Coexpression Networks Implicate Human Midfetal Deep Cortical Projection Neurons in the Pathogenesis of Autism

被引：656

作者：

Willsey, A. Jeremy ^{[1
,2
]}

Sanders, Stephan J. ^{[1
,2
]}

Li, Mingfeng ^{[3
,4
]}

Dong, Shan ^{[1
,5
]}

Tebbenkamp, Andrew T. ^{[3
,4
]}

Muhle, Rebecca A. ^{[1
,4
,6
]}

Reilly, Steven K. ^{[1
]}

Lin, Leon ^{[7
]}

Fertuzinhos, Sofia ^{[3
,4
]}

Miller, Jeremy A. ^{[8
]}

Murtha, Michael T. ^{[9
]}

Bichsel, Candace ^{[3
,4
]}

Niu, Wei ^{[1
,4
,6
]}

Cotney, Justin ^{[1
]}

Ercan-Sencicek, A. Gulhan ^{[6
,9
]}

Gockley, Jake ^{[1
]}

Gupta, Abha R. ^{[6
,10
]}

Han, Wenqi ^{[3
,4
]}

He, Xin ^{[11
]}

Hoffman, Ellen J. ^{[6
,9
]}

Klei, Lambertus ^{[12
]}

Lei, Jing ^{[13
]}

Liu, Wenzhong ^{[1
]}

Liu, Li ^{[13
]}

Lu, Cong ^{[13
]}

Xu, Xuming ^{[3
,4
]}

Zhu, Ying ^{[3
,4
]}

Mane, Shrikant M. ^{[14
]}

Lein, Ed S. ^{[8
]}

Wei, Liping ^{[5
,15
]}

Noonan, James P. ^{[1
,4
]}

Roeder, Kathryn ^{[11
,13
]}

Devlin, Bernie ^{[12
]}

Sestan, Nenad ^{[3
,4
]}

State, Matthew W. ^{[1
,2
,6
,9
,16
]}

机构：

[1] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA

[2] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA

[3] Yale Univ, Sch Med, Dept Neurobiol, New Haven, CT 06510 USA

[4] Yale Univ, Sch Med, Kavli Inst Neurosci, New Haven, CT 06510 USA

[5] Peking Univ, Sch Life Sci, Ctr Bioinformat, State Key Lab Prot & Plant Gene Res, Beijing 100871, Peoples R China

[6] Yale Univ, Sch Med, Child Study Ctr, New Haven, CT 06510 USA

[7] Yale Univ, Dept Computat Biol & Bioinformat, New Haven, CT 06511 USA

[8] Allen Inst Brain Sci, Seattle, WA 98103 USA

[9] Yale Univ, Sch Med, Program Neurogenet, New Haven, CT 06510 USA

[10] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA

[11] Carnegie Mellon Univ, Ray & Stephanie Lane Ctr Computat Biol, Pittsburgh, PA 15213 USA

[12] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15213 USA

[13] Carnegie Mellon Univ, Dept Stat, Pittsburgh, PA 15213 USA

[14] Yale Univ, Sch Med, Yale Ctr Genom Anal, New Haven, CT 06417 USA

[15] Natl Inst Biol Sci, Beijing 102206, Peoples R China

[16] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06510 USA

来源：

CELL | 2013年 / 155卷 / 05期

基金：

加拿大健康研究院;

关键词：

SPECTRUM DISORDERS; NOVO MUTATIONS; GENES; RISK; CNVS;

D O I：

10.1016/j.cell.2013.10.020

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Autism spectrum disorder (ASD) is a complex developmental syndrome of unknown etiology. Recent studies employing exome- and genome-wide sequencing have identified nine high-confidence ASD (hcASD) genes. Working from the hypothesis that ASD-associated mutations in these biologically pleiotropic genes will disrupt intersecting developmental processes to contribute to a common phenotype, we have attempted to identify time periods, brain regions, and cell types in which these genes converge. We have constructed coexpression networks based on the hcASD "seed'' genes, leveraging a rich expression data set encompassing multiple human brain regions across human development and into adulthood. By assessing enrichment of an independent set of probable ASD (pASD) genes, derived from the same sequencing studies, we demonstrate a key point of convergence in midfetal layer 5/6 cortical projection neurons. This approach informs when, where, and in what cell types mutations in these specific genes may be productively studied to clarify ASD pathophysiology.

引用

页码：997 / 1007

页数：11

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