DOI: 10.1038/nature09146

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This work has “Bronze” OA status. This means it is free to read on the publisher landing page, but without any identifiable license.

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. Magalhães,Catarina Correia,Brett S. Abrahams,Joana Almeida,Elena Bacchelli,Gary D. Bader,Anthony Bailey,Gillian Baird,Agatino Battaglia,T. P. Berney,Nadia Bolshakova,Sven Bölte,Patrick Bolton,Thomas Bourgeron,S. Brennan,Jessica Brian,Susan E. Bryson,Andrew R. Carson,Guillermo Casallo,Jillian P. Casey,Brian Hon‐Yin Chung,Lynne Cochrane,Christina Corsello,Emily L. Crawford,Andrew Crossett,Cheryl Cytrynbaum,Géraldine Dawson,Maretha de Jonge,Richard Delorme,Irene Drmic,Eftichia Duketis,Frederico Duque,Annette Estes,Penny Farrar,Bridget A. Fernandez,Susan E. Folstein,Éric Fombonne,Christine M. Freitag,John R. Gilbert,Christopher Gillberg,Joseph T. Glessner,Jeremy Goldberg,Andrew Green,Jonathan Green,Stephen J. Guter,Hákon Hákonarson,Elizabeth A. Heron,Matthew Hill,Richard Holt,Jennifer Howe,Gillian Hughes,Vanessa Hus,Roberta Igliozzi,Cecilia Kim,Sabine M. Klauck,Alexander Kolevzon,Olena Korvatska,Vlad Kustanovich,Clara Lajonchere,Janine 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 J. Mahoney,Carine Mantoulan,Christian R. Marshall,Helen McConachie,Christopher J. McDougle,Jane McGrath,William M. McMahon,Alison Merikangas,Ohsuke Migita,Nancy J. Minshew,Ghazala Mirza,Jeff Munson,Stanley F. Nelson,Carolyn Noakes,Abdul Noor,Gudrun Nygren,Guiomar Oliveira,Κaterina Papanikolaou,Jeremy 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 Rogé,Michael Rutter,Laura J. Bierut,John P. Rice,Jeff Salt,Katherine Sansom,Daisuke Sato,Ricardo Segurado,Ana Sequeira,Lili Senman,Naisha Shah,Val C. Sheffield,Latha Soorya,Inês Sousa,Olaf Stein,Nuala Sykes,Vera Stoppioni,Christina P. Strawbridge,Raffaella Tancredi,Katherine E. Tansey,Bhooma Thiruvahindrapduram,Ann Thompson,Susanne Thomson,Ana Tryfon,John Tsiantis,Hermán van Engeland,John B. Vincent,Fred R. 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. Nürnberger,Andrew D. Paterson,Margaret A. Pericak‐Vance,Gerard D. Schellenberg,Péter Szatmári,Astrid M. Vicente,Veronica J. Vieland,Ellen M. Wijsman,Stephen W. Scherer,James S. Sutcliffe,Catalina Betancur

Copy-number variation

Autism

Genetics

2010

The autism spectrum disorders (ASDs) are a group of conditions typically characterized by repetitive behaviour, severely restricted interests and difficulties with social interactions and communication. ASDs are highly heritable, yet the underlying genetic determinants remain largely unknown. A genome-wide analysis reveals that people with ASDs carry a higher load of rare copy-number variants — segments of DNA for which the copy number differs between individual genomes — which are either inherited or arise de novo. The results implicate several novel genes as ASD candidates and point to the importance of cellular proliferation, projection and motility as well as specific signalling pathways in this disorder. The autistic spectrum disorders (ASDs) are highly heritable, yet the underlying genetic determinants remain largely unknown. Here, a genome-wide analysis of rare copy number variants (CNVs) has been carried out, revealing that ASD sufferers carry a higher load of rare, genic CNVs than do controls. Many of these CNVs are de novo and inherited. The results implicate several novel genes in ASDs, and point to the importance of cellular proliferation, projection and motility, as well as specific signalling pathways, in these disorders. 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 behaviours1. 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. 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 × 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.

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“Functional impact of global rare copy number variation in autism spectrum disorders” is a paper by Dalila Pinto Alistair T. Pagnamenta Lambertus Klei Richard Anney Daniele Merico Regina Regan Judith Conroy Tiago R. Magalhães Catarina Correia Brett S. Abrahams Joana Almeida Elena Bacchelli Gary D. Bader Anthony Bailey Gillian Baird Agatino Battaglia T. P. Berney Nadia Bolshakova Sven Bölte Patrick Bolton Thomas Bourgeron S. Brennan Jessica Brian Susan E. Bryson Andrew R. Carson Guillermo Casallo Jillian P. Casey Brian Hon‐Yin Chung Lynne Cochrane Christina Corsello Emily L. Crawford Andrew Crossett Cheryl Cytrynbaum Géraldine Dawson Maretha de Jonge Richard Delorme Irene Drmic Eftichia Duketis Frederico Duque Annette Estes Penny Farrar Bridget A. Fernandez Susan E. Folstein Éric Fombonne Christine M. Freitag John R. Gilbert Christopher Gillberg Joseph T. Glessner Jeremy Goldberg Andrew Green Jonathan Green Stephen J. Guter Hákon Hákonarson Elizabeth A. Heron Matthew Hill Richard Holt Jennifer Howe Gillian Hughes Vanessa Hus Roberta Igliozzi Cecilia Kim Sabine M. Klauck Alexander Kolevzon Olena Korvatska Vlad Kustanovich Clara Lajonchere Janine 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 J. Mahoney Carine Mantoulan Christian R. Marshall Helen McConachie Christopher J. McDougle Jane McGrath William M. McMahon Alison Merikangas Ohsuke Migita Nancy J. Minshew Ghazala Mirza Jeff Munson Stanley F. Nelson Carolyn Noakes Abdul Noor Gudrun Nygren Guiomar Oliveira Κaterina Papanikolaou Jeremy 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 Rogé Michael Rutter Laura J. Bierut John P. Rice Jeff Salt Katherine Sansom Daisuke Sato Ricardo Segurado Ana Sequeira Lili Senman Naisha Shah Val C. Sheffield Latha Soorya Inês Sousa Olaf Stein Nuala Sykes Vera Stoppioni Christina P. Strawbridge Raffaella Tancredi Katherine E. Tansey Bhooma Thiruvahindrapduram Ann Thompson Susanne Thomson Ana Tryfon John Tsiantis Hermán van Engeland John B. Vincent Fred R. 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. Nürnberger Andrew D. Paterson Margaret A. Pericak‐Vance Gerard D. Schellenberg Péter Szatmári Astrid M. Vicente Veronica J. Vieland Ellen M. Wijsman Stephen W. Scherer James S. Sutcliffe Catalina Betancur published in 2010. It has an Open Access status of “bronze”. You can read and download a PDF Full Text of this paper here.