Home LiteratureArticle Details
PMID: 19855392 Published · ppublish English Journal Article Meta-Analysis Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't

Microduplications of 16p11.2 are associated with schizophrenia.

Nature genetics ·Vol. 41 ·No. 11 ·2009-11-00 ·Pages 1223-7

McCarthy SE, Makarov V, Kirov G, Addington AM, McClellan J, Yoon S, Perkins DO, Dickel DE, Kusenda M, Krastoshevsky O, Krause V, Kumar RA, Grozeva D, Malhotra D, Walsh T, Zackai EH, Kaplan P, Ganesh J, Krantz ID, Spinner NB, Roccanova P, Bhandari A, Pavon K, Lakshmi B, Leotta A, Kendall J, Lee YH, Vacic V, Gary S, Iakoucheva LM, Crow TJ, Christian SL, Lieberman JA, Stroup TS, Lehtimäki T, Puura K, Haldeman-Englert C, Pearl J, Goodell M, Willour VL, Derosse P, Steele J, Kassem L, Wolff J, Chitkara N, McMahon FJ, Malhotra AK, Potash JB, Schulze TG, Nöthen MM, Cichon S, Rietschel M, Leibenluft E, Kustanovich V, Lajonchere CM, Sutcliffe JS, Skuse D, Gill M, Gallagher L, Mendell NR, Wellcome Trust Case Control Consortium, Craddock N, Owen MJ, O'Donovan MC, Shaikh TH, Susser E, Delisi LE, Sullivan PF, Deutsch CK, Rapoport J, Levy DL, King MC, Sebat J

Abstract

Recurrent microdeletions and microduplications of a 600-kb genomic region of chromosome 16p11.2 have been implicated in childhood-onset developmental disorders. 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 x 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 x 10(-7)), bipolar disorder (P = 0.017) and autism (P = 1.9 x 10(-7)). In contrast, the reciprocal microdeletion was associated only with autism and developmental disorders (P = 2.3 x 10(-13)). Head circumference was larger in patients with the microdeletion than in patients with the microduplication (P = 0.0007).

