Microduplications of 16p11.2 are Associated with Schizophrenia

Shane McCarthy; Vladimir Makarov; George Kirov; Anjene Addington; Jon McClellan; Seungtai Yoon; Dianna Perkins; Diane E Dickel; Mary Kusenda; Olga Krastoshevsky; Verena Krause; Ravinesh A Kumar; Detelina Grozeva; Dheeraj Malhotra; Tom Walsh; Elaine H Zackai; Paige Kaplan; Jaya Ganesh; Ian D Krantz; Nancy B Spinner; Patricia Roccanova; Abhishek Bhandari; Kevin Pavon; B Lakshmi; Anthony Leotta; Jude Kendall; Yoon-ha Lee; Vladimir Vacic; Sydney Gary; Lilia Iakoucheva; Timothy J Crow; Susan L Christian; Jeffrey Lieberman; Scott Stroup; Terho Lehtimäki; Kaija Puura; Chad Haldeman-Englert; Justin Pearl; Meredith Goodell; Virginia L Willour; Pamela DeRosse; Jo Steele; Layla Kassem; Jessica Wolff; Nisha Chitkara; Francis J McMahon; Anil K Malhotra; James B Potash; Thomas G Schulze; Markus M Nöthen; Sven Cichon; Marcella Rietschel; Ellen Leibenluft; Vlad Kustanovich; Clara M Lajonchere; James S Sutcliffe; David Skuse; Michael Gill; Louise Gallagher; Nancy R Mendell; Nick Craddock; Michael J Owen; Michael C O’Donovan; Tamim H Shaikh; Ezra Susser; Lynn E DeLisi; Patrick F Sullivan; Curtis K Deutsch; Judith Rapoport; Deborah L Levy; Mary-Claire King; Jonathan Sebat

doi:10.1038/ng.474

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Microduplications of 16p11.2 are Associated with Schizophrenia

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Peer reviewed

Microduplications of 16p11.2 are Associated with Schizophrenia

Shane McCarthy, Vladimir Makarov, George Kirov, Anjene Addington, Jon McClellan, Seungtai Yoon, Dianna Perkins, Diane E Dickel, Mary Kusenda, Olga Krastoshevsky, …

Nature genetics, Vol.41(11), pp.1223-1227

11/2009

DOI: 10.1038/ng.474

PMCID: PMC2951180

PMID: 19855392

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Abstract

Recurrent microdeletions and microduplications of a 600 kb genomic region of chromosome 16p11.2 have been implicated in childhood-onset developmental disorders 1 - 3 . Here we report the strong association of 16p11.2 microduplications with schizophrenia in two large cohorts. In the primary sample, the microduplication was detected in 12/1906 (0.63%) cases and 1/3971 (0.03%) controls ( P =1.2×10 -5 , OR=25.8). In the replication sample, the microduplication was detected in 9/2645 (0.34%) cases and 1/2420 (0.04%) controls ( P =0.022, OR=8.3). For the series combined, microduplication of 16p11.2 was associated with 14.5-fold increased risk of schizophrenia (95% C.I. [3.3, 62]). A meta-analysis of multiple psychiatric disorders showed a significant association of the microduplication with schizophrenia, bipolar disorder and autism. The reciprocal microdeletion was associated only with autism and developmental disorders. Analysis of patient clinical data showed that head circumference was significantly larger in patients with the microdeletion compared with patients with the microduplication (P = 0.0007). Our results suggest that the microduplication of 16p11.2 confers substantial risk for schizophrenia and other psychiatric disorders, whereas the reciprocal microdeletion is associated with contrasting clinical features.

