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Published Online: 1 December 2012

Up-Regulation of NOTCH4 Gene Expression in Bipolar Disorder

Ingrid Dieset, M.D., Srdjan Djurovic, Ph.D., Martin Tesli, M.D., Sigrun Hope, M.D., Morten Mattingsdal, Ph.D., Annika Michelsen, Ph.D., Inge Joa, Ph.D., … Show All … , Tor Ketil Larsen, M.D., Ph.D., Ingrid Agartz, M.D., Ph.D., Ingrid Melle, M.D., Ph.D., Jan Ivar Røssberg, M.D., Ph.D., Pål Aukrust, M.D., Ph.D., Ole A. Andreassen, M.D., Ph.D., and Thor Ueland, Ph.D.Authors Info & Affiliations
Publication: American Journal of Psychiatry
Volume 169, Number 12
https://doi.org/10.1176/appi.ajp.2012.11091431
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Abstract

Objective

Immunopathogenic mechanisms have been implicated in schizophrenia and bipolar disorder, and genome-wide association studies (GWAS) point to the major histocompatibility complex, a region that contains many immune-related genes. One of the strongest candidate risk genes for schizophrenia and bipolar disorder is the NOTCH4 gene within the major histocompatibility complex. The authors investigated the NOTCH4 gene expression in individuals with bipolar disorder and schizophrenia relative to healthy comparison subjects and identified putative expression quantitative trait loci in and around the NOTCH4 gene.

Method

The authors measured and compared NOTCH4 mRNA in whole blood in 690 individuals (479 patients and 211 healthy comparison subjects) and adjusted for a range of confounders. The authors also genotyped 20 single-nucleotide polymorphisms (SNPs) and investigated possible associations between expression quantitative trait loci and NOTCH4 expression.

Results

The authors found a strong association between NOTCH4 expression and bipolar disorder after adjusting for a range of confounders and multiple testing. In addition, seven SNPs within the NOTCH4 gene region were associated with enhanced NOTCH4 mRNA levels. Three of these expression quantitative trait loci were independent (not in linkage disequilibrium).

Conclusions

The results indicate that the association between NOTCH4 DNA markers and bipolar disorder is related to altered function at the mRNA level, supporting the notion that NOTCH4 pathways are involved in the pathophysiology of bipolar disorder.

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Information & Authors

Information

Published In

Go to American Journal of Psychiatry
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American Journal of Psychiatry
Volume 169 • Number 12 • December 2012
Pages: 1292 - 1300
PubMed: 23212060

History

Received: 26 September 2011
Revision received: 5 March 2012
Revision received: 21 April 2012
Revision received: 1 June 2012
Accepted: 20 July 2012
Published online: 1 December 2012
Published in print: December 2012

