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

Dalila Pinto; Alistair T. Pagnamenta; Lambertus Klei; Richard Anney; Daniele Merico; Regina Regan; Judith Conroy; Tiago R. Magalhaes; Catarina Correia; Brett S. Abrahams; Joana Almeida; Elena Bacchelli; Gary D. Bader; Anthony J. Bailey; Gillian Baird; Agatino Battaglia; Tom Berney; Nadia Bolshakova; Sven Bölte; Patrick F. Bolton; Thomas Bourgeron; Sean Brennan; Jessica Brian; Susan E. Bryson; Andrew R. Carson; Guillermo Casallo; Jillian Casey; Brian H.Y. Chung; Lynne Cochrane; Christina Corsello; Emily L. Crawford; Andrew Crossett; Cheryl Cytrynbaum; Geraldine Dawson; Maretha De Jonge; Richard Delorme; Irene Drmic; Eftichia Duketis; Frederico Duque; Annette Estes; Penny Farrar; Bridget A. Fernandez; Susan E. Folstein; Eric Fombonne; Christine M. Freitag; John Gilbert; Christopher Gillberg; Joseph T. Glessner; Jeremy Goldberg; Andrew Green; Jonathan Green; Stephen J. Guter; Hakon Hakonarson; Elizabeth A. Heron; Matthew Hill; Richard Holt; Jennifer L. Howe; Gillian Hughes; Vanessa Hus; Roberta Igliozzi; Cecilia Kim; Sabine M. Klauck; Alexander Kolevzon; Olena Korvatska; Vlad Kustanovich; Clara M. Lajonchere; Janine A. Lamb; Magdalena Laskawiec; Marion Leboyer; Ann Le Couteur; Bennett L. Leventhal; Anath C. Lionel; Xiao Qing Liu; Catherine Lord; Linda Lotspeich; Sabata C. Lund; Elena Maestrini; William Mahoney; Carine Mantoulan; Christian R. Marshall; Helen McConachie; Christopher J. McDougle; Jane McGrath; William M. McMahon; Alison Merikangas; Ohsuke Migita; Nancy J. Minshew; Ghazala K. Mirza; Jeff Munson; Stanley F. Nelson; Carolyn Noakes; Abdul Noor; Gudrun Nygren; Guiomar Oliveira; Katerina Papanikolaou; Jeremy R. Parr; Barbara Parrini; Tara Paton; Andrew Pickles; Marion Pilorge; Joseph Piven; Chris P. Ponting; David J. Posey; Annemarie Poustka; Fritz Poustka; Aparna Prasad; Jiannis Ragoussis; Katy Renshaw; Jessica Rickaby; Wendy Roberts; Kathryn Roeder; Bernadette Roge; Michael L. Rutter; Laura J. Bierut; John P. Rice; Jeff Salt; Katherine Sansom; Daisuke Sato; Ricardo Segurado; Ana F. Sequeira; Lili Senman; Naisha Shah; Val C. Sheffield; Latha Soorya; Ins Sousa; Olaf Stein; Nuala Sykes; Vera Stoppioni; Christina Strawbridge; Raffaella Tancredi; Katherine Tansey; Bhooma Thiruvahindrapduram; Ann P. Thompson; Susanne Thomson; Ana Tryfon; John Tsiantis; Herman Van Engeland; John B. Vincent; Fred Volkmar; Simon Wallace; Kai Wang; Zhouzhi Wang; Thomas H. Wassink; Caleb Webber; Rosanna Weksberg; Kirsty Wing; Kerstin Wittemeyer; Shawn Wood; Jing Wu; Brian L. Yaspan; Danielle Zurawiecki; Lonnie Zwaigenbaum; Joseph D. Buxbaum; Rita M. Cantor; Edwin H. Cook; Hilary Coon; Michael L. Cuccaro; Bernie Devlin; Sean Ennis; Louise Gallagher; Daniel H. Geschwind; Michael Gill; Jonathan L. Haines; Joachim Hallmayer; Judith Miller; Anthony P. Monaco; John I. Nurnberger; Andrew D. Paterson; Margaret A. Pericak-Vance; Gerard D. Schellenberg; Peter Szatmari; Astrid M. Vicente; Veronica J. Vieland; Ellen M. Wijsman; Stephen W. Scherer; James S. Sutcliffe; Catalina Betancur

