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Large recurrent microdeletions associated with schizophrenia

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Reduced fecundity, associated with severe mental disorders1, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism2, schizophrenia3 and mental retardation4. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation4,5 and autism2. In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia.

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Figure 1: The genomic architecture of the 1q21.1, 15q11.2 and 15q13.3 deletions.

Change history

  • 11 September 2008

    The AOP version of this paper carried incorrect affiliations for 'Genetic Risk and Outcome in Psychosis' group. This was corrected for print on 11 September 2008.


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We want to thank the subjects and their relatives and staff at the recruitment centres. This work was sponsored by EU grant LSHM-CT-2006-037761 (Project SGENE), Simons Foundation and R01MH71425-01A1. Genotyping of the Dutch samples was sponsored by NIMH funding, R01 MH078075. This work was also supported by the Chinese National Natural Science Foundation and the National Genomic Network (NGFN-2) of the German Federal Ministry of Education and Research (BMBF). M.M.N. received support from the Alfried Krupp von Bohlen und Halbach-Stiftung. We are grateful to S. Schreiber and M. Krawczak for providing genotype data for PopGen controls, and to K.-H. Jöckel and R. Erbel for providing control individuals from the Heinz Nixdorf Recall Study. We thank L. Priebe and M. Alblas for technical assistance and analysis of CNV data from Bonn.

Author Contributions H.S., D.R., E.S., D.C., L.P., D.S.C. and K.S. wrote the first draft of the paper. M.H., B.B.M., K.D.J., P.M., I.G., H.-J.M., A.H., A.C.N., C.C., G.F., N.W., J.L., J.S., A.T., T.T., E.B., M.D.F., R.M., M.R, S.T., M.W., T.L., C.V., T.W.M., A.G.W., H.U., S.D., I.M., J.O., O.A.A., A.G., M.R., R.O., J.B., R.S.K., L.A.K. and B.F. recruited, diagnosed and gathered phenotypes. H.S., D.R., R.F., E.S., T.S., C.F., P.M., T.T, J.R.G., U.T., H.P., D.G., T.W., D.C., L.P., D.S.C. and K.S. planned, supervised and coordinated the work. H.S., S.C., A.I., S.S., A.G., T.E.T., O.P.H.P., B.V.H., D.G., K.V.S., M.M.N., T.H. and A.K. analysed the data. A.S., A.J., A.J., A.B., S.M. and T.B. performed genotyping and experimental work. All authors contributed to the current version of the paper.

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Correspondence to David St Clair or Kari Stefansson.

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K.S. and J.R.G. are CEO and CSO, respectively, of deCODE genetics and hold equity positions in the company.

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Stefansson, H., Rujescu, D., Cichon, S. et al. Large recurrent microdeletions associated with schizophrenia. Nature 455, 232–236 (2008).

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