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Large recurrent microdeletions associated with schizophrenia

Nature 455, 232–236 (11 September 2008) | Download Citation

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Abstract

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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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.

References

  1. 1.

    Fertility and sibship size in a psychiatric patient population. A comparison with national census data. Acta Psychiatr. Scand. 60, 483–503 (1979)

  2. 2.

    et al. Association between microdeletion and microduplication at 16p11.2 and autism. N. Engl. J. Med. 358, 667–675 (2008)

  3. 3.

    et al. Genome-wide association identifies a common variant in the reelin gene that increases the risk of schizophrenia only in women. PLoS Genet. 4, e28 (2008)

  4. 4.

    et al. Clinical implementation of chromosomal microarray analysis: summary of 2513 postnatal cases. PLoS ONE 2, e327 (2007)

  5. 5.

    et al. Diagnostic genome profiling in mental retardation. Am. J. Hum. Genet. 77, 606–616 (2005)

  6. 6.

    et al. Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum. Mol. Genet. 9, 1415–1423 (2000)

  7. 7.

    et al. Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nature Genet. 38, 1038–1042 (2006)

  8. 8.

    et al. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320, 539–543 (2008)

  9. 9.

    et al. Connexin 50 gene on human chromosome 1q21 is associated with schizophrenia in matched case control and family-based studies. J. Med. Genet. 44, 532–536 (2007)

  10. 10.

    , , , & Location of a major susceptibility locus for familial schizophrenia on chromosome 1q21-q22. Science 288, 678–682 (2000)

  11. 11.

    et al. Genomewide genetic linkage analysis confirms the presence of susceptibility loci for schizophrenia, on chromosomes 1q32.2, 5q33.2, and 8p21–22 and provides support for linkage to schizophrenia, on chromosomes 11q23.3–24 and 20q12.1–11.23. Am. J. Hum. Genet. 68, 661–673 (2001)

  12. 12.

    , , , & Linkage of schizophrenia with chromosome 1q loci in Taiwanese families. Mol. Psychiatry 8, 445–452 (2003)

  13. 13.

    et al. A two-stage linkage analysis of Chinese schizophrenia pedigrees in 10 target chromosomes. Biochem. Biophys. Res. Commun. 342, 1049–1057 (2006)

  14. 14.

    et al. Detection of a novel familial deletion of four genes between BP1 and BP2 of the Prader-Willi/Angelman syndrome critical region by oligo-array CGH in a child with neurological disorder and speech impairment. Cytogenet. Genome Res. 116, 135–140 (2007)

  15. 15.

    , & The behavioral phenotype in fragile X: symptoms of autism in very young children with fragile X syndrome, idiopathic autism, and other developmental disorders. J. Dev. Behav. Pediatr. 22, 409–417 (2001)

  16. 16.

    & Autistic-like symptomatology in Prader-Willi syndrome: a review of recent findings. Curr. Psychiatry Rep. 9, 159–164 (2007)

  17. 17.

    et al. The Prader-Willi phenotype of fragile X syndrome. J. Dev. Behav. Pediatr. 28, 133–138 (2007)

  18. 18.

    , & The female and the fragile X syndrome: data on clinical and psychological findings in 7 fra(X) carriers. Clin. Genet. 37, 341–346 (1990)

  19. 19.

    et al. Neurobehavioral characteristics of CGG amplification status in fragile X females. Am. J. Med. Genet. 54, 378–383 (1994)

  20. 20.

    , , & Presynaptic type III neuregulin1-ErbB signaling targets α7 nicotinic acetylcholine receptors to axons. J. Cell Biol. 181, 511–521 (2008)

  21. 21.

    et al. Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proc. Natl Acad. Sci. USA 94, 587–592 (1997)

  22. 22.

    et al. Characterization of a 5.3 Mb deletion in 15q14 by comparative genomic hybridization using a whole genome “tiling path” BAC array in a girl with heart defect, cleft palate, and developmental delay. Am. J. Med. Genet. A 143, 172–178 (2007)

  23. 23.

    , , , & Performance deficit of α7 nicotinic receptor knockout mice in a delayed matching-to-place task suggests a mild impairment of working/episodic-like memory. Genes Brain Behav. 5, 433–440 (2006)

  24. 24.

    et al. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc. Natl Acad. Sci. USA 92, 7612–7616 (1995)

  25. 25.

