Multiple Recurrent De Novo CNVs, Including Duplications of the 7q11.23 Williams Syndrome Region, Are Strongly Associated with Autism

Stephan J Sanders; A. Gulhan Ercan-Sencicek; Vanessa Hus; Rui Luo; Michael T Murtha; Daniel Moreno-De-Luca; Su H Chu; Michael P Moreau; Abha R Gupta; Susanne A Thomson; Christopher E Mason; Kaya Bilguvar; Patricia B.S Celestino-Soper; Murim Choi; Emily L Crawford; Lea Davis; Nicole R Davis Wright; Rahul M Dhodapkar; Michael DiCola; Nicholas M DiLullo; Thomas V Fernandez; Vikram Fielding-Singh; Daniel O Fishman; Stephanie Frahm; Rouben Garagaloyan; Gerald S Goh; Sindhuja Kammela; Lambertus Klei; Jennifer K Lowe; Sabata C Lund; Anna D McGrew; Kyle A Meyer; William J Moffat; John D Murdoch; Brian J O'Roak; Gordon T Ober; Rebecca S Pottenger; Melanie J Raubeson; Youeun Song; Qi Wang; Brian L Yaspan; Timothy W Yu; Ilana R Yurkiewicz; Arthur L Beaudet; Rita M Cantor; Martin Curland; Dorothy E Grice; Murat Günel; Richard P Lifton; Shrikant M Mane; Donna M Martin; Chad A Shaw; Michael Sheldon; Jay A Tischfield; Christopher A Walsh; Eric M Morrow; David H Ledbetter; Eric Fombonne; Catherine Lord; Christa Lese Martin; Andrew I Brooks; James S Sutcliffe; Edwin H Cook; Daniel Geschwind; Kathryn Roeder; Bernie Devlin; Matthew W State

doi:10.1016/j.neuron.2011.05.002

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Multiple Recurrent De Novo CNVs, Including Duplications of the 7q11.23 Williams Syndrome Region, Are Strongly Associated with Autism

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Multiple Recurrent De Novo CNVs, Including Duplications of the 7q11.23 Williams Syndrome Region, Are Strongly Associated with Autism

Stephan J Sanders, A. Gulhan Ercan-Sencicek, Vanessa Hus, Rui Luo, Michael T Murtha, Daniel Moreno-De-Luca, Su H Chu, Michael P Moreau, Abha R Gupta, Susanne A Thomson, …

Neuron (Cambridge, Mass.), Vol.70(5), pp.863-885

06/09/2011

DOI: https://doi.org/10.1016/j.neuron.2011.05.002

PMID: 21658581

Abstract

We have undertaken a genome-wide analysis of rare copy-number variation (CNV) in 1124 autism spectrum disorder (ASD) families, each comprised of a single proband, unaffected parents, and, in most kindreds, an unaffected sibling. We find significant association of ASD with de novo duplications of 7q11.23, where the reciprocal deletion causes Williams-Beuren syndrome, characterized by a highly social personality. We identify rare recurrent de novo CNVs at five additional regions, including 16p13.2 (encompassing genes USP7 and C16orf72) and Cadherin 13, and implement a rigorous approach to evaluating the statistical significance of these observations. Overall, large de novo CNVs, particularly those encompassing multiple genes, confer substantial risks (OR = 5.6; CI = 2.6–12.0, p = 2.4 × 10-7). We estimate there are 130–234 ASD-related CNV regions in the human genome and present compelling evidence, based on cumulative data, for association of rare de novo events at 7q11.23, 15q11.2-13.1, 16p11.2, and Neurexin 1. ► Association of duplications of the Williams syndrome region, 7q11.23 ► Replication of findings of increased de novo CNVs in autism spectrum disorders ► Strong association with ASD at 7q11.23, 15q11.2-13, 16p11.2, and NRXN1 ► Prediction of 130–234 ASD-related de novo CNV regions

