Scientific Understanding of Consciousness
Nature 460, 753-757 (6 August 2009)
Common variants on chromosome 6p22.1 are associated with schizophrenia
Jianxin Shi1, Douglas F. Levinson1, Jubao Duan2, Alan R. Sanders2, Yonglan Zheng2, Itsik Pe'er3, Frank Dudbridge4, Peter A. Holmans5, Alice S. Whittemore6, Bryan J. Mowry7, Ann Olincy8, Farooq Amin9, C. Robert Cloninger10, Jeremy M. Silverman11, Nancy G. Buccola12, William F. Byerley13, Donald W. Black14, Raymond R. Crowe14, Jorge R. Oksenberg15, Daniel B. Mirel16, Kenneth S. Kendler17, Robert Freedman8 & Pablo V. Gejman2
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California 94304, USA
Center for Psychiatric Genetics, NorthShore University HealthSystem Research Institute, Evanston, Illinois 60201, USA
Department of Computer Science, Columbia University, New York, New York 10027, USA
Medical Research Council-Biostatistics Unit, Institute of Public Health, Cambridge CB2 2SR, UK
MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Heath Park, Cardiff CF23 6BQ, UK
Department of Health Research and Policy, Stanford University, Stanford, California 94304, USA
Queensland Centre for Mental Health Research, and Queensland Institute for Medical Research, Brisbane, Queensland 4072, Australia
Department of Psychiatry, University of Colorado Denver, Aurora, Colorado 80045, USA
Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, and Emory University, Atlanta, Georgia 30322, USA
Department of Psychiatry, Washington University, St Louis, Missouri 63110, USA
Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029, USA
School of Nursing, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA
Department of Psychiatry, University of California at San Francisco, San Francisco, California 94143, USA
Mental Health Clinical Research Center, and Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA
Department of Neurology, School of Medicine, University of California at San Francisco, San Francisco, California 94143, USA
Center for Genotyping and Analysis, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA
Departments of Psychiatry, and Human Genetics, Virginia Commonwealth University, Richmond, Virginia 23298, USA
Schizophrenia, a devastating psychiatric disorder, has a prevalence of 0.5–1%, with high heritability (80–85%) and complex transmission.
The symptoms and course of schizophrenia are variable, without forming distinct familial subtypes. There are positive (delusions and hallucinations), negative (reduced emotions, speech and interest), and disorganized (disrupted syntax and behaviour) symptoms, as well as mood symptoms in many cases. Onset is typically in adolescence or early adulthood, and rarely in childhood. The course of illness can range from acute episodes with primarily positive symptoms to the more common chronic or relapsing patterns often accompanied by cognitive disability and histories of childhood conduct or developmental disorders.
Here we show that schizophrenia is significantly associated with single nucleotide polymorphisms (SNPs) in the extended major histocompatibility complex region on chromosome 6.
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Nature 460, 744-747 (6 August 2009)
Common variants conferring risk of schizophrenia
Hreinn Stefansson, Roel A. Ophoff, Stacy Steinberg, Ole A. Andreassen, Sven Cichon, Dan Rujescu, Thomas Werge, Olli P. H. Pietiläinen, Ole Mors, Preben B. Mortensen, Engilbert Sigurdsson, Omar Gustafsson, Mette Nyegaard, Annamari Tuulio-Henriksson, Andres Ingason, Thomas Hansen, Jaana Suvisaari, Jouko Lonnqvist, Tiina Paunio, Anders D. Børglum, Annette Hartmann, Anders Fink-Jensen, Merete Nordentoft, David Hougaard, Bent Norgaard-Pedersen, Yvonne Böttcher, Jes Olesen, René Breuer, Hans-Jürgen Möller, Ina Giegling, Henrik B. Rasmussen, Sally Timm, Manuel Mattheisen, István Bitter, János M. Réthelyi, Brynja B. Magnusdottir, Thordur Sigmundsson, Pall Olason, Gisli Masson, Jeffrey R. Gulcher, Magnus Haraldsson, Ragnheidur Fossdal, Thorgeir E. Thorgeirsson, Unnur Thorsteinsdottir, Mirella Ruggeri, Sarah Tosato, Barbara Franke, Eric Strengman, Lambertus A. Kiemeney, Ingrid Melle, Srdjan Djurovic, Lilia Abramova, Vasily Kaleda, Julio Sanjuan, Rosa de Frutos, Elvira Bramon, Evangelos Vassos, Gillian Fraser, Ulrich Ettinger, Marco Picchioni, Nicholas Walker, Timi Toulopoulou, Anna C. Need, Dongliang Ge, Joeng Lim Yoon, Kevin V. Shianna, Nelson B. Freimer, Rita M. Cantor, Robin Murray, Augustine Kong, Vera Golimbet, Angel Carracedo, Celso Arango, Javier Costas, Erik G. Jönsson, Lars Terenius, Ingrid Agartz, Hannes Petursson, Markus M. Nöthen, Marcella Rietschel, Paul M. Matthews, Pierandrea Muglia, Leena Peltonen, David St Clair, David B. Goldstein, Kari Stefansson & David A. Collier
deCODE genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.
