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).
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Accession codes
References
Weiss, L.A. et al. Association between microdeletion and microduplication at 16p11.2 and autism. N. Engl. J. Med. 358, 667–675 (2008).
Kumar, R.A. et al. Recurrent 16p11.2 microdeletions in autism. Hum. Mol. Genet. 17, 628–638 (2008).
Marshall, C.R. et al. Structural variation of chromosomes in autism spectrum disorder. Am. J. Hum. Genet. 82, 477–488 (2008).
Walsh, T. et al. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320, 539–543 (2008).
Stone, J.L. et al. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455, 237–241 (2008).
Kirov, G. et al. Support for the involvement of large CNVs in the pathogenesis of schizophrenia. Hum. Mol. Genet. 14, 796–803 (2009).
Karayiorgou, M. et al. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc. Natl. Acad. Sci. USA 92, 7612–7616 (1995).
Millar, J.K. et al. Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum. Mol. Genet. 9, 1415–1423 (2000).
Stefansson, H. et al. Large recurrent microdeletions associated with schizophrenia. Nature 455, 232–236 (2008).
Rujescu, D. et al. Disruption of the neurexin 1 gene is associated with schizophrenia. Hum. Mol. Genet. 18, 988–996 (2009).
Friedman, J.I. et al. CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy. Mol. Psychiatry 13, 261–266 (2008).
Kirov, G. et al. Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia. Hum. Mol. Genet. 17, 458–465 (2008).
Ghebranious, N., Giampietro, P.F., Wesbrook, F.P. & Rezkalla, S.H. A novel microdeletion at 16p11.2 harbors candidate genes for aortic valve development, seizure disorder, and mild mental retardation. Am. J. Med. Genet. A. 143, 1462–1471 (2007).
Sebat, J. et al. Strong association of de novo copy number mutations with autism. Science 316, 445–449 (2007).
Manolio, T.A. et al. New models of collaboration in genome-wide association studies: the Genetic Association Information Network. Nat. Genet. 39, 1045–1051 (2007).
Bijlsma, E.K. et al. Extending the phenotype of recurrent rearrangements of 16p11.2: deletions in mentally retarded patients without autism and in normal individuals. Eur. J. Med. Genet. 52, 77–87 (2009).
Mefford, H.C. et al. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N. Engl. J. Med. 359, 1685–1699 (2008).
Brunetti-Pierri, N. et al. Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nat. Genet. 40, 1466–1471 (2008).
Sharp, A.J. et al. Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nat. Genet. 38, 1038–1042 (2006).
Ousley, O., Rockers, K., Dell, M.L., Coleman, K. & Cubells, J.F. A review of neurocognitive and behavioral profiles associated with 22q11 deletion syndrome: implications for clinical evaluation and treatment. Curr. Psychiatry Rep. 9, 148–158 (2007).
Kim, H.G. et al. Disruption of neurexin 1 associated with autism spectrum disorder. Am. J. Hum. Genet. 82, 199–207 (2008).
Szatmari, P. et al. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat. Genet. 39, 319–328 (2007).
Woodhouse, W. et al. Head circumference in autism and other pervasive developmental disorders. J. Child Psychol. Psychiatry 37, 665–671 (1996).
Fidler, D.J., Bailey, J.N. & Smalley, S.L. Macrocephaly in autism and other pervasive developmental disorders. Dev. Med. Child Neurol. 42, 737–740 (2000).
Courchesne, E., Carper, R. & Akshoomoff, N. Evidence of brain overgrowth in the first year of life in autism. J. Am. Med. Assoc. 290, 337–344 (2003).
Butler, M.G. et al. Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J. Med. Genet. 42, 318–321 (2005).
Dementieva, Y.A. et al. Accelerated head growth in early development of individuals with autism. Pediatr. Neurol. 32, 102–108 (2005).
Redcay, E. & Courchesne, E. When is the brain enlarged in autism? A meta-analysis of all brain size reports. Biol. Psychiatry 58, 1–9 (2005).
