Letter abstract
Nature Genetics 41, 1223 - 1227 (2009)
Published online: 25 October 2009 | doi:10.1038/ng.474
Microduplications of 16p11.2 are associated with schizophrenia
Shane E McCarthy1, Vladimir Makarov1, George Kirov2, Anjene M Addington3, Jon McClellan4, Seungtai Yoon1, Diana O Perkins5, Diane E Dickel6, Mary Kusenda1,7, Olga Krastoshevsky8, Verena Krause8, Ravinesh A Kumar9, Detelina Grozeva2, Dheeraj Malhotra1, Tom Walsh6, Elaine H Zackai10, Paige Kaplan11, Jaya Ganesh11, Ian D Krantz10, Nancy B Spinner10, Patricia Roccanova1, Abhishek Bhandari1, Kevin Pavon1, B Lakshmi1,12, Anthony Leotta1, Jude Kendall1, Yoon-ha Lee1, Vladimir Vacic1, Sydney Gary1, Lilia M Iakoucheva13, Timothy J Crow14, Susan L Christian9, Jeffrey A Lieberman15,16, T Scott Stroup15, Terho Lehtimäki17, Kaija Puura18, Chad Haldeman-Englert10, Justin Pearl19, Meredith Goodell20, Virginia L Willour20, Pamela DeRosse21, Jo Steele19, Layla Kassem19, Jessica Wolff19, Nisha Chitkara21, Francis J McMahon19, Anil K Malhotra21, James B Potash20, Thomas G Schulze19,22, Markus M Nöthen23,24, Sven Cichon23,24, Marcella Rietschel22,25, Ellen Leibenluft26, Vlad Kustanovich27, Clara M Lajonchere27, James S Sutcliffe28, David Skuse29, Michael Gill30, Louise Gallagher30, Nancy R Mendell31, Wellcome Trust Case Control Consortium, Nick Craddock2, Michael J Owen2, Michael C O'Donovan2, Tamim H Shaikh10, Ezra Susser15, Lynn E DeLisi33,34, Patrick F Sullivan35, Curtis K Deutsch33,36, Judith Rapoport3, Deborah L Levy8,33, Mary-Claire King6 & Jonathan Sebat1
Abstract
Recurrent microdeletions and microduplications of a 600-kb genomic region of chromosome 16p11.2 have been implicated in childhood-onset developmental disorders1, 2, 3. We report the association of 16p11.2 microduplications with schizophrenia in two large cohorts. The microduplication was detected in 12/1,906 (0.63%) cases and 1/3,971 (0.03%) controls (P = 1.2 
10-5, OR = 25.8) from the initial cohort, and in 9/2,645 (0.34%) cases and 1/2,420 (0.04%) controls (P = 0.022, OR = 8.3) of the replication cohort. The 16p11.2 microduplication was associated with a 14.5-fold increased risk of schizophrenia (95% CI (3.3, 62)) in the combined sample. A meta-analysis of datasets for multiple psychiatric disorders showed a significant association of the microduplication with schizophrenia (P = 4.8 10-7), bipolar disorder (P = 0.017) and autism (P = 1.9 10-7). In contrast, the reciprocal microdeletion was associated only with autism and developmental disorders (P = 2.3 10-13). Head circumference was larger in patients with the microdeletion than in patients with the microduplication (P = 0.0007).
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.
- Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK.
- Child Psychiatry Branch, National Institute for Mental Health, National Institutes of Health, Bethesda, Maryland, USA.
- Department of Psychiatry, University of Washington, Seattle, Washington, USA.
- Department of Psychiatry, University of North Carolina, Chapel Hill, North Carolina, USA.
- Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
- Graduate Program in Genetics State University of New York, Stony Brook, New York, USA.
- Psychology Research Laboratory, McLean Hospital, Belmont, Massachusetts, USA.
- Department of Human Genetics, University of Chicago, Chicago, Illinois, USA.
- Division of Human GeneticsThe Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
- Section of Biochemical Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
- Laboratory of Statistical Genetics, The Rockefeller University, New York, USA.
- The Prince of Wales International Center for SANE Research, Warneford Hospital, Oxford, UK.
- College of Physicians and Surgeons of Columbia University, Columbia University, New York, USA.
- New York State Psychiatric Hospital, New York, New York, USA.
- Department of Clinical Chemistry, Tampere University and University Hospital, Tampere, Finland.
- Department of Child Psychiatry, Tampere University and University Hospital, Tampere, Finland.
- Genetic Basis of Mood and Anxiety Disorders Unit, National Institute for Mental Health, National Institutes of Health, Bethesda, Maryland, USA.
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
- Department of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, New York, USA.
- Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany.
- Department of Genomics, Life and Brain Center.
- Institute of Human Genetics, University of Bonn, Germany.
- Department of Psychiatry and Psychotherapy, University of Bonn, Germany.
- Mood and Anxiety Disorders Program, National Institute for Mental Health, National Institutes of Health, Bethesda, Maryland, USA.
- Autism Genetic Resource Exchange, Autism Speaks, Los Angeles, California, USA.
- Center for Molecular Neuroscience, Vanderbilt University, Nashville, Tennessee, USA.
- Behavioral Sciences Unit, Institute of Child Health University College London, London, UK.
- Department of Psychiatry, School of Medicine, Trinity College Dublin, Dublin, Ireland.
- Department of Applied Mathematics and Statistics, State University of New York, Stony Brook, New York. USA.
- Wellcome Trust Case Control Consortium Affiliations are provided in the Supplementary Note.
- Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA.
- VA Boston Healthcare System, Brockton, Massachusetts, USA.
- Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
- Eunice Kennedy Shriver Center, University of Massachusetts Medical School, Waltham, Massachusetts, USA.
Correspondence to: Jonathan Sebat1 e-mail: sebat@cshl.edu.
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