Journal ArticleDOI
Association between Microdeletion and Microduplication at 16p11.2 and Autism
Lauren A. Weiss,Yiping Shen,Joshua M. Korn,Joshua M. Korn,Dan E. Arking,David T. Miller,Ragnheidur Fossdal,Evald Saemundsen,Hreinn Stefansson,Todd Green,Todd Green,Orah S. Platt,Douglas M. Ruderfer,Douglas M. Ruderfer,Christopher A. Walsh,David Altshuler,David Altshuler,Aravinda Chakravarti,Aravinda Chakravarti,Rudolph E. Tanzi,Kari Stefansson,Susan L. Santangelo,James F. Gusella,James F. Gusella,Pamela Sklar,Pamela Sklar,Bai-Lin Wu,Mark J. Daly,Mark J. Daly +28 more
TLDR
A novel, recurrent microdeletion and a reciprocal microduplication that carry substantial susceptibility to autism and appear to account for approximately 1% of cases are identified.Abstract:
BACKGROUND Autism spectrum disorder is a heritable developmental disorder in which chromosomal abnormalities are thought to play a role. METHODS As a first component of a genomewide association study of families from the Autism Genetic Resource Exchange (AGRE), we used two novel algorithms to search for recurrent copy-number variations in genotype data from 751 multiplex families with autism. Specific recurrent de novo events were further evaluated in clinical-testing data from Children's Hospital Boston and in a large population study in Iceland. RESULTS Among the AGRE families, we observed five instances of a de novo deletion of 593 kb on chromosome 16p11.2. Using comparative genomic hybridization, we observed the identical deletion in 5 of 512 children referred to Children's Hospital Boston for developmental delay, mental retardation, or suspected autism spectrum disorder, as well as in 3 of 299 persons with autism in an Icelandic population; the deletion was also carried by 2 of 18,834 unscreened Icelandic control subjects. The reciprocal duplication of this region occurred in 7 affected persons in AGRE families and 4 of the 512 children from Children's Hospital Boston. The duplication also appeared to be a high-penetrance risk factor. CONCLUSIONS We have identified a novel, recurrent microdeletion and a reciprocal microduplication that carry substantial susceptibility to autism and appear to account for approximately 1% of cases. We did not identify other regions with similar aggregations of large de novo mutations.read more
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Journal ArticleDOI
Finding the missing heritability of complex diseases
Teri A. Manolio,Francis S. Collins,Nancy J. Cox,David Goldstein,Lucia A. Hindorff,David J. Hunter,Mark I. McCarthy,Erin M. Ramos,Lon R. Cardon,Aravinda Chakravarti,Judy H. Cho,Alan E. Guttmacher,Augustine Kong,Leonid Kruglyak,Leonid Kruglyak,Elaine R. Mardis,Charles N. Rotimi,Montgomery Slatkin,David Valle,Alice S. Whittemore,Michael Boehnke,Andrew G. Clark,Evan E. Eichler,Greg Gibson,Jonathan L. Haines,Trudy F. C. Mackay,Steven A. McCarroll,Peter M. Visscher +27 more
TL;DR: This paper examined potential sources of missing heritability and proposed research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.
Journal ArticleDOI
Genome-wide association studies for complex traits: consensus, uncertainty and challenges
Mark I. McCarthy,Mark I. McCarthy,Gonçalo R. Abecasis,Lon R. Cardon,Lon R. Cardon,David Goldstein,Julian Little,John P. A. Ioannidis,John P. A. Ioannidis,Joel N. Hirschhorn,Joel N. Hirschhorn,Joel N. Hirschhorn +11 more
TL;DR: This Review highlights the knowledge gained, defines areas of emerging consensus, and describes the challenges that remain as researchers seek to obtain more complete descriptions of the susceptibility architecture of biomedical traits of interest and to translate the information gathered into improvements in clinical management.
Journal ArticleDOI
Consensus Statement : Chromosomal Microarray Is a First-Tier Clinical Diagnostic Test for Individuals with Developmental Disabilities or Congenital Anomalies
David T. Miller,Margaret P Adam,Margaret P Adam,Swaroop Aradhya,Leslie G. Biesecker,Arthur R. Brothman,Nigel P. Carter,Deanna M. Church,John A. Crolla,Evan E. Eichler,Charles J. Epstein,W. Andrew Faucett,Lars Feuk,Jan M. Friedman,Ada Hamosh,Laird G. Jackson,Erin B. Kaminsky,Klaas Kok,Ian D. Krantz,Robert M. Kuhn,Charles Lee,James Ostell,Carla Rosenberg,Stephen W. Scherer,Nancy B. Spinner,Dimitri J. Stavropoulos,James Tepperberg,Erik C. Thorland,Joris Vermeesch,Darrel Waggoner,Michael S. Watson,Christa Lese Martin,David H. Ledbetter +32 more
TL;DR: Chromosomal microarray (CMA) is increasingly utilized for genetic testing of individuals with unexplained developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), or multiple congenital anomalies (MCA).