doi:10.1038/nature09146

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

Dalila Pinto, Alistair T. Pagnamenta, Lambertus Klei, Richard Anney, Daniele Merico, Regina Regan, Judith Conroy, Tiago R. Magalhaes, Catarina Correia, Brett S. Abrahams, Joana Almeida, Elena Bacchelli, Gary D. Bader, Anthony J. Bailey, Gillian Baird, Agatino Battaglia, Tom Berney, Nadia Bolshakova, Sven Bölte, Patrick F. BoltonThomas Bourgeron, Sean Brennan, Jessica Brian, Susan E. Bryson, Andrew R. Carson, Guillermo Casallo, Jillian Casey, Brian H.Y. Chung, Lynne Cochrane, Christina Corsello, Emily L. Crawford, Andrew Crossett, Cheryl Cytrynbaum, Geraldine Dawson, Maretha De Jonge, Richard Delorme, Irene Drmic, Eftichia Duketis, Frederico Duque, Annette Estes, Penny Farrar, Bridget A. Fernandez, Susan E. Folstein, Eric Fombonne, Christine M. Freitag, John Gilbert, Christopher Gillberg, Joseph T. Glessner, Jeremy Goldberg, Andrew Green, Jonathan Green, Stephen J. Guter, Hakon Hakonarson, Elizabeth A. Heron, Matthew Hill, Richard Holt, Jennifer L. Howe, Gillian Hughes, Vanessa Hus, Roberta Igliozzi, Cecilia Kim, Sabine M. Klauck, Alexander Kolevzon, Olena Korvatska, Vlad Kustanovich, Clara M. Lajonchere, Janine A. Lamb, Magdalena Laskawiec, Marion Leboyer, Ann Le Couteur, Bennett L. Leventhal, Anath C. Lionel, Xiao Qing Liu, Catherine Lord, Linda Lotspeich, Sabata C. Lund, Elena Maestrini, William Mahoney, Carine Mantoulan, Christian R. Marshall, Helen McConachie, Christopher J. McDougle, Jane McGrath, William M. McMahon, Alison Merikangas, Ohsuke Migita, Nancy J. Minshew, Ghazala K. Mirza, Jeff Munson, Stanley F. Nelson, Carolyn Noakes, Abdul Noor, Gudrun Nygren, Guiomar Oliveira, Katerina Papanikolaou, Jeremy R. Parr, Barbara Parrini, Tara Paton, Andrew Pickles, Marion Pilorge, Joseph Piven, Chris P. Ponting, David J. Posey, Annemarie Poustka, Fritz Poustka, Aparna Prasad, Jiannis Ragoussis, Katy Renshaw, Jessica Rickaby, Wendy Roberts, Kathryn Roeder, Bernadette Roge, Michael L. Rutter, Laura J. Bierut, John P. Rice, Jeff Salt, Katherine Sansom, Daisuke Sato, Ricardo Segurado, Ana F. Sequeira, Lili Senman, Naisha Shah, Val C. Sheffield, Latha Soorya, Ins Sousa, Olaf Stein, Nuala Sykes, Vera Stoppioni, Christina Strawbridge, Raffaella Tancredi, Katherine Tansey, Bhooma Thiruvahindrapduram, Ann P. Thompson, Susanne Thomson, Ana Tryfon, John Tsiantis, Herman Van Engeland, John B. Vincent, Fred Volkmar, Simon Wallace, Kai Wang, Zhouzhi Wang, Thomas H. Wassink, Caleb Webber, Rosanna Weksberg, Kirsty Wing, Kerstin Wittemeyer, Shawn Wood, Jing Wu, Brian L. Yaspan, Danielle Zurawiecki, Lonnie Zwaigenbaum, Joseph D. Buxbaum, Rita M. Cantor, Edwin H. Cook, Hilary Coon, Michael L. Cuccaro, Bernie Devlin, Sean Ennis, Louise Gallagher, Daniel H. Geschwind, Michael Gill, Jonathan L. Haines, Joachim Hallmayer, Judith Miller, Anthony P. Monaco, John I. Nurnberger, Andrew D. Paterson, Margaret A. Pericak-Vance, Gerard D. Schellenberg, Peter Szatmari, Astrid M. Vicente, Veronica J. Vieland, Ellen M. Wijsman, Stephen W. Scherer, James S. Sutcliffe, Catalina Betancur

Research output: Contribution to journal › Article › peer-review

1605 Scopus citations

Abstract

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 disability². Although ASDs are known to be highly heritable ( ∼90%)³, the underlying genetic determinants are still largely unknown.Hereweanalysed 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 ASDand/or intellectual disability (1.69 fold, P=3.4×310^-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.

