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

Sean Brennan; Dalila Pinto; Alistair Pagnamenta; Lambertus Klei; Richard Anney; Daniele Merico; Regina Regan; Judith Conroy; Tiago Magalhaes; Catarina Correia; Brett Abrahams; Joana Almeida; Elena Bacchelli; Gary Bader; Anthony Bailey; Gillian Baird; Agatino Battaglia; Tom Berney; Nadia Bolshakova; Sven Bölte; Patrick Bolton; Thomas Bourgeron; Jessica Brian; Susan Bryson; Andrew Carson; Guillermo Casallo; Jillian Casey; Brian Chung; Lynne Cochrane; Christina Corsello; Emily Crawford; Andrew Crossett; Cheryl Cytrynbaum; Geraldine Dawson; Maretha De Jonge; Richard Delorme; Irene Drmic; Eftichia Duketis; Frederico Duque; Annette Estes; Penny Farrar; Bridget Fernandez; Susan Folstein; Eric Fombonne; Christine Freitag; John Gilbert; Christopher Gillberg; Joseph Glessner; Jeremy Goldberg; Andrew Green; Jonathan Green; Stephen Guter; Hakon Hakonarson; Elizabeth Heron; Matthew Hill; Richard Holt; Jennifer Howe; Gillian Hughes; Vanessa Hus; Roberta Igliozzi; Cecilia Kim; Sabine Klauck; Alexander Kolevzon; Olena Korvatska; Vlad Kustanovich; Clara Lajonchere; Janine Lamb; Magdalena Laskawiec; Marion Leboyer; Ann Le Couteur; Bennett Leventhal; Anath Lionel; Xiao-Qing Liu; Catherine Lord; Linda Lotspeich; Sabata Lund; Elena Maestrini; William Mahoney; Carine Mantoulan; Christian Marshall; Helen Mcconachie; Christopher Mcdougle; Jane Mcgrath; William Mcmahon; Alison Merikangas; Ohsuke Migita; Nancy Minshew; Ghazala Mirza; Jeff Munson; Stanley Nelson; Carolyn Noakes; Abdul Noor; Gudrun Nygren; Guiomar Oliveira; Katerina Papanikolaou; Jeremy Parr; Barbara Parrini; Tara Paton; Andrew Pickles; Marion Pilorge; Sahlgrenska akademin

doi:10.1038/nature09146

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

Journal article

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Peer reviewed

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

Sean Brennan, Dalila Pinto, Alistair Pagnamenta, Lambertus Klei, Richard Anney, Daniele Merico, Regina Regan, Judith Conroy, Tiago Magalhaes, Catarina Correia, …

Nature, Vol.466(7304), pp.368-372

07/15/2010

DOI: https://doi.org/10.1038/nature09146

PMID: 20531469

Abstract

Case-Control Studies

Cell Movement

Child

Child Development Disorders, Pervasive

Cytoprotection

DNA Copy Number Variations

Gene Dosage

Genetic Predisposition to Disease

Genome-Wide Association Study

Humans

Social Behavior

Europe

Genetics

Life Sciences

Signal Transduction

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.

