Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder

题目：自闭症、精神分裂症和双向情感障碍中的转录组范围异构体水平失调

作者：

Michael J. Gandal^1,2,3,4,*, Pan Zhang^5,, Evi Hadjimichael^6,7,8,9,, […] Chunyu Liu^10,17,27,*, Lilia M. Iakoucheva^5,*, Dalila Pinto^6,7,8,9,*, Daniel H. Geschwind^1,2,3,4,*

通讯作者单位（共12个）：

¹Department of Psychiatry, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA.

²Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.

³Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA.

⁴Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.

⁵Department of Psychiatry, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093, USA.

⁶Department of Psychiatry, and Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

⁷Department of Genetics and Genomic Sciences, and Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

⁸The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

⁹Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

¹⁰The School of Life Sciences, Central South University, Changsha, Hunan 410078, China.

¹⁷Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY 13210, USA.

²⁷School of Psychology, Shaanxi Normal University, Xian, Shaanxi 710000, China.

发表期刊、时间、影响因子：

Science 14 Dec 2018:
Vol. 362, Issue 6420, eaat8127
DOI: 10.1126/science.aat8127

摘要：

Most genetic risk for psychiatric disease lies in regulatory regions, implicating pathogenic dysregulation of gene expression and splicing. However, comprehensive assessments of transcriptomic organization in diseased brains are limited. In this work, we integrated genotypes and RNA sequencing in brain samples from 1695 individuals with autism spectrum disorder (ASD), schizophrenia, and bipolar disorder, as well as controls. More than 25% of the transcriptome exhibits differential splicing or expression, with isoform-level changes capturing the largest disease effects and genetic enrichments. Coexpression networks isolate disease-specific neuronal alterations, as well as microglial, astrocyte, and interferon-response modules defining previously unidentified neural-immune mechanisms. We integrated genetic and genomic data to perform a transcriptome-wide association study, prioritizing disease loci likely mediated by cis effects on brain expression. This transcriptome-wide characterization of the molecular pathology across three major psychiatric disorders provides a comprehensive resource for mechanistic insight and therapeutic development.

大部分精神疾病的遗传风险存在于调节区域，即基因表达和剪切的致病的调节异常。然而，对患病大脑组织转录组的全面评估是有限的。在这项工作中，我们整合了来自1695名患有自闭症、精神分裂症和双相情感障碍的病人以及对照组的大脑样品中的基因型及RNA测序。超过25％的转录组表现出差异剪接或表达，同种型水平的变化捕获最大的疾病效应和遗传富集。共表达网络隔离了疾病-特定的神经元变化，以及小神经胶质细胞、形状胶质细胞和干扰素应答模块，定义之前未鉴别的神经-免疫机制。我们整合了遗传和基因组数据来进行转录组范围的关联研究，优先选择有可能被在大脑表达中的顺势作用介导的疾病基因座。这个在三种主要精神障碍中的分子病理学转录组特征为机制上的深入了解以及治疗上的发展提供了全面的资源。

图表选析

图7 疾病中明显的神经-免疫轨迹
(A) 共表达网络完善了在ASD、SCZ和BD中上调的神经-免疫/炎症过程。之前的工作已经从星状胶质细胞和小神经胶质细胞群体中证实了对这个信号的特殊贡献（13，19）。这次我们验证了来自明显的干扰素应答和核转录因子信号模块的另外的贡献。（B）四个被鉴别的神经免疫模块对均分别显示了固有基因和疾病的联系。星形胶质细胞和干扰素应答模块在ASD和SCZ中上调。核转录因子信号在三种精神障碍中均上调。小神经胶质细胞模块在ASD中上调，在另外两种病中下调。（C）每个模块中最高的中心基因被展示出来，还有共表达支持的边界（浅灰色，皮尔森相关系数 > 0.5）和已知的蛋白-蛋白互作（黑色线）。节点遵循图5C中的配色组合。星形胶质细胞模块中的中枢（geneM3 / isoM1）包括几种经典的特异性星形胶质细胞标记物，包括SOX9，GJA1，SPON1和NOTCH2。小神经胶质细胞模块中的枢纽基因包括几种经典的特异性小神经胶质细胞标志物，包括AIF1, CSF1R, TYROBP和TMEM119。核转录因子模块包括许多已知的下游转录因子靶点（JAK3, STAT3, JUNB和FOS）和上游激活物（IL1R1，九个TNF受体超家族成员）。（D）每个模块都会显示前四个GO浓缩曲目。（E）已知细胞类型特异标志物基因的模块富集，从对神经免疫细胞类型（98-102）测序研究中核对。（F）跨年龄的模块固有基因表达阐述了独特的、动态的每种疾病的神经免疫轨迹。