Broad transcriptomic dysregulation occurs across the cerebral cortex in ASD.
Broad transcriptomic dysregulation occurs across the cerebral cortex in ASD.
复制标题
DOI：
10.1038/s41586-022-05377-7
复制
发表时间：
2022-11
期刊：
影响因子：
64.8
通讯作者：
Geschwind, Daniel H.
中科院分区：
文献类型：
--
作者：
Gandal, Michael J.;Haney, Jillian R.;Wamsley, Brie;Yap, Chloe X.;Parhami, Sepideh;Emani, Prashant S.;Chang, Nathan;Chen, George T.;Hoftman, Gil D.;de Alba, Diego;Ramaswami, Gokul;Hartl, Christopher L.;Bhattacharya, Arjun;Luo, Chongyuan;Jin, Ting;Wang, Daifeng;Kawaguchi, Riki;Quintero, Diana;Ou, Jing;Wu, Ye Emily;Parikshak, Neelroop N.;Swarup, Vivek;Belgard, T. Grant;Gerstein, Mark;Pasaniuc, Bogdan;Geschwind, Daniel H.
神经精神障碍传统上缺乏明确的大脑病理学，但最近的研究表明，分子水平上的失调，以转录和表观遗传学改变为特征。在自闭症谱系障碍(ASD)中，这种分子病理涉及小胶质细胞、星形胶质细胞和神经免疫基因的上调，突触基因的下调，以及皮质基因表达梯度的减弱。然而，这些变化是仅限于皮质联合区域，还是更广泛，目前尚不清楚。为了解决这个问题，我们对来自ASD患者和神经典型对照组的112个尸检样本中的725个大脑样本进行了RNA测序分析，这些样本跨越了11个皮质区域。我们发现ASD患者大脑皮质中广泛存在转录转录变化，表现出从前到后的梯度，初级视觉皮质的差异最大，与皮质区域之间典型的转录差异减弱相一致。单核RNA测序和甲基化分析表明，这种强大的分子特征反映了细胞类型特异性基因表达的变化，特别是影响兴奋性神经元和胶质细胞。罕见的和常见的ASD相关的遗传变异都聚集在涉及突触信号的下调的共表达模块中，而共同的变异单独在上调的蛋白伴侣基因模块中丰富。这些结果突显了ASD患者大脑皮层广泛的分子变化，从联合皮质延伸到广泛涉及主要感觉区域。RNA测序揭示了自闭症谱系障碍患者大脑皮层广泛的转录变化，除了关联区外，还包括主要感觉区域，以及区域认同感的减弱。
Neuropsychiatric disorders classically lack defining brain pathologies, but recent work has demonstrated dysregulation at the molecular level, characterized by transcriptomic and epigenetic alterations. In autism spectrum disorder (ASD), this molecular pathology involves the upregulation of microglial, astrocyte and neural–immune genes, the downregulation of synaptic genes, and attenuation of gene-expression gradients in cortex. However, whether these changes are limited to cortical association regions or are more widespread remains unknown. To address this issue, we performed RNA-sequencing analysis of 725 brain samples spanning 11 cortical areas from 112 post-mortem samples from individuals with ASD and neurotypical controls. We find widespread transcriptomic changes across the cortex in ASD, exhibiting an anterior-to-posterior gradient, with the greatest differences in primary visual cortex, coincident with an attenuation of the typical transcriptomic differences between cortical regions. Single-nucleus RNA-sequencing and methylation profiling demonstrate that this robust molecular signature reflects changes in cell-type-specific gene expression, particularly affecting excitatory neurons and glia. Both rare and common ASD-associated genetic variation converge within a downregulated co-expression module involving synaptic signalling, and common variation alone is enriched within a module of upregulated protein chaperone genes. These results highlight widespread molecular changes across the cerebral cortex in ASD, extending beyond association cortex to broadly involve primary sensory regions. RNA sequencing reveals widespread transcriptomic changes across the cerebral cortex in autism spectrum disorder, including primary sensory regions, in addition to association regions, as well as an attenuation of regional identity.
登录
查看更多内容
DOI：
10.1093/biostatistics/kxr054
发表时间：
2012-04
期刊：
Biostatistics (Oxford, England)
影响因子：
--
作者：
Hansen KD;Irizarry RA;Wu Z
通讯作者：
Wu Z
影响因子：
16.2
作者：
Cadwell, Cathryn R.;Bhaduri, Aparna;Mostajo-Radji, Mohammed A.;Keefe, Matthew G.;Nowakowski, Tomasz J.
通讯作者：
Nowakowski, Tomasz J.
影响因子：
14.9
作者：
Frankish A;Diekhans M;Ferreira AM;Johnson R;Jungreis I;Loveland J;Mudge JM;Sisu C;Wright J;Armstrong J;Barnes I;Berry A;Bignell A;Carbonell Sala S;Chrast J;Cunningham F;Di Domenico T;Donaldson S;Fiddes IT;García Girón C;Gonzalez JM;Grego T;Hardy M;Hourlier T;Hunt T;Izuogu OG;Lagarde J;Martin FJ;Martínez L;Mohanan S;Muir P;Navarro FCP;Parker A;Pei B;Pozo F;Ruffier M;Schmitt BM;Stapleton E;Suner MM;Sycheva I;Uszczynska-Ratajczak B;Xu J;Yates A;Zerbino D;Zhang Y;Aken B;Choudhary JS;Gerstein M;Guigó R;Hubbard TJP;Kellis M;Paten B;Reymond A;Tress ML;Flicek P
通讯作者：
Flicek P
影响因子：
64.8
作者：
Klingler, Esther;Tomasello, Ugo;Jabaudon, Denis
通讯作者：
Jabaudon, Denis
DOI：
10.1073/pnas.1010356107
发表时间：
2010-09-07
影响因子：
11.1
作者：
Collins, Christine E.;Airey, David C.;Kaas, Jon H.
通讯作者：
Kaas, Jon H.