Original language	English
Pages (from-to)	368-372
Number of pages	5
Journal	Nature
Volume	466
Issue number	7304
DOIs	https://doi.org/10.1038/nature09146
State	Published - Jul 15 2010

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10.1038/nature09146

Cite this

Pinto, D., Pagnamenta, A. T., Klei, L., Anney, R., Merico, D., Regan, R., Conroy, J., Magalhaes, T. R., Correia, C., Abrahams, B. S., Almeida, J., Bacchelli, E., Bader, G. D., Bailey, A. J., Baird, G., Battaglia, A., Berney, T., Bolshakova, N., Bölte, S., ... Betancur, C. (2010). Functional impact of global rare copy number variation in autism spectrum disorders. Nature, 466(7304), 368-372. https://doi.org/10.1038/nature09146

@article{5fc7f9cb450e43bb869bf6cd8a8a7ef4,

title = "Functional impact of global rare copy number variation in autism spectrum disorders",

abstract = "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 disability2. Although ASDs are known to be highly heritable ( ∼90%)3, the underlying genetic determinants are still largely unknown.Hereweanalysed 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 ASDand/or intellectual disability (1.69 fold, P=3.4×310-4). 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.",

author = "Dalila Pinto and Pagnamenta, {Alistair T.} and Lambertus Klei and Richard Anney and Daniele Merico and Regina Regan and Judith Conroy and Magalhaes, {Tiago R.} and Catarina Correia and Abrahams, {Brett S.} and Joana Almeida and Elena Bacchelli and Bader, {Gary D.} and Bailey, {Anthony J.} and Gillian Baird and Agatino Battaglia and Tom Berney and Nadia Bolshakova and Sven B{\"o}lte and Bolton, {Patrick F.} and Thomas Bourgeron and Sean Brennan and Jessica Brian and Bryson, {Susan E.} and Carson, {Andrew R.} and Guillermo Casallo and Jillian Casey and Chung, {Brian H.Y.} and Lynne Cochrane and Christina Corsello and Crawford, {Emily L.} and Andrew Crossett and Cheryl Cytrynbaum and Geraldine Dawson and {De Jonge}, Maretha and Richard Delorme and Irene Drmic and Eftichia Duketis and Frederico Duque and Annette Estes and Penny Farrar and Fernandez, {Bridget A.} and Folstein, {Susan E.} and Eric Fombonne and Freitag, {Christine M.} and John Gilbert and Christopher Gillberg and Glessner, {Joseph T.} and Jeremy Goldberg and Andrew Green and Jonathan Green and Guter, {Stephen J.} and Hakon Hakonarson and Heron, {Elizabeth A.} and Matthew Hill and Richard Holt and Howe, {Jennifer L.} and Gillian Hughes and Vanessa Hus and Roberta Igliozzi and Cecilia Kim and Klauck, {Sabine M.} and Alexander Kolevzon and Olena Korvatska and Vlad Kustanovich and Lajonchere, {Clara M.} and Lamb, {Janine A.} and Magdalena Laskawiec and Marion Leboyer and {Le Couteur}, Ann and Leventhal, {Bennett L.} and Lionel, {Anath C.} and Liu, {Xiao Qing} and Catherine Lord and Linda Lotspeich and Lund, {Sabata C.} and Elena Maestrini and William Mahoney and Carine Mantoulan and Marshall, {Christian R.} and Helen McConachie and McDougle, {Christopher J.} and Jane McGrath and McMahon, {William M.} and Alison Merikangas and Ohsuke Migita and Minshew, {Nancy J.} and Mirza, {Ghazala K.} and Jeff Munson and Nelson, {Stanley F.} and Carolyn Noakes and Abdul Noor and Gudrun Nygren and Guiomar Oliveira and Katerina Papanikolaou and Parr, {Jeremy R.} and Barbara Parrini and Tara Paton and Andrew Pickles and Marion Pilorge and Joseph Piven and Ponting, {Chris P.} and Posey, {David J.} and Annemarie Poustka and Fritz Poustka and Aparna Prasad and Jiannis Ragoussis and Katy Renshaw and Jessica Rickaby and Wendy Roberts and Kathryn Roeder and Bernadette Roge and Rutter, {Michael L.} and Bierut, {Laura J.} and Rice, {John P.} and Jeff Salt and Katherine Sansom and Daisuke Sato and Ricardo Segurado and Sequeira, {Ana F.} and Lili Senman and Naisha Shah and Sheffield, {Val C.} and Latha Soorya and Ins Sousa and Olaf Stein and Nuala Sykes and Vera Stoppioni and Christina Strawbridge and Raffaella Tancredi and Katherine Tansey and Bhooma Thiruvahindrapduram and Thompson, {Ann P.} and Susanne Thomson and Ana Tryfon and John Tsiantis and {Van Engeland}, Herman and Vincent, {John B.} and Fred Volkmar and Simon Wallace and Kai Wang and Zhouzhi Wang and Wassink, {Thomas H.} and Caleb Webber and Rosanna Weksberg and Kirsty Wing and Kerstin Wittemeyer and Shawn Wood and Jing Wu and Yaspan, {Brian L.} and Danielle Zurawiecki and Lonnie Zwaigenbaum and Buxbaum, {Joseph D.} and Cantor, {Rita M.} and Cook, {Edwin H.} and Hilary Coon and Cuccaro, {Michael L.} and Bernie Devlin and Sean Ennis and Louise Gallagher and Geschwind, {Daniel H.} and Michael Gill and Haines, {Jonathan L.} and Joachim Hallmayer and Judith Miller and Monaco, {Anthony P.} and Nurnberger, {John I.} and Paterson, {Andrew D.} and Pericak-Vance, {Margaret A.} and Schellenberg, {Gerard D.} and Peter Szatmari and Vicente, {Astrid M.} and Vieland, {Veronica J.} and Wijsman, {Ellen M.} and Scherer, {Stephen W.} and Sutcliffe, {James S.} and Catalina Betancur",