Department of Medical Genetics and Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands.
UCLA Center for Neurobehavioral Genetics, Charles E. Young Drive South, Los Angeles, California 90024, USA.
Department of Psychiatry, Ullevål University Hospital and Institute of Psychiatry, University of Oslo, Kirkeveien 166, N-0407 Oslo, Norway.
Department of Genomics, Life and Brain Center, University of Bonn, Sigmund-Freud-Strasse 25, D-53127 Bonn, Germany.
Division of Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig-Maximilians-University, Nubaumstrasse 7, 80336 Munich, Germany.
Research Institute of Biological Psychiatry, Mental Health Centre Sct. Hans Copenhagen University Hospital, DK-4000 Roskilde, Denmark.
Institute of Molecular Medicine, Biomedicum Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland.
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Skovagervej 2, 8240 Risskov, Denmark.
National Centre for Register-based Research, Aarhus University, Taasingegade 1, DK-8000 Aarhus, Denmark.
Department of Psychiatry, National University Hospital, Hringbraut, 101 Reykjavik, Iceland.
University of Iceland, School of Medicine, Laeknagardi, 101 Reykjavik, Iceland.
Department of Human Genetics, The Bartholin Building, Aarhus University, DK-8000 Arhus C, Denmark.
Department of Mental Health and Alcohol Research, National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland.
Department for Molecular Medicine, National Public Health Institute, Biomedicum, Haartmaninkatu 8, 00290 Helsinki, Finland.
Mental Health Centre Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen Ø, Denmark.
Psychiatric Centre Bisbebjerg, Building 13A, Bispebjerg Hospital, Bispebjerg Bakke 23, 2400 Copenhagen NV, Denmark.
Section of Neonatal Screening and Hormones, Department Clinical Chemistry and Immunology, The State Serum Institute, Artillerivej 5, 2300 Copenhagen S, Denmark.
Department of Neurology, 57 Nordre Ringvej, Glostrup Hospital, Glostrup, DK-2600 Copenhagen, Denmark.
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, University of Heidelberg, J5, D-68159 Mannheim, Germany.
Department of Psychiatry, Ludwig-Maximilians-University, Nubaumstrasse 7, 80336 Munich, Germany.
Mental Health Centre Frederiksberg, Copenhagen University Hospital, DK-2000 Frederiksberg, Denmark.
Semmelweis University, Department of Psychiatry and Psychotherapy, Budapest 1083, Hungary.
Section of Psychiatry and Clinical Psychology, University of Verona, Verona, 37134 Verona, Italy.
Department of Human Genetics, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
Department of Epidemiology and Biostatistics and Department of Urology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
Department of Medical Genetics, Ulleval University Hospital and Institute of Psychiatry, University of Oslo, Kirkeveien 166, N-0407 Oslo, Norway.
Mental Health Research Center, Russian Academy of Medical Sciences, Zagorodnoe sh. 2/2, 117152 Moscow, Russia.
Unidad de Psiquiatría, Facultad de Medicina, Universidad de Valencia, CIBERSAM, 46010 Valencia, Spain.
Departamento de Genética. Facultad de Biología, Universidad de Valencia, CIBERSAM, Spain.
Division of Psychological Medicine, Institute of Psychiatry, King's College, London SE5 8AF, UK.
Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College, London SE5 8AF, UK.
Department of Mental Health, University of Aberdeen, Royal Cornhill Hospital, Aberdeen AB25 2ZD, UK.
Ravenscraig hospital, Inverkip Road, Greenock PA16 9HA, UK.
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.
Department of Human Genetics, UCLA, 695 Charles Young Drive South, Los Angeles, California 90095, USA.
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.
Hospital General Universitario Gregorio Marañón, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Madrid, Spain.
Fundación Pública Galega de Medicina Xenómica, and CIBER de Enfermedades Raras (CIBERER), 46010 Valencia, Spain.
Department of Clinical Neuroscience, HUBIN project, Karolinska Institutet and Hospital, R5:00, SE-171 76 Stockholm, Sweden.
Institute of Human Genetics, University of Bonn, Wilhelmstrasse 31, D-53111 Bonn, Germany.
Clinical Imaging Centre, Clinical Pharmacology and Discovery Medicine, GlaxoSmithKline, Hammersmith Hospital, London W12 ONN, UK.
Medical Genetics, GlaxoSmithKline R&D, Via A. Fleming 4, 37135 Verona, Italy.
Psychiatric Laboratory, Department of Psychiatry, West China Hospital, Sichuan University, 610065 Sichuan, China.
Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Postbus 85060, 3508 AB, Utrecht, The Netherlands.
Academic Medical Centre University of Amsterdam, Department of Psychiatry, Amsterdam, NL326 Groot-Amsterdam, The Netherlands.
Maastricht University Medical Centre, South Limburg Mental Health Research and Teaching Network, P. Debyelaan 25, 6229 HX Maastricht, Maastricht, The Netherlands.
University Medical Center Groningen, Department of Psychiatry, University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands.
