达分析所用的同一批自闭症及对照个体的多个脑区的染色质状态与DNA甲基化差异进行了系统鉴定。我们评估了DNA甲基化、组蛋白修饰及DNA序列改变如何导致观测到的基因表达差异。本研究史无前例地整合了这些通常相互独立（生成时通常未考虑整合需求）的数据集，明确了自闭症谱系障碍中潜在的共同分子通路，以及这些差异在miRNA、染色质调控装置及DNA甲基化层面的潜在机制。以下子研究隶属于dbGaP数据库中的PsychENCODE发布项目，提供了额外的分子数据集： PsychENCODE：RNA测序 - SRRM4剪接研究 phs000872 PsychENCODE：模式形成、剪接及长链非编码RNA的全局变化 phs001061 PsychENCODE：胎儿皮层板层的染色质接触图谱 phs001190 PsychENCODE：自闭症谱系障碍的表观遗传失调 phs001220 本研究使用了可获取的来自哈佛大脑与组织库自闭症组织项目脑库，以及美国国立儿童健康与人类发展研究所尤尼斯·肯尼迪·施赖弗发育障碍大脑与组织库的组织样本，并对病例组与对照组进行了均衡匹配。 本数据集为该研究的首次数据发布，剩余的额外个体与脑区样本、额外的表观遗传数据集，以及完整的差异基因表达、差异剪接与共表达分析结果，将在未来发布。