note = "Funding Information: Acknowledgements The authors acknowledge the families participating in the study and the main funders of the Autism Genome Project Consortium (AGP): Autism Speaks (USA), the Health Research Board (HRB; Ireland), The Medical Research Council (MRC; UK), Genome Canada/Ontario Genomics Institute, and the Hilibrand Foundation (USA). Additional support for individual groups was provided by the US National Institutes of Health (NIH grants HD055751, HD055782, HD055784, HD35465, MH52708, MH55284, MH57881, MH061009, MH06359, MH066673, MH080647, MH081754, MH66766, NS026630, NS042165, NS049261), the Canadian Institute for Advanced Research (CIFAR), the Canadian Institutes for Health Research (CIHR), Assistance Publique–H{\^o}pitaux de Paris (France), Autistica, Canada Foundation for Innovation/Ontario Innovation Trust, Deutsche Forschungsgemeinschaft (grant Po 255/17-4) (Germany), EC Sixth FP AUTISM MOLGEN, Fundac¸{\~a}o Calouste Gulbenkian (Portugal), Fondation de France, Fondation FondaMental (France), Fondation Orange (France), Fondation pour la Recherche M{\'e}dicale (France), Fundac¸{\~a}o para a Ci{\^e}ncia e Tecnologia (Portugal), the Hospital for Sick Children Foundation and University of Toronto (Canada), INSERM (France), Institut Pasteur (France), the Italian Ministry of Health (convention 181 of 19.10.2001), the John P Hussman Foundation (USA), McLaughlin Centre (Canada), Ontario Ministry of Research and Innovation (Canada), the Seaver Foundation (USA), the Swedish Science Council, The Centre for Applied Genomics (Canada), the Utah Autism Foundation (USA) and the Wellcome Trust core award 075491/Z/04 (UK). D.P. is supported by fellowships from the Royal Netherlands Academy of Arts and Sciences (TMF/DA/5801) and the Netherlands Organization for Scientific Research (Rubicon 825.06.031). S.W.S. holds the GlaxoSmithKline-CIHR Pathfinder Chair in Genetics and Genomics at the University of Toronto and the Hospital for Sick Children (Canada).",

