Common variants conferring risk of schizophrenia

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  • Hreinn Stefansson, deCODE genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.
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  • Roel A. Ophoff, UCLA Center for Neurobehavioral Genetics, Charles E. Young Drive South, Los Angeles, California 90024, USA.
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  • Stacy Steinberg, deCODE genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.
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  • Ole A. Andreassen, Department of Psychiatry, Ullevål University Hospital and Institute of Psychiatry, University of Oslo, Kirkeveien 166, N-0407 Oslo, Norway.
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  • Sven Cichon, Department of Genomics, Life and Brain Center, University of Bonn, Sigmund-Freud-Strasse 25, D-53127 Bonn, Germany.
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  • Dan Rujescu, Division of Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig-Maximilians-University, Nußbaumstrasse 7, 80336 Munich, Germany.
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  • Thomas Werge, Neuro- og Sansefag, Denmark
  • Olli P. H. Pietiläinen, Institute of Molecular Medicine, Biomedicum Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland.
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  • Ole Mors, Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Skovagervej 2, 8240 Risskov, Denmark., Denmark
  • Preben B. Mortensen, National Centre for Register-based Research, Aarhus University, Taasingegade 1, DK-8000 Aarhus, Denmark., Denmark
  • Engilbert Sigurdsson, Department of Psychiatry, National University Hospital, Hringbraut, 101 Reykjavik, Iceland.
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  • Omar Gustafsson, deCODE genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.
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  • Mette Nyegaard, Department of Human Genetics, The Bartholin Building, Aarhus University, DK-8000 Arhus C, Denmark., Denmark
  • Annamari Tuulio-Henriksson, Department of Mental Health and Alcohol Research, National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland.
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  • Andres Ingason, deCODE genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.
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  • Thomas Hansen, Research Institute of Biological Psychiatry, Mental Health Centre Sct. Hans Copenhagen University Hospital, DK-4000 Roskilde, Denmark., Denmark
  • Jaana Suvisaari, Department of Mental Health and Alcohol Research, National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland.
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  • Jouko Lonnqvist, Department of Mental Health and Alcohol Research, National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland.
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  • Tiina Paunio, Department for Molecular Medicine, National Public Health Institute, Biomedicum, Haartmaninkatu 8, 00290 Helsinki, Finland.
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  • Anders D. Børglum, Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Skovagervej 2, 8240 Risskov, Denmark., Denmark
  • Annette Hartmann, Division of Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig-Maximilians-University, Nußbaumstrasse 7, 80336 Munich, Germany.
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  • Anders Fink-Jensen, Neuro- og Sansefag, Denmark
  • Merete Nordentoft, Neuro- og Sansefag, Denmark
  • David Hougaard, Section of Neonatal Screening and Hormones, Department Clinical Chemistry and Immunology, The State Serum Institute, Artillerivej 5, 2300 Copenhagen S, Denmark.
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  • Bent Norgaard-Pedersen, Section of Neonatal Screening and Hormones, Department Clinical Chemistry and Immunology, The State Serum Institute, Artillerivej 5, 2300 Copenhagen S, Denmark.
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  • Yvonne Böttcher, deCODE genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.
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  • Jes Olesen, Neuro- og Sansefag, Denmark
  • René Breuer, Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, University of Heidelberg, J5, D-68159 Mannheim, Germany.
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  • Hans-Jürgen Möller, Department of Psychiatry, Ludwig-Maximilians-University, Nußbaumstrasse 7, 80336 Munich, Germany.
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  • Ina Giegling, Division of Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig-Maximilians-University, Nußbaumstrasse 7, 80336 Munich, Germany.
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  • Henrik B. Rasmussen, Research Institute of Biological Psychiatry, Mental Health Centre Sct. Hans Copenhagen University Hospital, DK-4000 Roskilde, Denmark.
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  • Sally Timm, Neuro- og Sansefag, Denmark
  • Manuel Mattheisen
  • István Bitter, Semmelweis University, Department of Psychiatry and Psychotherapy, Budapest 1083, Hungary.
