Functional impact of global rare copy number variation in autism spectrum disorders

被引：1480

作者：

Pinto, Dalila ^{[1
,2
]}

Pagnamenta, Alistair T. ^{[3
]}

Klei, Lambertus ^{[4
]}

Anney, Richard ^{[5
]}

Merico, Daniele ^{[6
]}

Regan, Regina ^{[7
]}

Conroy, Judith ^{[7
]}

Magalhaes, Tiago R. ^{[8
,9
,10
]}

Correia, Catarina ^{[8
,9
,10
]}

Abrahams, Brett S. ^{[11
,12
]}

Almeida, Joana ^{[13
]}

Bacchelli, Elena ^{[14
]}

Bader, Gary D. ^{[6
,87
]}

Bailey, Anthony J. ^{[15
]}

Baird, Gillian ^{[16
]}

Battaglia, Agatino ^{[17
]}

Berney, Tom ^{[18
,65
,66
]}

Bolshakova, Nadia ^{[5
]}

Boelte, Sven ^{[19
]}

Bolton, Patrick F. ^{[20
]}

Bourgeron, Thomas ^{[21
]}

Brennan, Sean ^{[5
]}

Brian, Jessica ^{[22
]}

Bryson, Susan E. ^{[23
]}

Carson, Andrew R. ^{[1
,2
]}

Casallo, Guillermo ^{[1
,2
]}

Casey, Jillian ^{[7
]}

Chung, Brian H. Y. ^{[1
,2
]}

Cochrane, Lynne ^{[5
]}

Corsello, Christina ^{[24
]}

Crawford, Emily L. ^{[25
,26
,27
]}

Crossett, Andrew ^{[28
]}

Cytrynbaum, Cheryl ^{[1
,2
]}

Dawson, Geraldine ^{[29
,30
]}

de Jonge, Maretha ^{[31
]}

Delorme, Richard ^{[32
]}

Drmic, Irene ^{[22
]}

Duketis, Eftichia ^{[19
]}

Duque, Frederico ^{[13
]}

Estes, Annette ^{[33
]}

Farrar, Penny ^{[3
]}

Fernandez, Bridget A. ^{[34
,35
]}

Folstein, Susan E. ^{[36
]}

Fombonne, Eric ^{[37
]}

Freitag, Christine M. ^{[19
]}

Gilbert, John ^{[36
]}

Gillberg, Christopher ^{[38
]}

Glessner, Joseph T. ^{[39
]}

Goldberg, Jeremy ^{[40
]}

Green, Andrew ^{[7
]}

机构：

[1] Hosp Sick Children, Ctr Appl Genom, Toronto, ON M5G 1L7, Canada

[2] Hosp Sick Children, Program Genet & Genom Biol, Toronto, ON M5G 1L7, Canada

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

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

[5] Trinity Coll Dublin, Sch Med, Dept Psychiat, Autism Genet Grp, Dublin 8, Ireland

[6] Univ Toronto, Banting & Best Dept Med Res, Terrence Donnelly Ctr Cellular & Biomol Res, Toronto, ON M5S 3E1, Canada

[7] Univ Coll Dublin, Sch Med & Med Sci, Dublin 4, Ireland

[8] Inst Nacl Saude Dr Ricardo Jorge, P-1649016 Lisbon, Portugal

[9] Gulbenkian Inst Sci, P-2780156 Oeiras, Portugal

[10] BioFIG Ctr Biodivers Funct & Integrat Genom, P-1749016 Lisbon, Portugal

[11] Univ Calif Los Angeles, David Geffen Sch Med, Program Neurogenet, Dept Neurol, Los Angeles, CA 90095 USA

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

[13] Hosp Pediat Coimbra, P-3000076 Coimbra, Portugal

[14] Univ Bologna, Dept Biol, I-40126 Bologna, Italy

[15] Univ Oxford, Warneford Hosp, Dept Psychiat, Oxford OX3 7JX, England

[16] Guys Hosp, Newcomen Ctr, London SE1 9RT, England

[17] Stella Maris Inst Child & Adolescent Neuropsychia, I-56128 Pisa, Italy

[18] Univ Newcastle, Sir James Spence Inst, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England

