Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism.
Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism.
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DOI：
10.1038/nature20612
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发表时间：
2016-12-15
期刊：
影响因子：
64.8
通讯作者：
Geschwind DH
中科院分区：
文献类型：
--
作者：
Parikshak NN;Swarup V;Belgard TG;Irimia M;Ramaswami G;Gandal MJ;Hartl C;Leppa V;Ubieta LT;Huang J;Lowe JK;Blencowe BJ;Horvath S;Geschwind DH
自闭症谱系障碍(ASD)涉及到大量的遗传因素。这些贡献具有深刻的异质性，但可能会汇聚在尚未得到很好理解的共同道路上。在这里，通过对迄今分析的最大样本队列的死后全基因组转录组分析，据我们所知，我们询问了非编码转录组、选择性剪接和上游分子调控因子，以拓宽我们对ASD分子收敛的理解。我们的分析揭示了与ASD相关的灵长类特定的长非编码RNA(LncRNAs)的调节异常，活动依赖的神经元特定外显子的选择性剪接下调，以及额叶和颞叶之间基因表达的正常差异减弱。我们的数据表明，参与神经元命运指定的转录因子SOX5有助于缩小区域差异。我们进一步证明，ASD的一个遗传亚型，染色体15q11.2-13.1重复综合征(Dup15q)，与特发性ASD的核心转录转录特征相同。共表达网络分析显示，ASD患者在最初的20年中表现出与年龄相关的小胶质细胞和突触功能的变化，这表明ASD的遗传风险可能会影响局部皮质基因表达的变化。我们的发现说明了在复杂的神经精神障碍中，不同的遗传扰动如何导致在多个生物学水平上的表型收敛。
Autism spectrum disorder (ASD) involves substantial genetic contributions. These contributions are profoundly heterogeneous but may converge on common pathways that are not yet well understood. Here, through post-mortem genome-wide transcriptome analysis of the largest cohort of samples analysed so far, to our knowledge, we interrogate the noncoding transcriptome, alternative splicing, and upstream molecular regulators to broaden our understanding of molecular convergence in ASD. Our analysis reveals ASD-associated dysregulation of primate-specific long noncoding RNAs (lncRNAs), downregulation of the alternative splicing of activity-dependent neuron-specific exons, and attenuation of normal differences in gene expression between the frontal and temporal lobes. Our data suggest that SOX5, a transcription factor involved in neuron fate specification, contributes to this reduction in regional differences. We further demonstrate that a genetically defined subtype of ASD, chromosome 15q11.2–13.1 duplication syndrome (dup15q), shares the core transcriptomic signature observed in idiopathic ASD. Co-expression network analysis reveals that individuals with ASD show age-related changes in the trajectory of microglial and synaptic function over the first two decades, and suggests that genetic risk for ASD may influence changes in regional cortical gene expression. Our findings illustrate how diverse genetic perturbations can lead to phenotypic convergence at multiple biological levels in a complex neuropsychiatric disorder.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
WGCNA：用于加权相关网络分析的 R 包。
影响因子：
3
作者：
Langfelder P;Horvath S
通讯作者：
Horvath S
影响因子：
30.8
作者：
Gratten, Jacob;Visscher, Peter M.;Wray, Naomi R.
通讯作者：
Wray, Naomi R.
影响因子：
64.8
作者：
Iossifov, Ivan;O'Roak, Brian J.;Sanders, Stephan J.;Ronemus, Michael;Krumm, Niklas;Levy, Dan;Stessman, Holly A.;Witherspoon, Kali T.;Vives, Laura;Patterson, Karynne E.;Smith, Joshua D.;Paeper, Bryan;Nickerson, Deborah A.;Dea, Jeanselle;Dong, Shan;Gonzalez, Luis E.;Mandell, Jeffrey D.;Mane, Shrikant M.;Murtha, Michael T.;Sullivan, Catherine A.;Walker, Michael F.;Waqar, Zainulabedin;Wei, Liping;Willsey, A. Jeremy;Yamrom, Boris;Lee, Yoon-ha;Grabowska, Ewa;Dalkic, Ertugrul;Wang, Zihua;Marks, Steven;Andrews, Peter;Leotta, Anthony;Kendall, Jude;Hakker, Inessa;Rosenbaum, Julie;Ma, Beicong;Rodgers, Linda;Troge, Jennifer;Narzisi, Giuseppe;Yoon, Seungtai;Schatz, Michael C.;Ye, Kenny;McCombie, W. Richard;Shendure, Jay;Eichler, Evan E.;State, Matthew W.;Wigler, Michael
通讯作者：
Wigler, Michael
影响因子：
30.8
作者：
Bulik-Sullivan, Brendan K.;Loh, Po-Ru;Finucane, Hilary K.;Ripke, Stephan;Yang, Jian;Patterson, Nick;Daly, Mark J.;Price, Alkes L.;Neale, Benjamin M.
通讯作者：
Neale, Benjamin M.