Journal ArticleDOI
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,Tiago R. Magalhaes,Catarina Correia,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 Bolton,Thomas Bourgeron,Sean Brennan,Jessica Brian,Susan E. Bryson,Andrew R. Carson,Guillermo Casallo,Jillian P. Casey,Brian H.Y. Chung,Lynne E 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 Lajonchere,Janine A. Lamb,Magdalena Laskawiec,Marion Leboyer,Ann Le Couteur,Bennett L. Leventhal,Anath C. Lionel,Anath C. Lionel,Xiao-Qing Liu,Catherine Lord,Linda Lotspeich,Sabata C. Lund,Elena Maestrini,William M. Mahoney,Carine Mantoulan,Christian R. Marshall,Helen McConachie,Christopher J. McDougle,Jane McGrath,William M. McMahon,Alison K. Merikangas,Ohsuke Migita,Nancy J. Minshew,Ghazala 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 Rogé,Michael Rutter,Laura J. Bierut,John P. Rice,Jeff Salt,Katherine Sansom,Daisuke Sato,Ricardo Segurado,Ana Filipa Sequeira,Lili Senman,Lili Senman,Naisha Shah,Val C. Sheffield,Latha Soorya,Inês Sousa,Olaf Stein,Nuala Sykes,Vera Stoppioni,Christina Strawbridge,Raffaella Tancredi,Katherine E. Tansey,Bhooma Thiruvahindrapduram,Ann P. Thompson,Susanne Thomson,Ana Tryfon,John Tsiantis,Herman 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. Nurnberger,Andrew D. Paterson,Margaret A. Pericak-Vance,Gerard D. Schellenberg,Peter Szatmari,Astrid M. Vicente,Veronica J. Vieland,Veronica J. Vieland,Ellen M. Wijsman,Stephen W. Scherer,James S. Sutcliffe,Catalina Betancur +181 more
TL;DR: The genome-wide characteristics of rare (<1% frequency) copy number variation in ASD are analysed using dense genotyping arrays to reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
Journal ArticleDOI
Large recurrent microdeletions associated with schizophrenia
Hreinn Stefansson,Dan Rujescu,Sven Cichon,Olli Pietiläinen,Andres Ingason,Stacy Steinberg,Ragnheidur Fossdal,Engilbert Sigurdsson,Thordur Sigmundsson,Jacobine E. Buizer-Voskamp,Thomas Hansen,Thomas Hansen,Klaus D. Jakobsen,Klaus D. Jakobsen,Pierandrea Muglia,Clyde Francks,Paul M. Matthews,Arnaldur Gylfason,Bjarni V. Halldorsson,Daniel F. Gudbjartsson,Thorgeir E. Thorgeirsson,Asgeir Sigurdsson,Adalbjorg Jonasdottir,Aslaug Jonasdottir,Asgeir Björnsson,Sigurborg Mattiasdottir,Thorarinn Blondal,Magnús Haraldsson,Brynja B. Magnusdottir,Ina Giegling,Hans-Jürgen Möller,Annette M. Hartmann,Kevin V. Shianna,Dongliang Ge,Anna C. Need,Caroline Crombie,Gillian Fraser,Nicholas Walker,Jouko Lönnqvist,Jaana Suvisaari,Annamarie Tuulio-Henriksson,Tiina Paunio,T. Toulopoulou,Elvira Bramon,Marta Di Forti,Robin M. Murray,Mirella Ruggeri,Evangelos Vassos,Sarah Tosato,Muriel Walshe,Tao Li,Tao Li,Catalina Vasilescu,Thomas W. Mühleisen,August G. Wang,Henrik Ullum,Srdjan Djurovic,Ingrid Melle,Jes Olesen,Lambertus A. Kiemeney,Barbara Franke,Chiara Sabatti,Nelson B. Freimer,Jeffrey R. Gulcher,Unnur Thorsteinsdottir,Augustine Kong,Ole A. Andreassen,Roel A. Ophoff,Roel A. Ophoff,Alexander Georgi,Marcella Rietschel,Thomas Werge,Hannes Petursson,David Goldstein,Markus M. Nöthen,Leena Peltonen,Leena Peltonen,David A. Collier,David A. Collier,David St Clair,Kari Stefansson,Kari Stefansson +81 more
TL;DR: In a genome-wide search for CNVs associating with schizophrenia, a population-based sample was used to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring and three deletions significantly associate with schizophrenia and related psychoses in the combined sample.
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