Dataset Information

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. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), 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.

SUBMITTER: Pinto D

PROVIDER: S-EPMC3021798 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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

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

Nature 20100609 7304

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. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide charact ...[more]

PMID: 20531469

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Project description:BackgroundAutism spectrum disorders and schizophrenia have been associated with an overlapping set of copy number variant loci, but the nature and degree of overlap in copy number variants (deletions compared to duplications) between these two disorders remains unclear.MethodsWe systematically evaluated three lines of evidence: (1) the statistical bases for associations of autism spectrum disorders and schizophrenia with a set of the primary CNVs thus far investigated, from previous studies; (2) data from case series studies on the occurrence of these CNVs in autism spectrum disorders, especially among children, and (3) data on the extent to which the CNVs were associated with intellectual disability and developmental, speech, or language delays. We also conducted new analyses of existing data on these CNVs in autism by pooling data from seven case control studies.ResultsFour of the CNVs considered, dup 1q21.1, dup 15q11-q13, del 16p11.2, and dup 22q11.21, showed clear statistical evidence as autism risk factors, whereas eight CNVs, del 1q21.1, del 3q29, del 15q11.2, del 15q13.3, dup 16p11.2, dup 16p13.1, del 17p12, and del 22q11.21, were strongly statistically supported as risk factors for schizophrenia. Three of the CNVs, dup 1q21.1, dup 16p11.2, and dup 16p13.1, exhibited statistical support as risk factors for both autism and schizophrenia, although for each of these CNVs statistical significance was nominal for tests involving one of the two disorders. For the CNVs that were statistically associated with schizophrenia but were not statistically associated with autism, a notable number of children with the CNVs have been diagnosed with autism or ASD; children with these CNVs also demonstrate a high incidence of intellectual disability and developmental, speech, or language delays.ConclusionsThese findings suggest that although CNV loci notably overlap between autism and schizophrenia, the degree of strongly statistically supported overlap in specific CNVs at these loci remains limited. These analyses also suggest that relatively severe premorbidity to CNV-associated schizophrenia in children may sometimes be diagnosed as autism spectrum disorder.

Dataset Information

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

Publications

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

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