Authors

Details

Ingrid Dieset, M.D.
From the Division of Mental Health and Addiction, Oslo University Hospital Ullevål, Oslo, Norway; KG Jebsen Center for Psychosis Research, the Institute of Clinical Medicine, University of Oslo, Oslo; the Department of Psychiatry, Østfold Hospital, Fredrikstad, Norway; the Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo; the Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo; the Faculty of Medicine, University of Oslo, Oslo; the Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Norway; the Department of Medical Genetics, Oslo University Hospital Ullevål, Oslo; Stavanger University Hospital, Division of Psychiatry, Regional Center for Clinical Psychosis Research, Stavanger, Norway; the Department of Clinical Medicine, Section Psychiatry, University of Bergen, Norway; and Sørlandet Hospital HF, Kristiansand, Norway.
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Srdjan Djurovic, Ph.D.
From the Division of Mental Health and Addiction, Oslo University Hospital Ullevål, Oslo, Norway; KG Jebsen Center for Psychosis Research, the Institute of Clinical Medicine, University of Oslo, Oslo; the Department of Psychiatry, Østfold Hospital, Fredrikstad, Norway; the Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo; the Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo; the Faculty of Medicine, University of Oslo, Oslo; the Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Norway; the Department of Medical Genetics, Oslo University Hospital Ullevål, Oslo; Stavanger University Hospital, Division of Psychiatry, Regional Center for Clinical Psychosis Research, Stavanger, Norway; the Department of Clinical Medicine, Section Psychiatry, University of Bergen, Norway; and Sørlandet Hospital HF, Kristiansand, Norway.
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Martin Tesli, M.D.
From the Division of Mental Health and Addiction, Oslo University Hospital Ullevål, Oslo, Norway; KG Jebsen Center for Psychosis Research, the Institute of Clinical Medicine, University of Oslo, Oslo; the Department of Psychiatry, Østfold Hospital, Fredrikstad, Norway; the Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo; the Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo; the Faculty of Medicine, University of Oslo, Oslo; the Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Norway; the Department of Medical Genetics, Oslo University Hospital Ullevål, Oslo; Stavanger University Hospital, Division of Psychiatry, Regional Center for Clinical Psychosis Research, Stavanger, Norway; the Department of Clinical Medicine, Section Psychiatry, University of Bergen, Norway; and Sørlandet Hospital HF, Kristiansand, Norway.
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Sigrun Hope, M.D.
From the Division of Mental Health and Addiction, Oslo University Hospital Ullevål, Oslo, Norway; KG Jebsen Center for Psychosis Research, the Institute of Clinical Medicine, University of Oslo, Oslo; the Department of Psychiatry, Østfold Hospital, Fredrikstad, Norway; the Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo; the Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo; the Faculty of Medicine, University of Oslo, Oslo; the Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Norway; the Department of Medical Genetics, Oslo University Hospital Ullevål, Oslo; Stavanger University Hospital, Division of Psychiatry, Regional Center for Clinical Psychosis Research, Stavanger, Norway; the Department of Clinical Medicine, Section Psychiatry, University of Bergen, Norway; and Sørlandet Hospital HF, Kristiansand, Norway.
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Morten Mattingsdal, Ph.D.
From the Division of Mental Health and Addiction, Oslo University Hospital Ullevål, Oslo, Norway; KG Jebsen Center for Psychosis Research, the Institute of Clinical Medicine, University of Oslo, Oslo; the Department of Psychiatry, Østfold Hospital, Fredrikstad, Norway; the Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo; the Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo; the Faculty of Medicine, University of Oslo, Oslo; the Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Norway; the Department of Medical Genetics, Oslo University Hospital Ullevål, Oslo; Stavanger University Hospital, Division of Psychiatry, Regional Center for Clinical Psychosis Research, Stavanger, Norway; the Department of Clinical Medicine, Section Psychiatry, University of Bergen, Norway; and Sørlandet Hospital HF, Kristiansand, Norway.
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Annika Michelsen, Ph.D.
From the Division of Mental Health and Addiction, Oslo University Hospital Ullevål, Oslo, Norway; KG Jebsen Center for Psychosis Research, the Institute of Clinical Medicine, University of Oslo, Oslo; the Department of Psychiatry, Østfold Hospital, Fredrikstad, Norway; the Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo; the Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo; the Faculty of Medicine, University of Oslo, Oslo; the Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Norway; the Department of Medical Genetics, Oslo University Hospital Ullevål, Oslo; Stavanger University Hospital, Division of Psychiatry, Regional Center for Clinical Psychosis Research, Stavanger, Norway; the Department of Clinical Medicine, Section Psychiatry, University of Bergen, Norway; and Sørlandet Hospital HF, Kristiansand, Norway.