    Schizophrenia and velo-cardio-facial syndrome. Lancet 359, 426–430 (2002)

  26. 26.

    , & DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 131, 1235–1247 (2007)

  27. 27.

    et al. Novel approach to quantitative polymerase chain reaction using real-time detection: application to the detection of gene amplification in breast cancer. Int. J. Cancer 78, 661–666 (1998)

  28. 28.

    The International Schizophrenia Consortium. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 10.1038/nature07239 (this issue)

  29. 29.

    et al. QuantiSNP: an objective Bayes Hidden-Markov Model to detect and accurately map copy number variation using SNP genotyping data. Nucleic Acids Res. 35, 2013–2025 (2007)

  30. 30.

    , , , & A high-resolution survey of deletion polymorphism in the human genome. Nature Genet. 38, 75–81 (2006)

  31. 31.

    & Generalized additive models. Stat. Sci. 1, 297–310 (1986)

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Acknowledgements

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.

Author information

    • Hreinn Stefansson
    • , Dan Rujescu
    •  & Sven Cichon

    These authors contributed equally to this work.

Affiliations

  1. CNS Division, deCODE genetics, Sturlugata 8, IS-101 Reykjavík, Iceland

    • Hreinn Stefansson
    • , Andres Ingason
    • , Stacy Steinberg
    • , Ragnheidur Fossdal
    • , Arnaldur Gylfason
    • , Bjarni V. Halldorsson
    • , Daniel Gudbjartsson
    • , Thorgeir E. Thorgeirsson
    • , Asgeir Sigurdsson
    • , Adalbjorg Jonasdottir
    • , Aslaug Jonasdottir
    • , Asgeir Bjornsson
    • , Sigurborg Mattiasdottir
    • , Thorarinn Blondal
    • , Jeffrey R. Gulcher
    • , Unnur Thorsteinsdottir
    • , Augustine Kong
    •  & Kari Stefansson

  2. Division of Molecular and Clinical Neurobiology, Department of Psychiatry, Genetics Research Centre, Ludwig-Maximilians-University, Nußbaumstrasse 7, 80336 Munich, Germany

    • Dan Rujescu
    • , Ina Giegling
    • , Hans-Jürgen Möller
    •  & Annette Hartmann

  3. Department of Genomics, Life & Brain Center, University of Bonn, Sigmund-Freud-Strasse 25, D-53127 Bonn, Germany

    • Sven Cichon
    • , Catalina Vasilescu
    • , Thomas W. Mühleisen
    •  & Markus M. Nöthen

  4. Institute of Human Genetics, University of Bonn, Wilhelmstrasse 31, D-53111 Bonn, Germany

    • Sven Cichon
    •  & Markus M. Nöthen

  5. Department for Molecular Medicine, National Public Health Institute, Biomedicum, Haartmaninkatu 8, 00290 Helsinki, Finland

    • Olli P. H. Pietiläinen
    • , Tiina Paunio
    •  & Leena Peltonen

  6. Department of Psychiatry, National University Hospital, Hringbraut, 101 Reykjavík, Iceland

    • Engilbert Sigurdsson
    • , Thordur Sigmundsson
    • , Magnus Haraldsson
    • , Brynja B. Magnusdottir
    •  & Hannes Petursson

  7. The Netherlands Department of Medical Genetics and Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands

    • Jacobine E. Buizer-Voskamp
    •  & Roel A. Ophoff

  8. Research Institute of Biological Psychiatry, Mental Health Centre Sct. Hans Copenhagen University Hospital, DK-4000 Roskilde, Denmark

    • Thomas Hansen
    • , Klaus D. Jakobsen
    •  & Thomas Werge

  9. Centre for Pharmacogenomics, University of Copenhagen, DK-2200 Copenhagen N, Denmark

    • Thomas Hansen
    •  & Klaus D. Jakobsen

  10. Medical Genetics, GlaxoSmithKline R&D, Via A. Fleming 4, 37135 Verona, Italy

    • Pierandrea Muglia
    •  & Clyde Francks

  11. Clinical Imaging Centre, Clinical Pharmacology and Discovery Medicine, GlaxoSmithKline, Hammersmith Hospital, London W12 ONN, UK