MeSH Terms
Chromosomes, Human, Pair 16 Gene Duplication Genetic Predisposition to Disease Humans Risk Factors Schizophrenia/genetics
Authors & Affiliations
73 authors, click to expand affiliations / ORCID
McCarthy Shane E
Makarov Vladimir
Kirov George
Addington Anjene M
McClellan Jon
Yoon Seungtai
Perkins Diana O
Dickel Diane E
Kusenda Mary
Krastoshevsky Olga
Krause Verena
Kumar Ravinesh A
Grozeva Detelina
Malhotra Dheeraj
Walsh Tom
Zackai Elaine H
Kaplan Paige
Ganesh Jaya
Krantz Ian D
Spinner Nancy B
Roccanova Patricia
Bhandari Abhishek
Pavon Kevin
Lakshmi B
Leotta Anthony
Kendall Jude
Lee Yoon-Ha
Vacic Vladimir
Gary Sydney
Iakoucheva Lilia M
Crow Timothy J
Christian Susan L
Lieberman Jeffrey A
Stroup T Scott
Lehtimäki Terho
Puura Kaija
Haldeman-Englert Chad
Pearl Justin
Goodell Meredith
Willour Virginia L
Derosse Pamela
Steele Jo
Kassem Layla
Wolff Jessica
Chitkara Nisha
McMahon Francis J
Malhotra Anil K
Potash James B
Schulze Thomas G
Nöthen Markus M
Cichon Sven
Rietschel Marcella
Leibenluft Ellen
Kustanovich Vlad
Lajonchere Clara M
Sutcliffe James S
Skuse David
Gill Michael
Gallagher Louise
Mendell Nancy R
Wellcome Trust Case Control Consortium
Craddock Nick
Owen Michael J
O'Donovan Michael C
Shaikh Tamim H
Susser Ezra
Delisi Lynn E
Sullivan Patrick F
Deutsch Curtis K
Rapoport Judith
Levy Deborah L
King Mary-Claire
Sebat Jonathan
References (39)
39 references, click to expand
  1. Integrated detection and population-genetic analysis of SNPs and copy number variation.
    Nat Genet. 2008 Oct;40(10):1166-74 PMID: 18776908
  2. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11.
    Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7612-6 PMID: 7644464
  3. Head circumference in autism and other pervasive developmental disorders.
    J Child Psychol Psychiatry. 1996 Sep;37(6):665-71 PMID: 8894947
  4. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia.
    Science. 2008 Apr 25;320(5875):539-43 PMID: 18369103
  5. Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities.
    Nat Genet. 2008 Dec;40(12):1466-71 PMID: 19029900
  6. Disruption of neurexin 1 associated with autism spectrum disorder.
    Am J Hum Genet. 2008 Jan;82(1):199-207 PMID: 18179900
  7. Mapping early brain development in autism.
    Neuron. 2007 Oct 25;56(2):399-413 PMID: 17964254
  8. Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome.
    Nat Genet. 2006 Sep;38(9):1038-42 PMID: 16906162
  9. Disruption of the neurexin 1 gene is associated with schizophrenia.
    Hum Mol Genet. 2009 Mar 1;18(5):988-96 PMID: 18945720
  10. Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations.
    J Med Genet. 2005 Apr;42(4):318-21 PMID: 15805158
  11. Strong association of de novo copy number mutations with autism.
    Science. 2007 Apr 20;316(5823):445-9 PMID: 17363630
  12. New models of collaboration in genome-wide association studies: the Genetic Association Information Network.
    Nat Genet. 2007 Sep;39(9):1045-51 PMID: 17728769
  13. A novel microdeletion at 16p11.2 harbors candidate genes for aortic valve development, seizure disorder, and mild mental retardation.
    Am J Med Genet A. 2007 Jul 1;143A(13):1462-71 PMID: 17568417
  14. Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia.
    Hum Mol Genet. 2008 Feb 1;17(3):458-65 PMID: 17989066
  15. Rare chromosomal deletions and duplications increase risk of schizophrenia.
    Nature. 2008 Sep 11;455(7210):237-41 PMID: 18668038
  16. Systematic assessment of copy number variant detection via genome-wide SNP genotyping.
    Nat Genet. 2008 Oct;40(10):1199-203 PMID: 18776910
  17. Growth of head circumference in autistic infants during the first year of life.
    J Autism Dev Disord. 2008 Mar;38(3):411-8 PMID: 17647099
  18. When is the brain enlarged in autism? A meta-analysis of all brain size reports.
    Biol Psychiatry. 2005 Jul 1;58(1):1-9 PMID: 15935993
  19. Extending the phenotype of recurrent rearrangements of 16p11.2: deletions in mentally retarded patients without autism and in normal individuals.
    Eur J Med Genet. 2009 Mar-Jun;52(2-3):77-87 PMID: 19306953
  20. Support for the involvement of large copy number variants in the pathogenesis of schizophrenia.
    Hum Mol Genet. 2009 Apr 15;18(8):1497-503 PMID: 19181681
  21. Knockout of ERK1 MAP kinase enhances synaptic plasticity in the striatum and facilitates striatal-mediated learning and memory.
    Neuron. 2002 May 30;34(5):807-20 PMID: 12062026
  22. CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy.