year = "2010",

month = jul,

day = "15",

doi = "10.1038/nature09146",

language = "English",

volume = "466",

pages = "368--372",

journal = "Nature",

issn = "0028-0836",

number = "7304",

}

Pinto, D, Pagnamenta, AT, Klei, L, Anney, R, Merico, D, Regan, R, Conroy, J, Magalhaes, TR, Correia, C, Abrahams, BS, Almeida, J, Bacchelli, E, Bader, GD, Bailey, AJ, Baird, G, Battaglia, A, Berney, T, Bolshakova, N, Bölte, S, Bolton, PF, Bourgeron, T, Brennan, S, Brian, J, Bryson, SE, Carson, AR, Casallo, G, Casey, J, Chung, BHY, Cochrane, L, Corsello, C, Crawford, EL, Crossett, A, Cytrynbaum, C, Dawson, G, De Jonge, M, Delorme, R, Drmic, I, Duketis, E, Duque, F, Estes, A, Farrar, P, Fernandez, BA, Folstein, SE, Fombonne, E, Freitag, CM, Gilbert, J, Gillberg, C, Glessner, JT, Goldberg, J, Green, A, Green, J, Guter, SJ, Hakonarson, H, Heron, EA, Hill, M, Holt, R, Howe, JL, Hughes, G, Hus, V, Igliozzi, R, Kim, C, Klauck, SM, Kolevzon, A, Korvatska, O, Kustanovich, V, Lajonchere, CM, Lamb, JA, Laskawiec, M, Leboyer, M, Le Couteur, A, Leventhal, BL, Lionel, AC, Liu, XQ, Lord, C, Lotspeich, L, Lund, SC, Maestrini, E, Mahoney, W, Mantoulan, C, Marshall, CR, McConachie, H, McDougle, CJ, McGrath, J, McMahon, WM, Merikangas, A, Migita, O, Minshew, NJ, Mirza, GK, Munson, J, Nelson, SF, Noakes, C, Noor, A, Nygren, G, Oliveira, G, Papanikolaou, K, Parr, JR, Parrini, B, Paton, T, Pickles, A, Pilorge, M, Piven, J, Ponting, CP, Posey, DJ, Poustka, A, Poustka, F, Prasad, A, Ragoussis, J, Renshaw, K, Rickaby, J, Roberts, W, Roeder, K, Roge, B, Rutter, ML, Bierut, LJ , Rice, JP, Salt, J, Sansom, K, Sato, D, Segurado, R, Sequeira, AF, Senman, L, Shah, N, Sheffield, VC, Soorya, L, Sousa, I, Stein, O, Sykes, N, Stoppioni, V, Strawbridge, C, Tancredi, R, Tansey, K, Thiruvahindrapduram, B, Thompson, AP, Thomson, S, Tryfon, A, Tsiantis, J, Van Engeland, H, Vincent, JB, Volkmar, F, Wallace, S, Wang, K, Wang, Z, Wassink, TH, Webber, C, Weksberg, R, Wing, K, Wittemeyer, K, Wood, S, Wu, J, Yaspan, BL, Zurawiecki, D, Zwaigenbaum, L, Buxbaum, JD, Cantor, RM, Cook, EH, Coon, H, Cuccaro, ML, Devlin, B, Ennis, S, Gallagher, L, Geschwind, DH, Gill, M, Haines, JL, Hallmayer, J, Miller, J, Monaco, AP, Nurnberger, JI, Paterson, AD, Pericak-Vance, MA, Schellenberg, GD, Szatmari, P, Vicente, AM, Vieland, VJ, Wijsman, EM, Scherer, SW, Sutcliffe, JS & Betancur, C 2010, 'Functional impact of global rare copy number variation in autism spectrum disorders', Nature, vol. 466, no. 7304, pp. 368-372. https://doi.org/10.1038/nature09146

TY - JOUR

T1 - Functional impact of global rare copy number variation in autism spectrum disorders

AU - Pinto, Dalila

AU - Pagnamenta, Alistair T.

AU - Klei, Lambertus

AU - Anney, Richard

AU - Merico, Daniele

AU - Regan, Regina

AU - Conroy, Judith

AU - Magalhaes, Tiago R.

AU - Correia, Catarina

AU - Abrahams, Brett S.

AU - Almeida, Joana

AU - Bacchelli, Elena

AU - Bader, Gary D.

AU - Bailey, Anthony J.