    • Paul M. Matthews

  12. Institute for Genome Sciences & Policy, Center for Population Genomics & Pharmacogenetics, 4011 GSRB II 103 Research Drive, Duke University, DUMC Box 3471, Durham, North Carolina 27708, USA

    • Kevin V. Shianna
    • , Dongliang Ge
    • , Anna C. Need
    •  & David B. Goldstein

  13. Department of Mental Health, University of Aberdeen, Royal Cornhill Hospital, Aberdeen AB25 2ZD, UK

    • Caroline Crombie
    • , Gillian Fraser
    •  & David St Clair

  14. Ravenscraig hospital, Inverkip Road, Greenock PA16 9HA, UK

    • Nicholas Walker

  15. Department of Mental Health and Addiction, National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland

    • Jouko Lonnqvist
    • , Jaana Suvisaari
    • , Annamarie Tuulio-Henriksson
    •  & Tiina Paunio

  16. Division of Psychological Medicine and Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King’s College, London SE5 8AF, UK

    • Timi Toulopoulou
    • , Elvira Bramon
    • , Marta Di Forti
    • , Robin Murray
    • , Evangelos Vassos
    • , Muriel Walshe
    • , Tao Li
    •  & David A. Collier

  17. Section of Psychiatry and Clinical Psychology, University of Verona, Verona, 37134 Verona, Italy

    • Mirella Ruggeri
    •  & Sarah Tosato

  18. Psychiatric Laboratory, Department of Psychiatry, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China

    • Tao Li
    •  & David A. Collier

  19. Department of Clinical Immunology, Copenhagen University Hospital, DK-2200 Copenhagen N, Denmark

    • August G. Wang

  20. Mental Health Centre Amager, Copenhagen University Hospital, DK-2300 Copenhagen S, Denmark

    • Henrik Ullum

  21. Institute of Psychiatry, University of Oslo, PO Box 1130, Blindern, N-0318 Oslo, Norway

    • Srdjan Djurovic
    •  & Ole A. Andreassen

  22. Departments of Medical Genetics and Psychiatry, Ulleval University Hospital, Kirkeveien 166, N-0407 Oslo, Norway

    • Srdjan Djurovic
    • , Ingrid Melle
    •  & Ole A. Andreassen

  23. Department of Neurology, 57 Nordre Ringvej, Glostrup Hospital, Glostrup, DK-2600 Copenhagen, Denmark

    • Jes Olesen

  24. Department of Epidemiology & Biostatistics (133 EPIB)/Department of Urology (659 URO), Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands

    • Lambertus A. Kiemeney

  25. Department of Human Genetics, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands

    • Barbara Franke

  26. Departments of Human Genetics and Statistics, UCLA, 695 Charles Young Drive South, Los Angeles, California 90095, USA

    • Chiara Sabatti

  27. UCLA Center for Neurobehavioral Genetics, Charles E. Young Drive South, Los Angeles, California 90024, USA

    • Nelson B. Freimer
    •  & Roel A. Ophoff

  28. Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, University of Heidelberg, J5, D-68159 Mannheim, Germany

    • Alexander Georgi
    •  & Marcella Rietschel

  29. Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK

    • Leena Peltonen

  30. The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA

    • Leena Peltonen

  31. University of Iceland, School of Medicine, Sturlugata 8, 101 Reykjavik, Iceland

    • Kari Stefansson

  32. Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.

    • René S. Kahn
    •  & Wiepke Cahn

  33. Academic Medical Centre University of Amsterdam, Department of Psychiatry, Amsterdam, The Netherlands.

    • Don H. Linszen
    •  & Lieuwe de Haan

  34. Maastricht University Medical Centre, South Limburg Mental Health Research and Teaching Network, Maastricht, The Netherlands.

    • Jim van Os
    • , Lydia Krabbendam
    •  & Inez Myin-Germeys

  35. University Medical Centre Groningen, Department of Psychiatry, University of Groningen, The Netherlands.

    • Richard Bruggeman

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Competing interests

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

Corresponding authors

Correspondence to David St Clair or Kari Stefansson.

The authors declare competing financial interests: details accompany the full-text HTML version of the paper at www.nature.com/nature.

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