Lainhart, J.E. et al. Head circumference and height in autism: a study by the Collaborative Program of Excellence in Autism. Am. J. Med. Genet. A. 140, 2257–2274 (2006).
Fukumoto, A. et al. Growth of head circumference in autistic infants during the first year of life. J. Autism Dev. Disord. 38, 411–418 (2008).
Courchesne, E. et al. Mapping early brain development in autism. Neuron 56, 399–413 (2007).
Mazzucchelli, C. et al. Knockout of ERK1 MAP kinase enhances synaptic plasticity in the striatum and facilitates striatal-mediated learning and memory. Neuron 34, 807–820 (2002).
Sakaguchi, G. et al. Doc2alpha is an activity-dependent modulator of excitatory synaptic transmission. Eur. J. Neurosci. 11, 4262–4268 (1999).
Miyazaki, T. et al. Disturbance of cerebellar synaptic maturation in mutant mice lacking BSRPs, a novel brain-specific receptor-like protein family. FEBS Lett. 580, 4057–4064 (2006).
Sebat, J. et al. Large-scale copy number polymorphism in the human genome. Science 305, 525–528 (2004).
Diskin, S.J. et al. Adjustment of genomic waves in signal intensities from whole-genome SNP genotyping platforms. Nucleic Acids Res. 36, e126 (2008).
Grubor, V. et al. Novel genomic alterations and clonal evolution in chronic lymphocytic leukemia revealed by representational oligonucleotide microarray analysis (ROMA). Blood 113, 1294–1303 (2009).
McCarroll, S.A. et al. Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat. Genet. 40, 1166–1174 (2008).
Cooper, G.M., Zerr, T., Kidd, J.M., Eichler, E.E. & Nickerson, D.A. Systematic assessment of copy number variant detection via genome-wide SNP genotyping. Nat. Genet. 40, 1199–1203 (2008).
Deutsch, C.K. Head Circumference in autism. in The Autism Encyclopedia (eds. Neisworth, J. & Wolfe, P.) 96–97 (Brookes, Baltimore, MD, 2004).
Deutsch, C.K. & Farkas, L.G. Quantitative methods of dysmorphology diagnosis. in Anthropometry of the Head and Face (ed. Farkas, L.G.) 151–158 (Raven, New York, 1994).
Acknowledgements
Schizophrenia: Funding support for the genome-wide association of schizophrenia study was provided by the National Institute of Mental Health (NIMH) (R01 MH67257, R01 MH59588, R01 MH59571, R01 MH59565, R01 MH59587, R01 MH60870, R01 MH59566, R01 MH59586, R01 MH61675, R01 MH60879, R01 MH81800, U01 MH46276, U01 MH46289 U01 MH46318, U01 MH79469 and U01 MH79470), and the genotyping of samples was provided through the genetic association information network (GAIN). The datasets used for the analyses described in this manuscript were obtained from the database of genotype and phenotype (dbGaP) found at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000021.v2.p1. Samples and associated phenotype data for the genome-wide association of schizophrenia study were provided by the Molecular Genetics of Schizophrenia Collaboration (PI: P.V. Gejman, Evanston Northwestern Healthcare (ENH) and Northwestern University, Evanston, Illinois, USA).
