Letter | Published:

Common variants conferring risk of schizophrenia

Nature 460, 744–747 (06 August 2009) | Download Citation

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Abstract

Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders1,2,3. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the ‘genomic disorders’, have not yet been characterized4. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.

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Acknowledgements

We thank the subjects and their relatives and staff at the recruitment centres. This work was sponsored by EU grants LSHM-CT-2006-037761 (Project SGENE), PIAP-GA-2008-218251 (Project PsychGene) and HEALTH-F2-2009-223423 (Project PsychCNVs). Genotyping of the Dutch samples was sponsored by NIMH funding, R01 MH078075. This work was also supported by the National Genomic Network (NGFN-2) of the German Federal Ministry of Education and Research (BMBF) and Marie Curie grant PIAP-GA-2008-218251 (PsychGene). 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. Recruitment of the patients from Munich was partially supported by GlaxoSmithKline. We are grateful to the Genetics Research Centre GmbH, an initiative by GlaxoSmithKline and LMU. The Northern Finland Birth Cohort 1966 (NFBC66) is thanked for providing population controls for the study. The genotyping of NFBC66 was financially supported by National Institutes of Health grant 1R01HL087679-01, STAMPEED.

Author Contributions H.S., S.S., D.A.C., D.S.C., D.R., E. Sigurdsson and K.S. wrote the first draft of the paper. M.H., B.B.M., P.M., I.G., H.-J.M., A.H., A.C.N., G.F., N.W., J.L., J. Suvisaari, A.T.-H., T.T., E.B., R.M., M.R., S. Tosato, S.D., I.M., J.O., O.A.A., M.R., R.A.O., L.A.K., O.G., A.D.B., M. Nyegaard, A.F.-J., M. Nordentoft, D.H., B.N.-P., Y.B., R.B., H.B.R., S. Timm, M.M., I.B., J.M.R., L.A., V.K., J. Sanjuan, R.F., E.V., U.E., M.P., J.L.Y., N.B.F., R.M.C., V.G., A.C., C.A., J.C., E.G.J., L.T., I.A., O.M., P.B.M., B.F., T.P. and GROUP recruited, diagnosed and gathered phenotypes. H.S., D.R., R.d.F., E. Strengman, T.S., P.M.M., T.T., J.R.G., U.T., H.P., D.B.G., T.W., D.A.C., L.P., A.K., D.S.C. and K.S. planned, supervised and coordinated the work. S.S., H.S., S.C., P.O., G.M., A.I., T.E.T., O.P.H.P., D.G., K.V.S., M.M.N., T.H. and A.K. analysed the data. All authors contributed to the current version of the paper.

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  1. deCODE genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.

    • Hreinn Stefansson
    • , Stacy Steinberg
    • , Omar Gustafsson
    • , Andres Ingason
    • , Yvonne Böttcher
    • , Pall Olason
    • , Gisli Masson
    • , Jeffrey R. Gulcher
    • , Ragnheidur Fossdal
    • , Thorgeir E. Thorgeirsson
    • , Unnur Thorsteinsdottir
    • , Augustine Kong
    •  & Kari Stefansson

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

    • Roel A. Ophoff
    •  & Eric Strengman

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

    • Roel A. Ophoff
    • , Nelson B. Freimer
    •  & Rita M. Cantor

  4. Department of Psychiatry, Ullevål University Hospital and Institute of Psychiatry, University of Oslo, Kirkeveien 166, N-0407 Oslo, Norway.

    • Ole A. Andreassen
    •  & Ingrid Melle

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

    • Sven Cichon
    •  & Manuel Mattheisen

  6. Division of Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig-Maximilians-University, Nußbaumstrasse 7, 80336 Munich, Germany.

    • Dan Rujescu
    • , Annette Hartmann
    •  & Ina Giegling

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

    • Thomas Werge
    • , Thomas Hansen
    •  & Henrik B. Rasmussen

  8. Institute of Molecular Medicine, Biomedicum Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland.

    • Olli P. H. Pietiläinen
    •  & Leena Peltonen

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

    • Olli P. H. Pietiläinen
    •  & Leena Peltonen

  10. Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Skovagervej 2, 8240 Risskov, Denmark.

    • Ole Mors
    •  & Anders D. Børglum

  11. National Centre for Register-based Research, Aarhus University, Taasingegade 1, DK-8000 Aarhus, Denmark.

    • Preben B. Mortensen

  12. Department of Psychiatry, National University Hospital, Hringbraut, 101 Reykjavik, Iceland.

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

  13. University of Iceland, School of Medicine, Laeknagardi, 101 Reykjavik, Iceland.

    • Engilbert Sigurdsson
    • , Brynja B. Magnusdottir
    • , Thordur Sigmundsson
    • , Magnus Haraldsson
    • , Unnur Thorsteinsdottir
    • , Hannes Petursson
    •  & Kari Stefansson

  14. Department of Human Genetics, The Bartholin Building, Aarhus University, DK-8000 Arhus C, Denmark.

    • Mette Nyegaard
    •  & Anders D. Børglum

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

    • Annamari Tuulio-Henriksson
    • , Jaana Suvisaari
    •  & Jouko Lonnqvist

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

    • Tiina Paunio

  17. Mental Health Centre Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen Ø, Denmark.

    • Anders Fink-Jensen

  18. Psychiatric Centre Bisbebjerg, Building 13A, Bispebjerg Hospital, Bispebjerg Bakke 23, 2400 Copenhagen NV, Denmark.

    • Merete Nordentoft

  19. Section of Neonatal Screening and Hormones, Department Clinical Chemistry and Immunology, The State Serum Institute, Artillerivej 5, 2300 Copenhagen S, Denmark.