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.
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Nature 460, 748-752 (6 August 2009)
Common polygenic variation contributes to risk of schizophrenia and bipolar disorder
The International Schizophrenia Consortium
Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
Stanley Center for Psychiatric Research, The Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
The Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
Queensland Institute of Medical Research, 300 Herston Road, Brisbane, Queensland 4006, Australia.
MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine, School of Medicine, Cardiff University, Cardiff C14 4XN, UK.
Departments of Genetics, Psychiatry, and Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Molecular Psychiatry Laboratory, Research Department of Mental Health Sciences, University College London Medical School, Windeyer Institute of Medical Sciences, 46 Cleveland Street, London W1T 4JF, UK.
Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland.
Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh EH10 5HF, UK.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Department of Neuroscience, Psychiatry, Ulleråker, Uppsala University, SE-750 17 Uppsala, Sweden.
Center for Genomic Psychiatry, University of Southern California, Los Angeles, California 90033, USA.
Institute of Medical Sciences,
Department of Mental Health, University of Aberdeen, Aberdeen AB25 2ZD, UK.
Department of Medical Genetics, University Hospital Maichin Dom, Sofia 1431, Bulgaria.
Department of Psychiatry, First Psychiatric Clinic, Alexander University Hospital, Sofia 1431, Bulgaria.
West Berkshire NHS Trust, 25 Erleigh Road, Reading RG3 5LR, UK.
Department of Psychiatry, University of Oxford, Warneford Hospital, Headington, Oxford OX3 7JX, UK.
Ravenscraig Hospital, Inverkip Road, Greenock PA16 9HA, UK.
State University of New York – Upstate Medical University, Syracuse, New York 13210, USA.
Washington VA Medical Center, Washington DC 20422, USA.
Department of Psychiatry, Georgetown University School of Medicine, Washington DC 20057, USA.
Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
Department of Psychiatry, Sao Miguel, 9500-310 Azores, Portugal.
Department of Psychiatry University of Coimbra, 3004-504 Coimbra, Portugal.
Schizophrenia is a severe mental disorder with a lifetime risk of about 1%, characterized by hallucinations, delusions and cognitive deficits, with heritability estimated at up to 80%. We performed a genome-wide association study of 3,322 European individuals with schizophrenia and 3,587 controls. Here we show, using two analytic approaches, the extent to which common genetic variation underlies the risk of schizophrenia. First, we implicate the major histocompatibility complex. Second, we provide molecular genetic evidence for a substantial polygenic component to the risk of schizophrenia involving thousands of common alleles of very small effect. We show that this component also contributes to the risk of bipolar disorder, but not to several non-psychiatric diseases.
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Nature 452, 93-97 (6 March 2008)
Identification of a serotonin/glutamate receptor complex implicated in psychosis
Javier González-Maeso, Rosalind L. Ang, Tony Yuen, Pokman Chan, Noelia V. Weisstaub, Juan F. López-Giménez, Mingming Zhou, Yuuya Okawa, Luis F. Callado, Graeme Milligan, Jay A. Gingrich, Marta Filizola, J. Javier Meana & Stuart C. Sealfon
Department of Neurology, Department of Psychiatry, Department of Structural and Chemical Biology and, Center for Translational Systems Biology, Mount Sinai School of Medicine, New York, New York 10029, USA
Department of Psychiatry, Sackler Institute Laboratories and, Lieber Center for Schizophrenia Research, Columbia University, and the New York State Psychiatric Institute, New York, New York 10032, USA
Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
CIBER of Mental Health, and, Department of Pharmacology, University of the Basque Country, E-48940 Leioa, Bizkaia, Spain
The psychosis associated with schizophrenia is characterized by alterations in sensory processing and perception. Some antipsychotic drugs were identified by their high affinity for serotonin 5-HT2A receptors (2AR). Drugs that interact with metabotropic glutamate receptors (mGluR) also have potential for the treatment of schizophrenia. The effects of hallucinogenic drugs, such as psilocybin and lysergic acid diethylamide, require the 2AR and resemble some of the core symptoms of schizophrenia. Here we show that the mGluR2 interacts through specific transmembrane helix domains with the 2AR, a member of an unrelated G-protein-coupled receptor family, to form functional complexes in brain cortex. The 2AR–mGluR2 complex triggers unique cellular responses when targeted by hallucinogenic drugs, and activation of mGluR2 abolishes hallucinogen-specific signalling and behavioural responses. In post-mortem human brain from untreated schizophrenic subjects, the 2AR is upregulated and the mGluR2 is downregulated, a pattern that could predispose to psychosis. These regulatory changes indicate that the 2AR–mGluR2 complex may be involved in the altered cortical processes of schizophrenia, and this complex is therefore a promising new target for the treatment of psychosis.
The onset of psychosis in schizophrenia usually occurs in later adolescence or early adulthood.
Our results are consistent with the hypothesis that the 2AR–mGluR2 complex integrates serotonin and glutamate signalling to regulate the sensory gating functions of the cortex, a process that is disrupted in psychosis.
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