Bipolar Disorder: Funding support for the whole-genome association study of bipolar disorder was provided by the NIMH and the genotyping of samples was provided through GAIN. The datasets used for the analyses described in this manuscript were obtained from dbGaP found at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000017.v2.p1. Samples and associated phenotype data for the collaborative genomic study of bipolar disorder were provided by the NIMH genetics initiative for bipolar disorder. Data and biomaterials were collected in four projects that participated in the NIMH bipolar disorder genetics initiative. From 1991–1998, the principal investigators and co-investigators were: Indiana University, Indianapolis, Indiana, USA, U01 MH46282, J. Nurnberger, M. Miller and E. Bowman; Washington University, St. Louis, Missouri, USA, U01 MH46280, T. Reich, A. Goate and J. Rice; Johns Hopkins University, Baltimore, Maryland, USA, U01 MH46274, J.R. DePaulo Jr., S. Simpson and C. Stine; NIMH Intramural Research Program, Clinical Neurogenetics Branch, Bethesda, Maryland, USA, E. Gershon, D. Kazuba and E. Maxwell. Data and biomaterials were collected as part of ten projects that participated in the NIMH bipolar disorder genetics initiative. From 1999–2003, the principal investigators and co-investigators were: Indiana University, Indianapolis, Indiana, USA, R01 MH59545, J. Nurnberger, M.J. Miller, E.S. Bowman, N.L. Rau, P.R. Moe, N. Samavedy, R. El-Mallakh (at University of Louisville, Louisville, Kentucky, USA), H. Manji (at Wayne State University, Detroit, Michigan, USA), D.A. Glitz (at Wayne State University, Detroit, Michigan, USA), E.T. Meyer, C. Smiley, T. Foroud, L. Flury, D.M. Dick and H. Edenberg; Washington University, St. Louis, Missouri, USA, R01 MH059534, J. Rice, T. Reich, A. Goate and L. Bierut; Johns Hopkins University, Baltimore, Maryland, USA, R01 MH59533, M. McInnis, J.R. DePaulo Jr., D.F. MacKinnon, F.M. Mondimore, J.B. Potash, P.P. Zandi, D. Avramopoulos and J. Payne; University of Pennsylvania, Philadelphia, Pennsylvania, USA, R01 MH59553, W. Berrettini; University of California at Irvine, Irvine, California, USA, R01 MH60068, W. Byerley and M. Vawter; University of Iowa, Iowa City, Iowa, USA, R01 MH059548, W. Coryell and R. Crowe; University of Chicago, Chicago, Illinois, USA, R01 MH59535, E. Gershon, J. Badner, F. McMahon, C. Liu, A. Sanders, M. Caserta, S. Dinwiddie, T. Nguyen and D. Harakal; University of California, San Diego, La Jolla, California, USA, R01 MH59567, J. Kelsoe and R. McKinney; Rush University, Chicago, Illinois, USA, R01 MH059556, W. Scheftner, H.M. Kravitz, D. Marta, A. Vaughn-Brown and L. Bederow; NIMH Intramural Research Program, Bethesda, Maryland, USA, 1Z01MH002810-01, F.J. McMahon, L. Kassem, S. Detera-Wadleigh, L. Austin and D.L. Murphy.
Funding for this study was provided by grants from T. and V. Stanley, the Simons Foundation J.M and C.D. Stone, grants from NARSAD to F.J.M., T.G.S., D.L.L., M.-C.K. and T.W., and grants from the Essel Foundation and the Sidney R. Baer, Jr. Foundation to D.L.L. and from the Margaret Price Investigatorship to J.B.P. and V.L.W. This work was supported by grants from the National Institutes of Health (NIH) Intramural Research Program, National Institutes of Health, including National Institute of Mental Health(NIMH) grant MH076431 to J.S., which reflects co-funding from Autism Speaks, and the Southwestern Autism Research and Resource Center, as well as NIH grants to J.S. (HF004222), M.-C.K., T.W. and J.M.C. (MH083989), D.L.L. and N.R.M. (MH071523; MH31340), J.M.C. (RR000037), P.F.S. (MH074027 and MH077139), J.S.S. (MH061009), L.E.D. (MH44245), T.H.S. (GM081519) and C.K.D. (MH081810; DE016442; HD04147). We gratefully acknowledge the resources provided by the Autism Genetic Resource Exchange (AGRE) Consortium and the participating AGRE families.