    Mol Psychiatry. 2008 Mar;13(3):261-6 PMID: 17646849
  23. Disturbance of cerebellar synaptic maturation in mutant mice lacking BSRPs, a novel brain-specific receptor-like protein family.
    FEBS Lett. 2006 Jul 24;580(17):4057-64 PMID: 16814779
  24. Doc2alpha is an activity-dependent modulator of excitatory synaptic transmission.
    Eur J Neurosci. 1999 Dec;11(12):4262-8 PMID: 10594652
  25. Novel genomic alterations and clonal evolution in chronic lymphocytic leukemia revealed by representational oligonucleotide microarray analysis (ROMA).
    Blood. 2009 Feb 5;113(6):1294-303 PMID: 18922857
  26. Evidence of brain overgrowth in the first year of life in autism.
    JAMA. 2003 Jul 16;290(3):337-44 PMID: 12865374
  27. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes.
    N Engl J Med. 2008 Oct 16;359(16):1685-99 PMID: 18784092
  28. Macrocephaly in autism and other pervasive developmental disorders.
    Dev Med Child Neurol. 2000 Nov;42(11):737-40 PMID: 11104344
  29. Head circumference and height in autism: a study by the Collaborative Program of Excellence in Autism.
    Am J Med Genet A. 2006 Nov 1;140(21):2257-74 PMID: 17022081
  30. Large-scale copy number polymorphism in the human genome.
    Science. 2004 Jul 23;305(5683):525-8 PMID: 15273396
  31. Structural variation of chromosomes in autism spectrum disorder.
    Am J Hum Genet. 2008 Feb;82(2):477-88 PMID: 18252227
  32. Association between microdeletion and microduplication at 16p11.2 and autism.
    N Engl J Med. 2008 Feb 14;358(7):667-75 PMID: 18184952
  33. Adjustment of genomic waves in signal intensities from whole-genome SNP genotyping platforms.
    Nucleic Acids Res. 2008 Nov;36(19):e126 PMID: 18784189
  34. A review of neurocognitive and behavioral profiles associated with 22q11 deletion syndrome: implications for clinical evaluation and treatment.
    Curr Psychiatry Rep. 2007 Apr;9(2):148-58 PMID: 17389127
  35. Large recurrent microdeletions associated with schizophrenia.
    Nature. 2008 Sep 11;455(7210):232-6 PMID: 18668039
  36. Accelerated head growth in early development of individuals with autism.
    Pediatr Neurol. 2005 Feb;32(2):102-8 PMID: 15664769
  37. Mapping autism risk loci using genetic linkage and chromosomal rearrangements.
    Nat Genet. 2007 Mar;39(3):319-28 PMID: 17322880
  38. Recurrent 16p11.2 microdeletions in autism.
    Hum Mol Genet. 2008 Feb 15;17(4):628-38 PMID: 18156158
  39. Disruption of two novel genes by a translocation co-segregating with schizophrenia.
    Hum Mol Genet. 2000 May 22;9(9):1415-23 PMID: 10814723
Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.474
Published
2009-11-00
Epub
2009-00-25
Pages
1223-7
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC2951180
Subset
IM
Grants
NIDCR NIH HHS · DE016442 · United States
NIMH NIH HHS · MH071523 · United States
NIMH NIH HHS · R01 MH077139 · United States
NIMH NIH HHS · MH061009 · United States
NICHD NIH HHS · HD04147 · United States
NIMH NIH HHS · MH083989 · United States
NIMH NIH HHS · K99 MH086756-01 · United States
NIMH NIH HHS · MH076431 · United States
NIMH NIH HHS · R01 MH071523 · United States
NIMH NIH HHS · MH081810 · United States
NIMH NIH HHS · R01 MH031340 · United States
NIMH NIH HHS · R01 MH074027 · United States
NIMH NIH HHS · MH077139 · United States
NIMH NIH HHS · R01 MH076431 · United States
NIMH NIH HHS · U24 MH081810 · United States
NIDCR NIH HHS · R41 DE016442 · United States
NIMH NIH HHS · K99 MH086756 · United States
NIMH NIH HHS · MH44245 · United States
NIMH NIH HHS · R01 MH061009 · United States
NIMH NIH HHS · MH31340 · United States
NIMH NIH HHS · MH074027 · United States
NIMH NIH HHS · R00 MH086756 · United States
NIMH NIH HHS · 1U24MH081810 · United States
NCRR NIH HHS · RR000037 · United States
NIDCR NIH HHS · R42 DE016442 · United States
NIGMS NIH HHS · GM081519 · United States
Wellcome Trust · 076113 · United Kingdom
NICHD NIH HHS · P30 HD004147 · United States
NIMH NIH HHS · R01 MH083989 · United States
NIMH NIH HHS · R01 MH091350 · United States
NCRR NIH HHS · M01 RR000037 · United States
NIMH NIH HHS · R00 MH086756-03 · United States
Intramural NIH HHS · ZIA MH002581-19 · United States
PHS HHS · HF004222 · United States
NIGMS NIH HHS · R01 GM081519 · United States
NIMH NIH HHS · N01 MH90001 · United States
Medical Research Council · G0800509 · United Kingdom
NIMH NIH HHS · K99 MH086756-02 · United States
External Links
PubMed source DOI: 10.1038/ng.474 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2