Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism.
Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism.
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DOI：
10.1016/j.cell.2013.10.031
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发表时间：
2013-11-21
期刊：
影响因子：
64.5
通讯作者：
Geschwind DH
中科院分区：
文献类型：
--
作者：
Parikshak NN;Luo R;Zhang A;Won H;Lowe JK;Chandran V;Horvath S;Geschwind DH
遗传学研究已经确定了数十个自闭症谱系障碍（ASD）易感基因，提出了两个关键问题：1)这些遗传位点是否集中在特定的生物学过程中？ 2)鉴于ASD与智力残疾（ID）的遗传重叠，ASD的表型特异性从何而来？为了解决这个问题，我们将ASD和ID风险基因映射到代表发育轨迹的共表达网络和代表胎儿和成人皮质层的转录谱上。在人类皮层发育过程中，ASD基因紧密结合在模块中，这些模块涉及不同的生物学功能，包括早期转录调节和突触发育。生物信息学分析表明，FMRP的翻译调控和常见转录因子的转录协同调控将这些过程联系起来。在回路水平上，ASD基因在皮层浅层和谷氨酸能投射神经元中富集。此外，我们发现ASD和ID风险基因的模式是不同的，为研究ASD的病理生理提供了一个新的生物学框架。
Genetic studies have identified dozens of autism spectrum disorder (ASD) susceptibility genes, raising two critical questions: 1) do these genetic loci converge on specific biological processes, and 2) where does the phenotypic specificity of ASD arise, given its genetic overlap with intellectual disability (ID)? To address this, we mapped ASD and ID risk genes onto co-expression networks representing developmental trajectories and transcriptional profiles representing fetal and adult cortical laminae. ASD genes tightly coalesce in modules that implicate distinct biological functions during human cortical development, including early transcriptional regulation and synaptic development. Bioinformatic analyses suggest translational regulation by FMRP and transcriptional co-regulation by common transcription factors connect these processes. At a circuit level, ASD genes are enriched in superficial cortical layers and glutamatergic projection neurons. Furthermore, we show that the patterns of ASD and ID risk genes are distinct, providing a novel biological framework for investigating the pathophysiology of ASD.
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影响因子：
16.2
作者：
Iossifov I;Ronemus M;Levy D;Wang Z;Hakker I;Rosenbaum J;Yamrom B;Lee YH;Narzisi G;Leotta A;Kendall J;Grabowska E;Ma B;Marks S;Rodgers L;Stepansky A;Troge J;Andrews P;Bekritsky M;Pradhan K;Ghiban E;Kramer M;Parla J;Demeter R;Fulton LL;Fulton RS;Magrini VJ;Ye K;Darnell JC;Darnell RB;Mardis ER;Wilson RK;Schatz MC;McCombie WR;Wigler M
通讯作者：
Wigler M
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：
8.8
作者：
Denaxa M;Kalaitzidou M;Garefalaki A;Achimastou A;Lasrado R;Maes T;Pachnis V
通讯作者：
Pachnis V
影响因子：
14.9
作者：
Basu SN;Kollu R;Banerjee-Basu S
通讯作者：
Banerjee-Basu S
影响因子：
3.5
作者：
Anney R;Klei L;Pinto D;Almeida J;Bacchelli E;Baird G;Bolshakova N;Bölte S;Bolton PF;Bourgeron T;Brennan S;Brian J;Casey J;Conroy J;Correia C;Corsello C;Crawford EL;de Jonge M;Delorme R;Duketis E;Duque F;Estes A;Farrar P;Fernandez BA;Folstein SE;Fombonne E;Gilbert J;Gillberg C;Glessner JT;Green A;Green J;Guter SJ;Heron EA;Holt R;Howe JL;Hughes G;Hus V;Igliozzi R;Jacob S;Kenny GP;Kim C;Kolevzon A;Kustanovich V;Lajonchere CM;Lamb JA;Law-Smith M;Leboyer M;Le Couteur A;Leventhal BL;Liu XQ;Lombard F;Lord C;Lotspeich L;Lund SC;Magalhaes TR;Mantoulan C;McDougle CJ;Melhem NM;Merikangas A;Minshew NJ;Mirza GK;Munson J;Noakes C;Nygren G;Papanikolaou K;Pagnamenta AT;Parrini B;Paton T;Pickles A;Posey DJ;Poustka F;Ragoussis J;Regan R;Roberts W;Roeder K;Roge B;Rutter ML;Schlitt S;Shah N;Sheffield VC;Soorya L;Sousa I;Stoppioni V;Sykes N;Tancredi R;Thompson AP;Thomson S;Tryfon A;Tsiantis J;Van Engeland H;Vincent JB;Volkmar F;Vorstman JA;Wallace S;Wing K;Wittemeyer K;Wood S;Zurawiecki D;Zwaigenbaum L;Bailey AJ;Battaglia A;Cantor RM;Coon H;Cuccaro ML;Dawson G;Ennis S;Freitag CM;Geschwind DH;Haines JL;Klauck SM;McMahon WM;Maestrini E;Miller J;Monaco AP;Nelson SF;Nurnberger JI Jr;Oliveira G;Parr JR;Pericak-Vance MA;Piven J;Schellenberg GD;Scherer SW;Vicente AM;Wassink TH;Wijsman EM;Betancur C;Buxbaum JD;Cook EH;Gallagher L;Gill M;Hallmayer J;Paterson AD;Sutcliffe JS;Szatmari P;Vieland VJ;Hakonarson H;Devlin B
通讯作者：
Devlin B