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  • János M. Réthelyi, Semmelweis University, Department of Psychiatry and Psychotherapy, Budapest 1083, Hungary.
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  • Brynja B. Magnusdottir, Department of Psychiatry, National University Hospital, Hringbraut, 101 Reykjavik, Iceland.
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  • Thordur Sigmundsson, Department of Psychiatry, National University Hospital, Hringbraut, 101 Reykjavik, Iceland.
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  • Pall Olason, deCODE genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.
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  • Gisli Masson, deCODE genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.
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  • Jeffrey R. Gulcher, deCODE genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.
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  • Magnus Haraldsson, Department of Psychiatry, National University Hospital, Hringbraut, 101 Reykjavik, Iceland.
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  • Ragnheidur Fossdal, deCODE genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.
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  • Thorgeir E. Thorgeirsson, deCODE genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.
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  • Unnur Thorsteinsdottir, deCODE genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.
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  • Mirella Ruggeri, Section of Psychiatry and Clinical Psychology, University of Verona, Verona, 37134 Verona, Italy.
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  • Sarah Tosato, Section of Psychiatry and Clinical Psychology, University of Verona, Verona, 37134 Verona, Italy.
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  • Barbara Franke, Department of Human Genetics, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
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  • Eric Strengman, Department of Medical Genetics and Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands.
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  • Lambertus A. Kiemeney, Department of Epidemiology and Biostatistics and Department of Urology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
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  • René S. Kahn, Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Postbus 85060, 3508 AB, Utrecht, The Netherlands.
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  • Don H. Linszen, Academic Medical Centre University of Amsterdam, Department of Psychiatry, Amsterdam, NL326 Groot-Amsterdam, The Netherlands.
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  • Jim van Os, Maastricht University Medical Centre, South Limburg Mental Health Research and Teaching Network, P. Debyelaan 25, 6229 HX Maastricht, Maastricht, The Netherlands.
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  • Durk Wiersma, University Medical Center Groningen, Department of Psychiatry, University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands.
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  • Richard Bruggeman, University Medical Center Groningen, Department of Psychiatry, University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands.
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  • Wiepke Cahn, Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Postbus 85060, 3508 AB, Utrecht, The Netherlands.
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  • Lieuwe de Haan, Academic Medical Centre University of Amsterdam, Department of Psychiatry, Amsterdam, NL326 Groot-Amsterdam, The Netherlands.
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  • Lydia Krabbendam, Maastricht University Medical Centre, South Limburg Mental Health Research and Teaching Network, P. Debyelaan 25, 6229 HX Maastricht, Maastricht, The Netherlands.
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  • Inez Myin-Germeys, Maastricht University Medical Centre, South Limburg Mental Health Research and Teaching Network, P. Debyelaan 25, 6229 HX Maastricht, Maastricht, The Netherlands.
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  • Ingrid Melle, Department of Psychiatry, Ullevål University Hospital and Institute of Psychiatry, University of Oslo, Kirkeveien 166, N-0407 Oslo, Norway.
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  • Srdjan Djurovic, Department of Medical Genetics, Ulleval University Hospital and Institute of Psychiatry, University of Oslo, Kirkeveien 166, N-0407 Oslo, Norway.
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  • Lilia Abramova, Mental Health Research Center, Russian Academy of Medical Sciences, Zagorodnoe sh. 2/2, 117152 Moscow, Russia.
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  • Vasily Kaleda, Mental Health Research Center, Russian Academy of Medical Sciences, Zagorodnoe sh. 2/2, 117152 Moscow, Russia.
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  • Julio Sanjuan, Unidad de Psiquiatría, Facultad de Medicina, Universidad de Valencia, CIBERSAM, 46010 Valencia, Spain.
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  • Rosa de Frutos, Departamento de Genética. Facultad de Biología, Universidad de Valencia, CIBERSAM, Spain.
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  • Elvira Bramon, Division of Psychological Medicine, Institute of Psychiatry, King’s College, London SE5 8AF, UK.