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Inge Joa, Ph.D.
From the Division of Mental Health and Addiction, Oslo University Hospital Ullevål, Oslo, Norway; KG Jebsen Center for Psychosis Research, the Institute of Clinical Medicine, University of Oslo, Oslo; the Department of Psychiatry, Østfold Hospital, Fredrikstad, Norway; the Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo; the Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo; the Faculty of Medicine, University of Oslo, Oslo; the Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Norway; the Department of Medical Genetics, Oslo University Hospital Ullevål, Oslo; Stavanger University Hospital, Division of Psychiatry, Regional Center for Clinical Psychosis Research, Stavanger, Norway; the Department of Clinical Medicine, Section Psychiatry, University of Bergen, Norway; and Sørlandet Hospital HF, Kristiansand, Norway.
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Tor Ketil Larsen, M.D., Ph.D.
From the Division of Mental Health and Addiction, Oslo University Hospital Ullevål, Oslo, Norway; KG Jebsen Center for Psychosis Research, the Institute of Clinical Medicine, University of Oslo, Oslo; the Department of Psychiatry, Østfold Hospital, Fredrikstad, Norway; the Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo; the Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo; the Faculty of Medicine, University of Oslo, Oslo; the Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Norway; the Department of Medical Genetics, Oslo University Hospital Ullevål, Oslo; Stavanger University Hospital, Division of Psychiatry, Regional Center for Clinical Psychosis Research, Stavanger, Norway; the Department of Clinical Medicine, Section Psychiatry, University of Bergen, Norway; and Sørlandet Hospital HF, Kristiansand, Norway.
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Ingrid Agartz, M.D., Ph.D.
From the Division of Mental Health and Addiction, Oslo University Hospital Ullevål, Oslo, Norway; KG Jebsen Center for Psychosis Research, the Institute of Clinical Medicine, University of Oslo, Oslo; the Department of Psychiatry, Østfold Hospital, Fredrikstad, Norway; the Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo; the Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo; the Faculty of Medicine, University of Oslo, Oslo; the Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Norway; the Department of Medical Genetics, Oslo University Hospital Ullevål, Oslo; Stavanger University Hospital, Division of Psychiatry, Regional Center for Clinical Psychosis Research, Stavanger, Norway; the Department of Clinical Medicine, Section Psychiatry, University of Bergen, Norway; and Sørlandet Hospital HF, Kristiansand, Norway.
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Ingrid Melle, M.D., Ph.D.
From the Division of Mental Health and Addiction, Oslo University Hospital Ullevål, Oslo, Norway; KG Jebsen Center for Psychosis Research, the Institute of Clinical Medicine, University of Oslo, Oslo; the Department of Psychiatry, Østfold Hospital, Fredrikstad, Norway; the Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo; the Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo; the Faculty of Medicine, University of Oslo, Oslo; the Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Norway; the Department of Medical Genetics, Oslo University Hospital Ullevål, Oslo; Stavanger University Hospital, Division of Psychiatry, Regional Center for Clinical Psychosis Research, Stavanger, Norway; the Department of Clinical Medicine, Section Psychiatry, University of Bergen, Norway; and Sørlandet Hospital HF, Kristiansand, Norway.
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Jan Ivar Røssberg, M.D., Ph.D.
From the Division of Mental Health and Addiction, Oslo University Hospital Ullevål, Oslo, Norway; KG Jebsen Center for Psychosis Research, the Institute of Clinical Medicine, University of Oslo, Oslo; the Department of Psychiatry, Østfold Hospital, Fredrikstad, Norway; the Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo; the Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo; the Faculty of Medicine, University of Oslo, Oslo; the Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Norway; the Department of Medical Genetics, Oslo University Hospital Ullevål, Oslo; Stavanger University Hospital, Division of Psychiatry, Regional Center for Clinical Psychosis Research, Stavanger, Norway; the Department of Clinical Medicine, Section Psychiatry, University of Bergen, Norway; and Sørlandet Hospital HF, Kristiansand, Norway.
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Pål Aukrust, M.D., Ph.D.
From the Division of Mental Health and Addiction, Oslo University Hospital Ullevål, Oslo, Norway; KG Jebsen Center for Psychosis Research, the Institute of Clinical Medicine, University of Oslo, Oslo; the Department of Psychiatry, Østfold Hospital, Fredrikstad, Norway; the Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo; the Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo; the Faculty of Medicine, University of Oslo, Oslo; the Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Norway; the Department of Medical Genetics, Oslo University Hospital Ullevål, Oslo; Stavanger University Hospital, