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Microduplications of 16p11.2 are associated with schizophrenia


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).

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Figure 1: Microduplications and microdeletions at 16p11.2 in persons with schizophrenia and controls.

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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 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 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.

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Authors and Affiliations




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.

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Correspondence to Jonathan Sebat.

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)

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McCarthy, S., Makarov, V., Kirov, G. et al. Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet 41, 1223–1227 (2009).

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