Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders

被引：697

作者：

Pinto, Dalila ^{[1
,2
,3
,4
,5
,6
]}

Delaby, Elsa ^{[7
,8
,9
]}

Merico, Daniele ^{[10
]}

Barbosa, Mafalda ^{[1
,2
,3
,4
]}

Merikangas, Alison ^{[11
]}

Klei, Lambertus ^{[12
]}

Thiruvahindrapuram, Bhooma ^{[10
]}

Xu, Xiao ^{[2
,4
,5
]}

Ziman, Robert ^{[10
]}

Wang, Zhuozhi ^{[10
]}

Vorstman, Jacob A. S. ^{[13
]}

Thompson, Ann ^{[14
]}

Regan, Regina ^{[15
,16
]}

Pilorge, Marion ^{[7
,8
,9
]}

Pellecchia, Giovanna ^{[10
]}

Pagnamenta, Alistair T. ^{[17
]}

Oliveira, Barbara ^{[18
,19
]}

Marshall, Christian R. ^{[10
,20
]}

Magalhaes, Tiago R. ^{[15
,16
]}

Lowe, Jennifer K. ^{[21
,22
]}

Howe, Jennifer L. ^{[10
]}

Griswold, Anthony J. ^{[23
,24
]}

Gilbert, John ^{[23
,24
]}

Duketis, Eftichia ^{[25
]}

Dombroski, Beth A. ^{[26
]}

De Jonge, Maretha V. ^{[13
]}

Cuccaro, Michael ^{[23
,24
]}

Crawford, Emily L. ^{[27
,28
]}

Correia, Catarina T. ^{[18
,19
]}

Conroy, Judith ^{[16
,29
]}

Conceicao, Ines C. ^{[18
,19
]}

Chiocchetti, Andreas G. ^{[25
]}

Casey, Jillian P. ^{[15
,16
]}

Cai, Guiqing ^{[1
,2
,3
]}

Cabrol, Christelle ^{[7
,8
,9
]}

Bolshakova, Nadia ^{[11
]}

Bacchelli, Elena ^{[30
]}

Anney, Richard ^{[11
]}

Gallinger, Steven ^{[31
]}

Cotterchio, Michelle ^{[32
]}

Casey, Graham ^{[33
]}

Zwaigenbaum, Lonnie ^{[34
]}

Wittemeyer, Kerstin ^{[35
]}

Wing, Kirsty ^{[17
]}

Wallace, Simon ^{[36
,37
]}

van Engeland, Herman ^{[13
]}

Tryfon, Ana ^{[1
,2
]}

Thomson, Susanne ^{[27
,28
]}

Soorya, Latha ^{[1
,2
]}

Roge, Bernadette ^{[38
]}

机构：

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

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

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

[4] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA

[5] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA

[6] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA

[7] Inst Natl Sante & Rech Med U1130, F-75005 Paris, France

[8] CNRS, UMR 8246, F-75005 Paris, France

[9] Sorbonne Univ, Univ Paris 06, Neurosci Paris Seine, F-75005 Paris, France

[10] Hosp Sick Children, Ctr Appl Gen, Program Genet & Genome Biol, Toronto, ON M5G 1L7, Canada

[11] Univ Dublin Trinity Coll, Sch Med, Discipline Psychiat, Dublin 8, Ireland

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

[13] Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Psychiat, NL-3584 CX Utrecht, Netherlands

[14] McMaster Univ, Offord Ctr Child Studies, Dept Psychiat & Behav Neurosci, Hamilton, ON L8S 4K1, Canada

[15] Our Ladys Childrens Hosp, Natl Childrens Res Ctr, Dublin 12, Ireland

[16] Univ Coll Dublin, Sch Med & Med Sci, Acad Ctr Rare Dis, Dublin 4, Ireland

[17] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England

[18] Inst Nacl Saude Doutor Ricardo Jorge, P-1649016 Lisbon, Portugal

[19] Univ Lisbon, Fac Sci, Ctr Biodivers Funct & Integrat Genom, P-1749016 Lisbon, Portugal

[20] Univ Toronto, McLaughlin Ctr, Toronto, ON M5S 1A1, Canada

[21] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90095 USA

[22] Univ Calif Los Angeles, Ctr Autism Res & Treatment, Semel Inst, David Geffen Sch Med, Los Angeles, CA 90095 USA

[23] Univ Miami, John P Hussman Inst Human Genom, Miami, FL 33136 USA

[24] Univ Miami, Dr John T Macdonald Fdn, Dept Human Genet, Miller Sch Med, Miami, FL 33136 USA

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

[26] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA

[27] Vanderbilt Univ, Ctr Human Genet Res, Vanderbilt Brain Inst, Nashville, TN 37232 USA

[28] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA

[29] Childrens Univ Hosp Temple St, Dublin 1, Ireland

[30] Univ Bologna, Dept Pharm & Biotechnol, I-40126 Bologna, Italy

[31] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada

[32] Canc Care Ontario, Toronto, ON M5G 2L7, Canada

[33] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA

[34] Univ Alberta, Dept Pediat, Edmonton, AB T6B 2H3, Canada

[35] Univ Birmingham, Sch Educ, Birmingham B15 2TT, W Midlands, England

[36] Univ Oxford, Dept Psychiat, Oxford OX3 7JX, England

[37] Warneford Hosp, Oxford OX3 7JX, England

[38] Univ Toulouse 2, Unite Rech Interdisciplinaire Octogone, Ctr Etud & Rech Psychopathol, F-31058 Toulouse, France

[39] Hosp Sick Children, Autism Res Unit, Toronto, ON M5G 1X8, Canada

[40] Ctr Hosp Coimbra, Pediat Hosp, Unidade Neurodesenvolvimento & Autismo Serv, Ctr Desenvolvimento Crianca, P-3000602 Coimbra, Portugal

[41] Ctr Hosp Coimbra, Ctr Invest & Formacao Clin, Pediat Hosp, P-3000602 Coimbra, Portugal

[42] Univ Coimbra, P-3000602 Coimbra, Portugal

[43] Univ Coimbra, P-3000354 Coimbra, Portugal

[44] Univ Coimbra, Univ Clin Pediat, P-3000354 Coimbra, Portugal

[45] Univ Coimbra, Inst Biomed Imaging & Life Sci, Fac Med, P-3000354 Coimbra, Portugal

[46] Vanderbilt Univ, Dept Pediat, Nashville, TN 37232 USA

[47] NewYorkPresbyterian Weill Cornell Med Ctr, New York, NY 10065 USA

[48] FondaMental Fdn, F-94010 Creteil, France

[49] Inst Natl Sante & Rech U955, F-94010 Creteil, France

[50] Univ Paris Est, Fac Med, F-94010 Creteil, France

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2014年 / 94卷 / 05期

基金：

加拿大健康研究院; 英国医学研究理事会;

关键词：

DE-NOVO MUTATIONS; COPY-NUMBER VARIATION; INTELLECTUAL DISABILITY; STRUCTURAL VARIATION; PHENOTYPE ONTOLOGY; DELETIONS; VARIANTS; DUPLICATIONS; RISK; INFORMATION;

D O I：

10.1016/j.ajhg.2014.03.018

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 x 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 x 10(-15), similar to 3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.

引用

页码：677 / 694

页数：18

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