AU - Baird, Gillian

AU - Battaglia, Agatino

AU - Berney, Tom

AU - Bolshakova, Nadia

AU - Bölte, Sven

AU - Bolton, Patrick F.

AU - Bourgeron, Thomas

AU - Brennan, Sean

AU - Brian, Jessica

AU - Bryson, Susan E.

AU - Carson, Andrew R.

AU - Casallo, Guillermo

AU - Casey, Jillian

AU - Chung, Brian H.Y.

AU - Cochrane, Lynne

AU - Corsello, Christina

AU - Crawford, Emily L.

AU - Crossett, Andrew

AU - Cytrynbaum, Cheryl

AU - Dawson, Geraldine

AU - De Jonge, Maretha

AU - Delorme, Richard

AU - Drmic, Irene

AU - Duketis, Eftichia

AU - Duque, Frederico

AU - Estes, Annette

AU - Farrar, Penny

AU - Fernandez, Bridget A.

AU - Folstein, Susan E.

AU - Fombonne, Eric

AU - Freitag, Christine M.

AU - Gilbert, John

AU - Gillberg, Christopher

AU - Glessner, Joseph T.

AU - Goldberg, Jeremy

AU - Green, Andrew

AU - Green, Jonathan

AU - Guter, Stephen J.

AU - Hakonarson, Hakon

AU - Heron, Elizabeth A.

AU - Hill, Matthew

AU - Holt, Richard

AU - Howe, Jennifer L.

AU - Hughes, Gillian

AU - Hus, Vanessa

AU - Igliozzi, Roberta

AU - Kim, Cecilia

AU - Klauck, Sabine M.

AU - Kolevzon, Alexander

AU - Korvatska, Olena

AU - Kustanovich, Vlad

AU - Lajonchere, Clara M.

AU - Lamb, Janine A.

AU - Laskawiec, Magdalena

AU - Leboyer, Marion

AU - Le Couteur, Ann

AU - Leventhal, Bennett L.

AU - Lionel, Anath C.

AU - Liu, Xiao Qing

AU - Lord, Catherine

AU - Lotspeich, Linda

AU - Lund, Sabata C.

AU - Maestrini, Elena

AU - Mahoney, William

AU - Mantoulan, Carine

AU - Marshall, Christian R.

AU - McConachie, Helen

AU - McDougle, Christopher J.

AU - McGrath, Jane

AU - McMahon, William M.

AU - Merikangas, Alison

AU - Migita, Ohsuke

AU - Minshew, Nancy J.

AU - Mirza, Ghazala K.

AU - Munson, Jeff

AU - Nelson, Stanley F.

AU - Noakes, Carolyn

AU - Noor, Abdul

AU - Nygren, Gudrun

AU - Oliveira, Guiomar

AU - Papanikolaou, Katerina

AU - Parr, Jeremy R.

AU - Parrini, Barbara

AU - Paton, Tara

AU - Pickles, Andrew

AU - Pilorge, Marion

AU - Piven, Joseph

AU - Ponting, Chris P.

AU - Posey, David J.

AU - Poustka, Annemarie

AU - Poustka, Fritz

AU - Prasad, Aparna

AU - Ragoussis, Jiannis

AU - Renshaw, Katy

AU - Rickaby, Jessica

AU - Roberts, Wendy

AU - Roeder, Kathryn

AU - Roge, Bernadette

AU - Rutter, Michael L.

AU - Bierut, Laura J.

AU - Rice, John P.

AU - Salt, Jeff

AU - Sansom, Katherine

AU - Sato, Daisuke

AU - Segurado, Ricardo

AU - Sequeira, Ana F.

AU - Senman, Lili

AU - Shah, Naisha

AU - Sheffield, Val C.

AU - Soorya, Latha

AU - Sousa, Ins

AU - Stein, Olaf

AU - Sykes, Nuala

AU - Stoppioni, Vera

AU - Strawbridge, Christina

AU - Tancredi, Raffaella

AU - Tansey, Katherine

AU - Thiruvahindrapduram, Bhooma

AU - Thompson, Ann P.

AU - Thomson, Susanne

AU - Tryfon, Ana

AU - Tsiantis, John

AU - Van Engeland, Herman

AU - Vincent, John B.

AU - Volkmar, Fred

AU - Wallace, Simon

AU - Wang, Kai

AU - Wang, Zhouzhi

AU - Wassink, Thomas H.

