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Common variants conferring risk of schizophrenia
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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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“Further, results from SGENE+ 60 implicate NRGN (neurogranin) which may act as a calcium sensor. 61”
From Genetic architectures of psychiatric disorders: the emerging picture and its implications (2012) · cites this paper as [61]
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Metadata
- Authors
- †Genetic Risk and Outcome in Psychosis (GROUP), Stefansson, H., Ophoff, R. A., Steinberg, S., Andreassen, O. A., Cichon, S., Rujescu, D., Werge, T., Pietiläinen, O. P. H., Mors, O., Mortensen, P. B., Sigurdsson, E., Gustafsson, O., Nyegaard, M., Tuulio-Henriksson, A., Ingason, A., Hansen, T., Suvisaari, J., Lonnqvist, J., Paunio, T., Børglum, A. D., Hartmann, A., Fink-Jensen, A., Nordentoft, M., Hougaard, D., Norgaard-Pedersen, B., Böttcher, Y., Olesen, J., Breuer, R., Möller, H.-J., Giegling, I., Rasmussen, H. B., Timm, S., Mattheisen, M., Bitter, I., Réthelyi, J. M., Magnusdottir, B. B., Sigmundsson, T., Olason, P., Masson, G., Gulcher, J. R., Haraldsson, M., Fossdal, R., Thorgeirsson, T. E., Thorsteinsdottir, U., Ruggeri, M., Tosato, S., Franke, B., Strengman, E., Kiemeney, L. A., Melle, I., Djurovic, S., Abramova, L., Kaleda, V., Sanjuan, J., de Frutos, R., Bramon, E., Vassos, E., Fraser, G., Ettinger, U., Picchioni, M., Walker, N., Toulopoulou, T., Need, A. C., Ge, D., Lim Yoon, J., Shianna, K. V., Freimer, N. B., Cantor, R. M., Murray, R., Kong, A., Golimbet, V., Carracedo, A., Arango, C., Costas, J., Jönsson, E. G., Terenius, L., Agartz, I., Petursson, H., Nöthen, M. M., Rietschel, M., Matthews, P. M., Muglia, P., Peltonen, L., St Clair, D., Goldstein, D. B., Stefansson, K., & Collier, D. A.
- Affiliations
- deCODE Genetics (Iceland) (IS)
- University of Bonn (DE)
- Sankt Hans Hospital (DK)
- Aarhus University Hospital (DK)
- Aarhus University (DK)
- Copenhagen University Hospital (DK)
- Statens Serum Institut (DK)
- Heidelberg University (DE)
- Ludwig-Maximilians-Universität München (DE)
- Semmelweis University (HU)
- University of Verona (IT)
- Radboud University Medical Center (NL)
- University of Oslo (NO)
- Mental Health Research Center of Russian Academy of Medical Sciences (RU)
- King's College London (GB)
- Duke University (US)
- University of California, Los Angeles (US)
- Hospital General Universitario Gregorio Marañón (ES)
- Karolinska Institutet (SE)
- University of Iceland (IS)
- GlaxoSmithKline (United Kingdom) (GB)
- Wellcome Sanger Institute (GB)
- University of Aberdeen (GB)
- ORCID
- Ophoff, Roel A.
- Steinberg, Stacy
- Andreassen, Ole A.
- Cichon, Sven
- Rujescu, Dan
- Werge, Thomas
- Pietiläinen, Olli P. H.
- Mors, Ole
- Mortensen, Preben B.
- Nyegaard, Mette
- Hansen, Thomas
- Suvisaari, Jaana
- Paunio, Tiina
- Børglum, Anders D.
- Hartmann, Annette
- Nordentoft, Merete
- Hougaard, David
- Böttcher, Yvonne
- Olesen, Jes
- Möller, Hans-Jürgen
- Giegling, Ina
- Mattheisen, Manuel
- Bitter, István
- Réthelyi, János M.
- Olason, Pall
- Haraldsson, Magnus
- Thorgeirsson, Thorgeir E.
- Ruggeri, Mirella
- Tosato, Sarah
- Franke, Barbara
- Strengman, Eric
- Kiemeney, Lambertus A.
- Melle, Ingrid
- Djurovic, Srdjan
- Bramon, Elvira
- Vassos, Evangelos
- Ettinger, Ulrich
- Picchioni, Marco
- Need, Anna C.
- Ge, Dongliang
- Freimer, Nelson B.
- Cantor, Rita M.
- Murray, Robin
- Kong, Augustine
- Arango, Celso
- Costas, Javier
- Jönsson, Erik G.
- Terenius, Lars
- Agartz, Ingrid
- Nöthen, Markus M.
- Rietschel, Marcella
- Matthews, Paul M.
- Muglia, Pierandrea
- Peltonen, Leena
- Goldstein, David B.
- Collier, David A.
- Venue
- Nature
- Published
- 2009-07-01
- Volume
- 460
- Issue
- 7256
- Pages
- 744-747
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3077530
- OpenAlex
- W2127205775
- Cited by
- 1,677
- References
- 39
- Citations by year
- 2026: 21 · 2025: 39 · 2024: 47 · 2023: 38 · 2022: 47 · 2021: 65 · 2020: 62 · 2019: 66 · 2018: 56 · 2017: 90 · 2016: 116 · 2015: 148 · 2014: 140 · 2013: 165 · 2012: 196
- FWCI
- 116.23
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- VU Research Portal (submittedVersion)
- Hirsla (Landspítali University Hospital) (submittedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- GlaxoSmithKline
- Wellcome Trust (089061)
- National Institute for Health and Care Research (PDA/02/06/016)
- Bundesministerium für Bildung und Forschung (NGFN-2)
- Alfried Krupp von Bohlen und Halbach-Stiftung
- National Institutes of Health (6r01hl087679-03)
- National Heart, Lung, and Blood Institute (R01 HL087679, 1-R01HL087679-01)
- National Institute of Mental Health (R01MH078075, MH078075)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- schizophrenia, genetic susceptibility, single nucleotide polymorphisms, copy number variation, major histocompatibility complex, neurogranin, TCF4, immune function, brain development, memory and cognition, mental illness
- MeSH terms
- Transcription Factor 4, Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 18, Chromosomes, Human, Pair 6, DNA-Binding Proteins, Genetic Markers, Genotype, Humans, Major Histocompatibility Complex, Schizophrenia, Transcription Factors, Genome, Human, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Neurogranin, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Genome-Wide Association Study
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