    • David Hougaard
    •  & Bent Norgaard-Pedersen

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

    • Jes Olesen

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

    • René Breuer
    •  & Marcella Rietschel

  22. Department of Psychiatry, Ludwig-Maximilians-University, Nußbaumstrasse 7, 80336 Munich, Germany.

    • Hans-Jürgen Möller

  23. Mental Health Centre Frederiksberg, Copenhagen University Hospital, DK-2000 Frederiksberg, Denmark.

    • Sally Timm

  24. Semmelweis University, Department of Psychiatry and Psychotherapy, Budapest 1083, Hungary.

    • István Bitter
    •  & János M. Réthelyi

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

    • Mirella Ruggeri
    •  & Sarah Tosato

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

    • Barbara Franke

  27. Department of Epidemiology and Biostatistics and Department of Urology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands.

    • Lambertus A. Kiemeney

  28. Department of Medical Genetics, Ulleval University Hospital and Institute of Psychiatry, University of Oslo, Kirkeveien 166, N-0407 Oslo, Norway.

    • Srdjan Djurovic

  29. Mental Health Research Center, Russian Academy of Medical Sciences, Zagorodnoe sh. 2/2, 117152 Moscow, Russia.

    • Lilia Abramova
    • , Vasily Kaleda
    •  & Vera Golimbet

  30. Unidad de Psiquiatría, Facultad de Medicina, Universidad de Valencia, CIBERSAM, 46010 Valencia, Spain.

    • Julio Sanjuan

  31. Departamento de Genética. Facultad de Biología, Universidad de Valencia, CIBERSAM, Spain.

    • Rosa de Frutos

  32. Division of Psychological Medicine, Institute of Psychiatry, King’s College, London SE5 8AF, UK.

    • Elvira Bramon
    • , Evangelos Vassos
    • , Ulrich Ettinger
    • , Marco Picchioni
    • , Robin Murray
    •  & David A. Collier

  33. Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King’s College, London SE5 8AF, UK.

    • Evangelos Vassos
    • , Ulrich Ettinger
    • , Timi Toulopoulou
    •  & Robin Murray

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

    • Gillian Fraser
    •  & David St Clair

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

    • Nicholas Walker

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

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

  37. Department of Human Genetics, UCLA, 695 Charles Young Drive South, Los Angeles, California 90095, USA.

    • Joeng Lim Yoon
    •  & Rita M. Cantor

  38. Fundación Pública Galega de Medicina Xenómica-Complexo Universitario Hospitalario de Santiago, and CIBER de Enfermedades Raras (CIBERER), IML- Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain.

    • Angel Carracedo

  39. Hospital General Universitario Gregorio Marañón, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Madrid, Spain.

    • Celso Arango

  40. Fundación Pública Galega de Medicina Xenómica, and CIBER de Enfermedades Raras (CIBERER), 46010 Valencia, Spain.

    • Javier Costas

  41. Department of Clinical Neuroscience, HUBIN project, Karolinska Institutet and Hospital, R5:00, SE-171 76 Stockholm, Sweden.

    • Erik G. Jönsson
    • , Lars Terenius
    •  & Ingrid Agartz

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

    • Markus M. Nöthen

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

    • Paul M. Matthews

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

    • Pierandrea Muglia

  45. Psychiatric Laboratory, Department of Psychiatry, West China Hospital, Sichuan University, 610065 Sichuan, China.

    • David A. Collier

  46. Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Postbus 85060, 3508 AB, Utrecht, The Netherlands.

    • René S. Kahn
    •  & Wiepke Cahn

  47. Academic Medical Centre University of Amsterdam, Department of Psychiatry, Amsterdam, NL326 Groot-Amsterdam, The Netherlands.

    • Don H. Linszen
    •  & Lieuwe de Haan

  48. Maastricht University Medical Centre, South Limburg Mental Health Research and Teaching Network, P. Debyelaan 25, 6229 HX Maastricht, Maastricht, The Netherlands.

    • Hreinn Stefansson
    • , Roel A. Ophoff
    • , Stacy Steinberg
    • , Jim van Os
    • , Lydia Krabbendam
    •  & Inez Myin-Germeys

  49. University Medical Center Groningen, Department of Psychiatry, University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands.

    • Durk Wiersma
    •  & Richard Bruggeman

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Competing interests

Some of the authors including Kari Stefansson (CEO of deCODE genetics), Jeffrey R. Gulcher (CSO of deCODE genetics) and Augustine Kong (VP Statistics at deCODE genetics) are shareholders in deCODE genetics.

Corresponding author

Correspondence to Kari Stefansson.

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