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Title: Multiple Recurrent De Novo CNVs, Including Duplications of the 7q11.23 Williams Syndrome Region, Are Strongly Associated with Autism
Creators: Stephan J Sanders - Program on Neurogenetics, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06520, USA
A. Gulhan Ercan-Sencicek - Program on Neurogenetics, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06520, USA
Vanessa Hus - University of Michigan Autism & Communication Disorders Center, 1111 E. Catherine Street, Ann Arbor, MI 48109-2054, USA
Rui Luo - Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
Michael T Murtha - Program on Neurogenetics, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06520, USA
Daniel Moreno-De-Luca - Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Suite 301, Atlanta, GA 30322, USA
Su H Chu - Department of Statistics, Carnegie Mellon University, Pittsburgh, PA 15213, USA
Michael P Moreau - Bionomics Research & Technology, Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, 170 Frelinghuysen Road, Piscataway, NJ 08854, USA
Abha R Gupta - Child Study Center, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06520, USA
Susanne A Thomson - Department of Molecular Physiology & Biophysics, Center for Molecular Neuroscience, Vanderbilt University, 6133 MRB 3, U9220 MRBIII, Nashville, TN 37232-8548, USA
Christopher E Mason - Department of Physiology and Biophysics and the Institute for Computational Biomedicine, Weill Cornell Medical College, 1305 York Avenue, Room Y13-04, PO Box 140, New York, NY 10021, USA
Kaya Bilguvar - Program on Neurogenetics, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06520, USA
Patricia B.S Celestino-Soper - Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, T617, Houston, TX 77030, USA
Murim Choi - Department of Genetics, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06520, USA
Emily L Crawford - Department of Molecular Physiology & Biophysics, Center for Molecular Neuroscience, Vanderbilt University, 6133 MRB 3, U9220 MRBIII, Nashville, TN 37232-8548, USA
Lea Davis - Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, 1747 W. Roosevelt Road, Room 155, Chicago, IL 60608, USA
Nicole R Davis Wright - Child Study Center, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06520, USA
Rahul M Dhodapkar - Child Study Center, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06520, USA
Michael DiCola - Bionomics Research & Technology, Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, 170 Frelinghuysen Road, Piscataway, NJ 08854, USA
Nicholas M DiLullo - Child Study Center, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06520, USA
Thomas V Fernandez - Child Study Center, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06520, USA
Vikram Fielding-Singh - Stanford University School of Medicine, Li Ka Shing Building, 291 Campus Drive, Stanford, CA 94305, USA
Daniel O Fishman - Vanderbilt University School of Medicine, 215 Light Hall, Nashville, TN 37232, USA
Stephanie Frahm - Bionomics Research & Technology, Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, 170 Frelinghuysen Road, Piscataway, NJ 08854, USA
Rouben Garagaloyan - Microangelo Associates LLC, 736 Hartzell Street, Pacific Palisades, CA 90272, USA
Gerald S Goh - Department of Genetics, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06520, USA
Sindhuja Kammela - Child Study Center, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06520, USA
Lambertus Klei - Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Jennifer K Lowe - Neurogenetics Program, Department of Neurology and Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, 2309 Gonda Building, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA
Sabata C Lund - University of Michigan Autism & Communication Disorders Center, 1111 E. Catherine Street, Ann Arbor, MI 48109-2054, USA
Anna D McGrew - Department of Molecular Physiology & Biophysics, Center for Molecular Neuroscience, Vanderbilt University, 6133 MRB 3, U9220 MRBIII, Nashville, TN 37232-8548, USA
Kyle A Meyer - Interdepartmental Neuroscience Program, Yale University, 333 Cedar Street, New Haven, CT 06510, USA
William J Moffat - Child Study Center, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06520, USA
John D Murdoch - Department of Genetics, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06520, USA
Brian J O'Roak - Department of Genome Sciences, University of Washington, Box 355065, Seattle, WA 98195, USA