[19] Goethe Univ Frankfurt, Dept Child & Adolescent Psychiat, D-60528 Frankfurt, Germany

[20] Inst Psychiat, Dept Child & Adolescent Psychiat, London SE5 8AF, England

[21] Univ Paris 07, CNRS, URA 2182, Inst Pasteur, F-75015 Paris, France

[22] Univ Toronto, Hosp Sick Children & Bloorview Kids Rehab, Autism Res Unit, Toronto, ON M5G 1X8, Canada

[23] Dalhousie Univ, Dept Pediat & Psychol, Halifax, NS B3K 6R8, Canada

[24] Univ Michigan, Autism & Communicat Disorders Ctr, Ann Arbor, MI 48109 USA

[25] Vanderbilt Univ, Dept Mol Physiol & Biophys, Vanderbilt Kennedy Ctr, Nashville, TN 37232 USA

[26] Vanderbilt Univ, Ctr Human Genet Res, Nashville, TN 37232 USA

[27] Vanderbilt Univ, Ctr Mol Neurosci, Nashville, TN 37232 USA

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

[29] Autism Speaks, New York, NY 10016 USA

[30] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA

[31] Univ Med Ctr, Dept Child Psychiat, NL-3508 GA Utrecht, Netherlands

[32] Hop Robert Debre, AP HP, Fdn FondaMental, INSERM,U955, F-75019 Paris, France

[33] Univ Washington, Dept Speech & Hearing Sci, Seattle, WA 98195 USA

[34] Mem Univ Newfoundland, Discipline Genet, St John, NF A1B 3V6, Canada

[35] Mem Univ Newfoundland, Discipline Med, St John, NF A1B 3V6, Canada

[36] Univ Miami, John P Hussman Inst Human Genom, Miami, FL 33101 USA

[37] McGill Univ, Div Psychiat, Montreal, PQ H3A 1A1, Canada

[38] Univ Gothenburg, Dept Child & Adolescent Psychiat, S-41345 Gothenburg, Sweden

[39] Childrens Hosp Philadelphia, Ctr Appl Genom, Div Human Genet, Philadelphia, PA 19104 USA

[40] McMaster Univ, Dept Psychiat & Behav Neurosci, Hamilton, ON L8N 3Z5, Canada

[41] Booth Hall Childrens Hosp, Acad Dept Child Psychiat, Manchester M9 7AA, Lancs, England

[42] Univ Illinois, Dept Psychiat, Inst Juvenile Res, Chicago, IL 60612 USA

[43] Univ Penn, Sch Med, Dept Pediat, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA

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

[45] Mt Sinai Sch Med, Dept Psychiat, Seaver Autism Ctr Res & Treatment, New York, NY 10029 USA

[46] Univ Washington, Dept Med, Seattle, WA 98195 USA

[47] Autism Speaks, Autism Genet Resource Exchange, Los Angeles, CA 90036 USA

[48] Univ Manchester, Ctr Integrated Genom Med Res, Manchester M13 9PT, Lancs, England

[49] Univ Paris 12, AP HP, Grp Hosp Henri Mondor Albert Chenevier, INSERM,U995,Dept Psychiat,Fdn FondaMental, F-94000 Creteil, France

[50] Nathan S Kline Inst Psychiat Res NKI, Orangeburg, NY 10962 USA

来源：

NATURE | 2010年 / 466卷 / 7304期

基金：

英国医学研究理事会; 加拿大创新基金会; 英国惠康基金; 美国国家卫生研究院;

关键词：

HIDDEN-MARKOV MODEL; SNP GENOTYPING DATA; GENETIC DISORDER; ASSOCIATION; MUTATIONS; LINKAGE; LOCI; ANCESTRY; REVEALS; COMPLEX;

D O I：

10.1038/nature09146

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 autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours(1). Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability(2). Although ASDs are known to be highly heritable (similar to 90%)(3), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P=0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P=3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.

引用

页码：368 / 372

页数：5

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