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Title: Subtitle: Microduplications of 16p11.2 are Associated with Schizophrenia
Creators: Shane McCarthy - Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA
Vladimir Makarov - Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA
George Kirov - Department of Psychological Medicine, School of Medicine, Cardiff University, Cardiff, UK
Anjene Addington - Child Psychiatry Branch, National Institute for Mental Health, National Institutes of Health, Bethesda, Maryland, USA
Jon McClellan - Department of Psychiatry, University of Washington, Seattle, Washington, USA
Seungtai Yoon - Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA
Dianna Perkins - Department of Psychiatry, University of North Carolina, Chapel Hill, North Carolina USA
Diane E Dickel - Department of Genome Sciences, University of Washington, Seattle, Washington, USA
Mary Kusenda - Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA
Olga Krastoshevsky - Psychology Research Laboratory, McLean Hospital, Belmont, Massachusetts, USA
Verena Krause - Psychology Research Laboratory, McLean Hospital, Belmont, Massachusetts, USA
Ravinesh A Kumar - Department of Human Genetics, University of Chicago, Chicago, Illinois, USA
Detelina Grozeva - Department of Psychological Medicine, School of Medicine, Cardiff University, Cardiff, UK
Dheeraj Malhotra - Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA
Tom Walsh - Department of Genome Sciences, University of Washington, Seattle, Washington, USA
Elaine H Zackai - Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
Paige Kaplan - Section of Biochemical Genetics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
Jaya Ganesh - Section of Biochemical Genetics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
Ian D Krantz - Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
Nancy B Spinner - Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
Patricia Roccanova - Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA
Abhishek Bhandari - Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA
Kevin Pavon - Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA
B Lakshmi - Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA
Anthony Leotta - Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA
Jude Kendall - Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA
Yoon-ha Lee - Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA
Vladimir Vacic - Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA
Sydney Gary - Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA
Lilia Iakoucheva - Laboratory of Statistical Genetics, The Rockefeller University, New York, USA
Timothy J Crow - The Prince of Wales International Center for SANE Research, Warneford Hospital, Oxford, UK
Susan L Christian - Department of Human Genetics, University of Chicago, Chicago, Illinois, USA
Jeffrey Lieberman - College of Physicians and Surgeons of Columbia University, Columbia University, New York, USA
Scott Stroup - Department of Psychiatry, University of North Carolina, Chapel Hill, North Carolina USA
Terho Lehtimäki - Department of Clinical Chemistry, University of Tampere, Tampere, Finland
Kaija Puura - Department of Child Psychiatry, Tampere University and University Hospital, Tampere, Finland
Chad Haldeman-Englert - Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
Justin Pearl - Genetic Basis of Mood and Anxiety Disorders Unit, National Institute for Mental Health, National Institutes of Health, Bethesda, Maryland, USA
Meredith Goodell - Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
Virginia L Willour - Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
Pamela DeRosse - Department of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, New York, USA
Jo Steele - Genetic Basis of Mood and Anxiety Disorders Unit, National Institute for Mental Health, National Institutes of Health, Bethesda, Maryland, USA
Layla Kassem - Genetic Basis of Mood and Anxiety Disorders Unit, National Institute for Mental Health, National Institutes of Health, Bethesda, Maryland, USA
Jessica Wolff - Genetic Basis of Mood and Anxiety Disorders Unit, National Institute for Mental Health, National Institutes of Health, Bethesda, Maryland, USA
Nisha Chitkara - Department of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, New York, USA
Francis J McMahon - Genetic Basis of Mood and Anxiety Disorders Unit, National Institute for Mental Health, National Institutes of Health, Bethesda, Maryland, USA
Anil K Malhotra - Department of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, New York, USA
James B Potash - Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
Thomas G Schulze - Genetic Basis of Mood and Anxiety Disorders Unit, National Institute for Mental Health, National Institutes of Health, Bethesda, Maryland, USA
Markus M Nöthen - Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany
Sven Cichon - Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany
Marcella Rietschel - Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, University of Heidelburg, Germany
Ellen Leibenluft - Mood and Anxiety Disorders Program, National Institute for Mental Health, National Institutes of Health, Bethesda, Maryland, USA
Vlad Kustanovich - Autism Genetic Resource Exchange, Autism Speaks, Los Angeles, California, USA
Clara M Lajonchere - Autism Genetic Resource Exchange, Autism Speaks, Los Angeles, California, USA
James S Sutcliffe - Center for Molecular Neuroscience, Vanderbilt University, Nashville, Tennessee, USA
David Skuse - Behavioral Sciences Unit, Institute of Child Health University College London, London, UK
Michael Gill - Department of Psychiatry, School of Medicine, Trinity College Dublin, Dublin, Ireland
Louise Gallagher - Department of Psychiatry, School of Medicine, Trinity College Dublin, Dublin, Ireland
Nancy R Mendell - Department of Applied Mathematics and Statistics, State University of New York, Stony Brook, New York. USA
Nick Craddock - Department of Psychological Medicine, School of Medicine, Cardiff University, Cardiff, UK
Michael J Owen - Department of Psychological Medicine, School of Medicine, Cardiff University, Cardiff, UK
Michael C O’Donovan - Department of Psychological Medicine, School of Medicine, Cardiff University, Cardiff, UK
Tamim H Shaikh - Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
Ezra Susser - College of Physicians and Surgeons of Columbia University, Columbia University, New York, USA
Lynn E DeLisi - Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA
Patrick F Sullivan - Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA
Curtis K Deutsch - Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA
Judith Rapoport - Child Psychiatry Branch, National Institute for Mental Health, National Institutes of Health, Bethesda, Maryland, USA
Deborah L Levy - Psychology Research Laboratory, McLean Hospital, Belmont, Massachusetts, USA
Mary-Claire King - Department of Genome Sciences, University of Washington, Seattle, Washington, USA
Jonathan Sebat - Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA
Resource Type: Journal article
Publication Details: Nature genetics, Vol.41(11), pp.1223-1227
DOI: 10.1038/ng.474
PMID: 19855392
PMCID: PMC2951180
NLM abbreviation: Nat Genet
ISSN: 1061-4036
eISSN: 1546-1718
Language: English
Date published: 11/2009
Academic Unit: Psychiatry; Iowa Neuroscience Institute
Record Identifier: 9984070781402771

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