Gordon T Ober - Child Study Center, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06520, USA
Rebecca S Pottenger - Computer Science, Princeton University, 1264 Frist Campus Center, Princeton, NJ 08544, USA
Melanie J Raubeson - Child Study Center, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06520, USA
Youeun Song - Child Study Center, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06520, USA
Qi Wang - Bionomics Research & Technology, Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, 170 Frelinghuysen Road, Piscataway, NJ 08854, USA
Brian L Yaspan - Department of Molecular Physiology & Biophysics, Center for Molecular Neuroscience, Vanderbilt University, 6133 MRB 3, U9220 MRBIII, Nashville, TN 37232-8548, USA
Timothy W Yu - Division of Genetics, Children's Hospital Boston, Harvard Medical School, Department of Neurology, Massachusetts General Hospital, 3 Blackfan Circle, Boston, MA 02115, USA
Ilana R Yurkiewicz - Child Study Center, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06520, USA
Arthur L Beaudet - Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, T617, Houston, TX 77030, USA
Rita M Cantor - Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
Martin Curland - Microangelo Associates LLC, 736 Hartzell Street, Pacific Palisades, CA 90272, USA
Dorothy E Grice - Division of Child and Adolescent Psychiatry, Department of Psychiatry, Columbia University and New York State Psychiatric Institute, 1051 Riverside Drive, Unit 78, New York, NY 10032, USA
Murat Günel - Program on Neurogenetics, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06520, USA
Richard P Lifton - Department of Genetics, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06520, USA
Shrikant M Mane - Yale Center for Genome Analysis, 137-141 Frontage Road, Building B-36, Orange, CT 06477, USA
Donna M Martin - Departments of Pediatrics and Human Genetics, 3520A MSRB I, 1150 W. Medical Center Drive, The University of Michigan Medical Center, Ann Arbor, MI 48109-5652, USA
Chad A Shaw - Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, T617, Houston, TX 77030, USA
Michael Sheldon - Department of Genetics and the Human Genetics Institute, Rutgers University, 145 Bevier Road, Room 136, Piscataway, NJ 08854-8082, USA
Jay A Tischfield - Department of Genetics and the Human Genetics Institute, Rutgers University, 145 Bevier Road, Room 136, Piscataway, NJ 08854-8082, USA
Christopher A Walsh - Howard Hughes Medical Institute and Division of Genetics, Children's Hospital Boston, and Neurology and Pediatrics, Harvard Medical School Center for Life Sciences, 3 Blackfan Circle, Boston, MA 02115, USA
Eric M Morrow - Department of Molecular Biology, Cell Biology and Biochemistry and Department of Psychiatry and Human Behavior, Brown University, 70 Ship Street, Box G-E4, Providence, RI 02912, USA
David H Ledbetter - Geisinger Health System, 100 North Academy Avenue, Danville, PA 17822-2201, USA
Eric Fombonne - Department of Psychiatry, McGill University, Montreal Children's Hospital, 4018 Sainte-Catherine West, Montreal, Quebec H3Z 1P2, Canada
Catherine Lord - University of Michigan Autism & Communication Disorders Center, 1111 E. Catherine Street, Ann Arbor, MI 48109-2054, USA
Christa Lese Martin - Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Suite 301, Atlanta, GA 30322, USA
Andrew I Brooks - Bionomics Research & Technology, Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, 170 Frelinghuysen Road, Piscataway, NJ 08854, USA
James S Sutcliffe - Department of Molecular Physiology & Biophysics, Center for Molecular Neuroscience, Vanderbilt University, 6133 MRB 3, U9220 MRBIII, Nashville, TN 37232-8548, USA
Edwin H Cook - Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, 1747 W. Roosevelt Road, Room 155, Chicago, IL 60608, USA
Daniel Geschwind - Neurogenetics Program, Department of Neurology and Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, 2309 Gonda Building, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA
Kathryn Roeder - Department of Statistics, Carnegie Mellon University, Pittsburgh, PA 15213, USA
Bernie Devlin - Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Matthew W State - Program on Neurogenetics, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06520, USA
Publication Details: Neuron (Cambridge, Mass.), Vol.70(5), pp.863-885
Date published: 06/09/2011
Publisher: Elsevier Inc
Academic Unit: Applied Psychology (GSAPP); Genetics (SAS)
Language: English
Resource Type: Journal article
Identifiers: 991031666172904646