Synaptic, transcriptional and chromatin genes disrupted in autism

被引：1874

作者：

De Rubeis, Silvia ^{[1
,2
]}

He, Xin ^{[3
]}

Goldberg, Arthur P. ^{[1
,2
,4
]}

Poultney, Christopher S. ^{[1
,2
]}

Samocha, Kaitlin ^{[5
]}

Cicek, A. Ercument ^{[3
]}

Kou, Yan ^{[1
,2
]}

Liu, Li ^{[6
]}

Fromer, Menachem ^{[2
,4
,5
]}

Walker, Susan ^{[7
]}

Singh, Tarjinder ^{[8
]}

Klei, Lambertus ^{[9
]}

Kosmicki, Jack ^{[5
]}

Fu, Shih-Chen ^{[1
,2
]}

Aleksic, Branko ^{[10
]}

Biscaldi, Monica ^{[11
,12
]}

Bolton, Patrick F. ^{[13
,14
]}

Brownfeld, Jessica M. ^{[1
,2
]}

Cai, Jinlu ^{[1
,2
]}

Campbell, Nicholas G. ^{[15
,16
]}

Carracedo, Angel ^{[17
,18
,19
]}

Chahrour, Maria H. ^{[20
,21
]}

Chiocchetti, Andreas G. ^{[22
]}

Coon, Hilary ^{[23
,24
]}

Crawford, Emily L. ^{[15
,16
]}

Crooks, Lucy ^{[8
]}

Curran, Sarah R. ^{[13
,14
]}

Dawson, Geraldine ^{[25
]}

Duketis, Eftichia ^{[22
]}

Fernandez, Bridget A. ^{[26
]}

Gallagher, Louise ^{[27
]}

Geller, Evan ^{[28
]}

Guter, Stephen J. ^{[29
]}

Hill, R. Sean ^{[20
,21
]}

Ionita-Laza, Iuliana ^{[30
]}

Gonzalez, Patricia Jimenez ^{[31
]}

Kilpinen, Helena ^{[32
]}

Klauck, Sabine M. ^{[33
]}

Kolevzon, Alexander ^{[1
,2
,34
]}

Lee, Irene ^{[35
]}

Lei, Jing ^{[6
]}

Lehtimaeki, Terho ^{[36
]}

Lin, Chiao-Feng ^{[28
]}

Ma'ayan, Avi ^{[37
]}

Marshall, Christian R. ^{[7
]}

McInnes, Alison L. ^{[38
]}

Neale, Benjamin ^{[39
]}

Owen, Michael J. ^{[40
,41
]}

Ozaki, Norio ^{[10
]}

Parellada, Mara ^{[42
]}

机构：

[1] Icahn Sch Med Mt Sinai, Seaver Autism Ctr Res & Treatment, New York, NY 10029 USA

[2] Mt Sinai Med Ctr, Dept Psychiat, New York, NY 10029 USA

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

[4] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA

[5] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA

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

[7] Hosp Sick Children, Ctr Appl Genom, Program Genet & Genome Biol, Toronto, ON M5G 0A4, Canada

[8] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England

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

[10] Nagoya Univ, Sch Med, Dept Psychiat, Nagoya, Aichi 4668550, Japan

[11] Univ Med Ctr Freiburg, Dept Child & Adolescent Psychiat Psychotherapy &, D-79106 Freiburg, Germany

[12] Ctr Mental Disorders, D-79106 Freiburg, Germany

[13] Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Child Psychiat, London SE5 8AF, England

[14] Kings Coll London, Inst Psychiat Psychol & Neurosci, SGDP Ctr, London SE5 8AF, England

[15] Vanderbilt Univ, Sch Med, Vanderbilt Brain Inst, Nashville, TN 37212 USA

[16] Vanderbilt Univ, Dept Mol Physiol & Biophys, Sch Med, Nashville, TN 37232 USA

[17] Univ Santiago de Compostela, CIBERER, Genom Med Grp, Santiago De Compostela 15706, Spain

[18] Galician Fdn Genom Med SERGAS, Santiago De Compostela 15706, Spain

[19] King Abdulaziz Univ, Ctr Excellence Genom Med Res, Jeddah 21589, Saudi Arabia

[20] Harvard Univ, Sch Med, Boston, MA 02115 USA

[21] Boston Childrens Hosp, Div Genet & Genom, Boston, MA 02115 USA

[22] Goethe Univ Frankfurt, Dept Child & Adolescent Psychiat Psychosomat & Ps, D-60528 Frankfurt, Germany

[23] Univ Utah, Dept Internal Med, Salt Lake City, UT 84132 USA

[24] Univ Utah, Dept Psychiat, Salt Lake City, UT 84108 USA

[25] Duke Univ, Duke Inst Brain Sci, Durham, NC 27708 USA

[26] Mem Univ Newfoundland, Disciplines Genet & Med, St John, NF A1B 3V6, Canada

[27] Trinity Coll Dublin, Sch Med, Dept Psychiat, Dublin 8, Ireland

[28] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[29] Univ Illinois, Dept Psychiat, Inst Juvenile Res, Chicago, IL 60608 USA

[30] Columbia Univ, Dept Biostat, New York, NY 10032 USA

[31] Hosp Nacl de Ninos Dr Saenz Herrera, CCSS, Child Dev & Behav Unit, San Jose, Costa Rica

[32] European Bioinformat Inst, European Mol Biol Lab, Cambridge CB10 1SD, England

[33] German Canc Res Ctr, Div Mol Genome Anal, D-69120 Heidelberg, Germany

[34] Icahn Sch Med Mt Sinai, Dept Pediat, New York, NY 10029 USA

[35] UCL, Inst Child Hlth, London WC1N 1EH, England

[36] Fimlab Labs, Dept Clin Chem, SF-33100 Tampere, Finland

[37] Icahn Sch Med Mt Sinai, Dept Pharmacol & Syst Therapeut, New York, NY 10029 USA

[38] Kaiser Permanente, Dept Psychiat, San Francisco, CA 94118 USA

[39] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[40] Cardiff Univ, MRC Ctr Neuropsychiat Genet & Genom, Cardiff CF24 4HQ, S Glam, Wales

[41] Cardiff Univ, Neurosci & Mental Hlth Res Inst, Cardiff CF24 4HQ, S Glam, Wales

[42] Univ Complutense, Hosp Gen Univ Gregorio Maranon, Child & Adolescent Psychiat Dept, IiSGM,CIBERSAM, E-28040 Madrid, Spain

[43] Newcastle Univ, Sch Neurosci, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England

[44] Tampere Univ, Dept Child Psychiat, Tampere 33521, Finland

[45] Tampere Univ Hosp, Tampere 33521, Finland

[46] Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA

[47] Baylor Coll Med, Dept Human Mol Genet, Houston, TX 77030 USA

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

[49] Univ Hosp RWTH Aachen, JARA Brain Translat Med, Translat Brain Med Psychiat & Neurol, Dept Child & Adolescent Psychiat Psychosomat Psyc, D-52056 Aachen, Germany

[50] Great Ormond St Hosp Sick Children, Natl Hlth Serv Fdn Trust, Dept Child & Adolescent Mental Hlth, London WC1N 3JH, England

来源：

NATURE | 2014年 / 515卷 / 7526期

基金：

美国国家卫生研究院;

关键词：

DE-NOVO MUTATIONS; COPY-NUMBER VARIATION; FRAMEWORK; NETWORK; RISK; DISCOVERY; UBIQUITIN;

D O I：

10.1038/nature13772

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.

引用

页码：209 / +

页数：16

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