The Autism Genetic Resource Exchange is a program of Autism Speaks and is supported, in part, by grant 1U24MH081810 from the National Institute of Mental Health to C.M. Lajonchere (PI). Funding for G.K., N. Craddock., M.J.O. and M.C.O. was provided by the Medical Research Council, UK, and the Wellcome Trust. The Clinical Antipsychotic Trials of Intervention Effectiveness project was funded by NIMH contract N01 MH90001. Funding was provided by the German Ministry of Education and Research BMBF (National Genome Research Network, NGFNplus, MooDS-Net grant no: 01GS08144 to SC and MN; grant no: 01GS08147 to MR). Genotyping of the Molecular Genetics of Schizophrenia study (PI Pablo Gejman) was funded by GAIN of the Foundation for the US NIH. This study makes use of data generated by the Wellcome Trust Case Control Consortium (full list of contributors is presented in the Supplementary Note Funding for that project was provided by the Wellcome Trust under award 076113. Microarray data and clinical information were provided by GAIN. Thanks to the New York Cancer Project, P. Gregersen and A. Lee for providing population control samples. Also, we wish to thank P. Gejman and D. Levinson for helpful discussions. Special thanks to J. Watson for helpful discussions and support.
Author information
Authors and Affiliations
Consortia
Contributions
J.S. organized and designed the study. S.E.M., J.S., S.Y., N.R.M., M.-C.K., G.K., D.G. and A.M.A. contributed to the analysis of genetic data. S.E.M., J.S., C.K.D. and D.L.L. contributed to the analysis of clinical data. S.E.M. and J.S prepared the manuscript. All authors contributed their critical reviews of the manuscript in its preparation. The following persons contributed to the collection of samples and data: (Schizophrenia) G.K., D.G., N. Craddock, M.J.O., M.C.O., WTCCC, A.M.A., J.R., D.O.P., J.A.L., J.S.S., P.F.S., J.M., D.E.D., T.W., M.-C.K., E.S., O.K., V. Kraus, D.L.L., T.J.C. and L.E.D.; (Bipolar Disorder) J.P., M.Goodell, V.L.W., P.D., S.G., J.S., L.K., J.W., N. Chitkara, F.J.M., A.K.M., J.B.P., T.G.S., M.M.N., S.C., M.R., E.L., G.K., D.G., N. Craddock, M.J.O., M.C.O. and WTCCC; (Autism) V. Kustanovich, C.M.L., E.H.Z., P.K., J.G., I.D.K., N.B.S., C.H-E., T.H.S., M.Gill, L.G., T.L., K. Puura, R.A.K., S.L.C., J.S.S. and D.S. Array-comparative genomic hybridization data collection, processing and management at CSHL were carried out by: S.E.M., D.M., V.M., S.Y., M.K., P.R., A.B., K. Pavon, B.L., A.L., J.K., Y.-H.L., L.M.I., V.V. and J.S.
Corresponding author
Supplementary information
Supplementary Text and Figures
Supplementary Tables 1–6, 8, Supplementary Figures 1–3 and Supplementary Note (PDF 805 kb)
Supplementary Table 7
Summary of Psychiatric Symptoms in 16p11.2 Microduplication Carriers (XLS 1369 kb)
Rights and permissions
About this article
Cite this article
McCarthy, S., Makarov, V., Kirov, G. et al. Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet 41, 1223–1227 (2009). https://doi.org/10.1038/ng.474
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng.474
This article is cited by
-
Characterizing Sleep Problems in 16p11.2 Deletion and Duplication
Journal of Autism and Developmental Disorders (2023)
-
Possible association of 16p11.2 copy number variation with altered lymphocyte and neutrophil counts
npj Genomic Medicine (2022)
-
Integration of genetic, transcriptomic, and clinical data provides insight into 16p11.2 and 22q11.2 CNV genes
Genome Medicine (2021)
-
Targeting the RHOA pathway improves learning and memory in adult Kctd13 and 16p11.2 deletion mouse models
Molecular Autism (2021)
-
Reversal of synaptic and behavioral deficits in a 16p11.2 duplication mouse model via restoration of the GABA synapse regulator Npas4
Molecular Psychiatry (2021)