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  • Evangelos Vassos, Division of Psychological Medicine, Institute of Psychiatry, King’s College, London SE5 8AF, UK.
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  • Gillian Fraser, Department of Mental Health, University of Aberdeen, Royal Cornhill Hospital, Aberdeen AB25 2ZD, UK.
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  • Ulrich Ettinger, Division of Psychological Medicine, Institute of Psychiatry, King’s College, London SE5 8AF, UK.
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  • Marco Picchioni, Division of Psychological Medicine, Institute of Psychiatry, King’s College, London SE5 8AF, UK.
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  • Nicholas Walker, Ravenscraig hospital, Inverkip Road, Greenock PA16 9HA, UK.
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  • Timi Toulopoulou, Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King’s College, London SE5 8AF, UK.
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  • Anna C. Need, 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.
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  • Dongliang Ge, 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.
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  • Joeng Lim Yoon, Department of Human Genetics, UCLA, 695 Charles Young Drive South, Los Angeles, California 90095, USA.
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  • Kevin V. Shianna, 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.
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  • Nelson B. Freimer, UCLA Center for Neurobehavioral Genetics, Charles E. Young Drive South, Los Angeles, California 90024, USA.
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  • Rita M. Cantor, UCLA Center for Neurobehavioral Genetics, Charles E. Young Drive South, Los Angeles, California 90024, USA.
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  • Robin Murray, Division of Psychological Medicine, Institute of Psychiatry, King’s College, London SE5 8AF, UK.
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  • Augustine Kong, deCODE genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.
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  • Vera Golimbet, Mental Health Research Center, Russian Academy of Medical Sciences, Zagorodnoe sh. 2/2, 117152 Moscow, Russia.
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  • Angel Carracedo, Fundación Pública Galega de Medicina Xenómica-Complexo Universitario Hospitalario de Santiago, and CIBER de Enfermedades Raras (CIBERER
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  • Celso Arango, Hospital General Universitario Gregorio Marañón, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Madrid, Spain.
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  • Javier Costas, Fundación Pública Galega de Medicina Xenómica, and CIBER de Enfermedades Raras (CIBERER), 46010 Valencia, Spain.
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  • Erik G. Jönsson, Department of Clinical Neuroscience, HUBIN project, Karolinska Institutet and Hospital, R5:00, SE-171 76 Stockholm, Sweden.
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  • Lars Terenius, Rektorsekretariatet, Denmark
  • Ingrid Agartz, Department of Clinical Neuroscience, HUBIN project, Karolinska Institutet and Hospital, R5:00, SE-171 76 Stockholm, Sweden.
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  • Hannes Petursson, Department of Psychiatry, National University Hospital, Hringbraut, 101 Reykjavik, Iceland.
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  • Markus M. Nöthen, Institute of Human Genetics, University of Bonn, Wilhelmstrasse 31, D-53111 Bonn, Germany.
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  • Marcella Rietschel, Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, University of Heidelberg, J5, D-68159 Mannheim, Germany.
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  • Paul M. Matthews, Clinical Imaging Centre, Clinical Pharmacology and Discovery Medicine, GlaxoSmithKline, Hammersmith Hospital, London W12 ONN, UK.
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  • Pierandrea Muglia, Medical Genetics, GlaxoSmithKline R&D, Via A. Fleming 4, 37135 Verona, Italy.
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  • Leena Peltonen, Institute of Molecular Medicine, Biomedicum Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland.
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  • David St Clair, Department of Mental Health, University of Aberdeen, Royal Cornhill Hospital, Aberdeen AB25 2ZD, UK.
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  • David B. Goldstein, 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.
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  • Kari Stefansson, deCODE genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.
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  • David A. Collier, Division of Psychological Medicine, Institute of Psychiatry, King’s College, London SE5 8AF, UK.
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 disorders. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the ‘genomic disorders’, have not yet been characterized. 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.
Original languageEnglish
JournalNature, Volume 460, Issue 7256, pp. 744-747 (2009).
Volume460
Pages (from-to)744-747
Publication statusPublished - 1 Aug 2009
Externally publishedYes

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