AU - Webber, Caleb

AU - Weksberg, Rosanna

AU - Wing, Kirsty

AU - Wittemeyer, Kerstin

AU - Wood, Shawn

AU - Wu, Jing

AU - Yaspan, Brian L.

AU - Zurawiecki, Danielle

AU - Zwaigenbaum, Lonnie

AU - Buxbaum, Joseph D.

AU - Cantor, Rita M.

AU - Cook, Edwin H.

AU - Coon, Hilary

AU - Cuccaro, Michael L.

AU - Devlin, Bernie

AU - Ennis, Sean

AU - Gallagher, Louise

AU - Geschwind, Daniel H.

AU - Gill, Michael

AU - Haines, Jonathan L.

AU - Hallmayer, Joachim

AU - Miller, Judith

AU - Monaco, Anthony P.

AU - Nurnberger, John I.

AU - Paterson, Andrew D.

AU - Pericak-Vance, Margaret A.

AU - Schellenberg, Gerard D.

AU - Szatmari, Peter

AU - Vicente, Astrid M.

AU - Vieland, Veronica J.

AU - Wijsman, Ellen M.

AU - Scherer, Stephen W.

AU - Sutcliffe, James S.

AU - Betancur, Catalina

N1 - Funding Information: Acknowledgements The authors acknowledge the families participating in the study and the main funders of the Autism Genome Project Consortium (AGP): Autism Speaks (USA), the Health Research Board (HRB; Ireland), The Medical Research Council (MRC; UK), Genome Canada/Ontario Genomics Institute, and the Hilibrand Foundation (USA). Additional support for individual groups was provided by the US National Institutes of Health (NIH grants HD055751, HD055782, HD055784, HD35465, MH52708, MH55284, MH57881, MH061009, MH06359, MH066673, MH080647, MH081754, MH66766, NS026630, NS042165, NS049261), the Canadian Institute for Advanced Research (CIFAR), the Canadian Institutes for Health Research (CIHR), Assistance Publique–Hôpitaux de Paris (France), Autistica, Canada Foundation for Innovation/Ontario Innovation Trust, Deutsche Forschungsgemeinschaft (grant Po 255/17-4) (Germany), EC Sixth FP AUTISM MOLGEN, Fundac¸ão Calouste Gulbenkian (Portugal), Fondation de France, Fondation FondaMental (France), Fondation Orange (France), Fondation pour la Recherche Médicale (France), Fundac¸ão para a Ciência e Tecnologia (Portugal), the Hospital for Sick Children Foundation and University of Toronto (Canada), INSERM (France), Institut Pasteur (France), the Italian Ministry of Health (convention 181 of 19.10.2001), the John P Hussman Foundation (USA), McLaughlin Centre (Canada), Ontario Ministry of Research and Innovation (Canada), the Seaver Foundation (USA), the Swedish Science Council, The Centre for Applied Genomics (Canada), the Utah Autism Foundation (USA) and the Wellcome Trust core award 075491/Z/04 (UK). D.P. is supported by fellowships from the Royal Netherlands Academy of Arts and Sciences (TMF/DA/5801) and the Netherlands Organization for Scientific Research (Rubicon 825.06.031). S.W.S. holds the GlaxoSmithKline-CIHR Pathfinder Chair in Genetics and Genomics at the University of Toronto and the Hospital for Sick Children (Canada).

PY - 2010/7/15

Y1 - 2010/7/15

N2 - 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 disability2. Although ASDs are known to be highly heritable ( ∼90%)3, the underlying genetic determinants are still largely unknown.Hereweanalysed 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 ASDand/or intellectual disability (1.69 fold, P=3.4×310-4). 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.

AB - 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 disability2. Although ASDs are known to be highly heritable ( ∼90%)3, the underlying genetic determinants are still largely unknown.Hereweanalysed 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 ASDand/or intellectual disability (1.69 fold, P=3.4×310-4). 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.

UR - http://www.scopus.com/inward/record.url?scp=77954657070&partnerID=8YFLogxK

U2 - 10.1038/nature09146

DO - 10.1038/nature09146

M3 - Article

C2 - 20531469

AN - SCOPUS:77954657070

SN - 0028-0836

VL - 466

SP - 368

EP - 372

JO - Nature

JF - Nature

IS - 7304

ER -

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

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