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Title: Functional impact of global rare copy number variation in autism spectrum disorders
Creators: Sean Brennan - Division of Mental Health and Addiction
Dalila Pinto - Program in Genetics and Genomic Biology
Alistair Pagnamenta - The Wellcome Trust Centre for Human Genetics [Oxford]
Lambertus Klei - Department of Psychiatry [Pittsburgh]
Richard Anney - Division of Mental Health and Addiction
Daniele Merico - Banting and Best Department of Medical Research
Regina Regan - Academic Centre on Rare Diseases
Judith Conroy - Academic Centre on Rare Diseases
Tiago Magalhaes - Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal]
Catarina Correia - Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal]
Brett Abrahams - Department of Neurology
Joana Almeida - Unidade de Neurodesenvolvimento e Autismo
Elena Bacchelli - Department of Pharmacy and Biotechnology
Gary Bader - Banting and Best Department of Medical Research
Anthony Bailey - Department of Psychiatry
Gillian Baird - Newcomen Centre
Agatino Battaglia - Department of Psychiatry and Behavioral Sciences [Stanford]
Tom Berney - Child and Adolescent Mental Health
Nadia Bolshakova - Division of Mental Health and Addiction
Sven Bölte - Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy
Patrick Bolton - Department of Child and Adolescent Psychiatry
Thomas Bourgeron - Génétique Humaine et Fonctions Cognitives
Jessica Brian - Autism Research Unit
Susan Bryson - Department of Pediatrics and Psychology
Andrew Carson - Program in Genetics and Genomic Biology
Guillermo Casallo - Program in Genetics and Genomic Biology
Jillian Casey - Academic Centre on Rare Diseases
Brian Chung - Program in Genetics and Genomic Biology
Lynne Cochrane - Division of Mental Health and Addiction
Christina Corsello - Autism and Communicative Disorders Centre
Emily Crawford - Department of Molecular Physiology & Biophysics and Psychiatry
Andrew Crossett - Department of Statistics
Cheryl Cytrynbaum - Program in Genetics and Genomic Biology
Geraldine Dawson - Scientific Affairs
Maretha De Jonge - Department of Psychiatry
Richard Delorme - Service de psychopathologie de l'enfant et de l'adolescent
Irene Drmic - Autism Research Unit
Eftichia Duketis - Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy
Frederico Duque - Unidade de Neurodesenvolvimento e Autismo
Annette Estes - Department of Speech and Hearing Sciences [Washington]
Penny Farrar - The Wellcome Trust Centre for Human Genetics [Oxford]
Bridget Fernandez - Disciplines of Genetics and Medicine
Susan Folstein - John P. Hussman Institute for Human Genomics
Eric Fombonne - Department of Psychiatry [Montréal]
Christine Freitag - Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy
John Gilbert - John P. Hussman Institute for Human Genomics
Christopher Gillberg - Department of Child and Adolescent Psychiatry
Joseph Glessner - The Center for Applied Genomics
Jeremy Goldberg - Department of Psychiatry and Behavioural Neurosciences
Andrew Green - Banting and Best Department of Medical Research
Jonathan Green - Academic Department of Child Psychiatry
Stephen Guter - Department of Psychiatry
Hakon Hakonarson - The Center for Applied Genomics
Elizabeth Heron - Division of Mental Health and Addiction
Matthew Hill - Division of Mental Health and Addiction
Richard Holt - The Wellcome Trust Centre for Human Genetics [Oxford]
Jennifer Howe - Program in Genetics and Genomic Biology
Gillian Hughes - Division of Mental Health and Addiction
Vanessa Hus - Autism and Communicative Disorders Centre
Roberta Igliozzi - Department of Psychiatry and Behavioral Sciences [Stanford]
Cecilia Kim - The Center for Applied Genomics
Sabine Klauck - Division of Molecular Genome Analysis
Alexander Kolevzon - Human Genetics Center
Olena Korvatska - Department of Medicine
Vlad Kustanovich - Autism Genetic Resource Exchange
Clara Lajonchere - Autism Genetic Resource Exchange
Janine Lamb - Centre for Integrated Genomic Medical Research, Manchester
Magdalena Laskawiec - Department of Psychiatry
Marion Leboyer - Institut Mondor de Recherche Biomédicale
Ann Le Couteur - Child and Adolescent Mental Health
Bennett Leventhal - Nathan Kline Institute for Psychiatric Research
Anath Lionel - Program in Genetics and Genomic Biology
Xiao-Qing Liu - Program in Genetics and Genomic Biology
Catherine Lord - Autism and Communicative Disorders Centre
Linda Lotspeich - Department of Psychiatry and Behavioral Sciences [Stanford]
Sabata Lund - Department of Molecular Physiology & Biophysics and Psychiatry
Elena Maestrini - Department of Pharmacy and Biotechnology
William Mahoney - Department of Pediatrics
Carine Mantoulan - Centre d'Etudes et de Recherches en PsychoPathologie
Christian Marshall - Program in Genetics and Genomic Biology
Helen Mcconachie - Child and Adolescent Mental Health
Christopher Mcdougle - Department of Psychiatry
Jane Mcgrath - Division of Mental Health and Addiction
William Mcmahon - Department of Developmental Neuroscience
Alison Merikangas - Division of Mental Health and Addiction
Ohsuke Migita - Program in Genetics and Genomic Biology
Nancy Minshew - Departments of Psychiatry and Neurology
Ghazala Mirza - The Wellcome Trust Centre for Human Genetics [Oxford]
Jeff Munson - Department of Psychiatry and Behavioural Sciences
Stanley Nelson - Department of Human Genetics, Los Angeles
Carolyn Noakes - Autism Research Unit
Abdul Noor - Centre for Addiction and Mental Health
Gudrun Nygren - Department of Child and Adolescent Psychiatry
Guiomar Oliveira - Unidade de Neurodesenvolvimento e Autismo
Katerina Papanikolaou - University Department of Child Psychiatry
Jeremy Parr - Institutes of Neuroscience and Health and Society
Barbara Parrini - Department of Psychiatry and Behavioral Sciences [Stanford]
Tara Paton - Program in Genetics and Genomic Biology
Andrew Pickles - Department of Medicine
Marion Pilorge - Physiopathologie des Maladies du Système Nerveux Central
Sahlgrenska akademin
Publication Details: Nature, Vol.466(7304), pp.368-372
Date published: 07/15/2010
Publisher: Nature Publishing Group
Academic Unit: Applied Psychology (GSAPP)
Language: English
Resource Type: Journal article
Identifiers: 991031665219304646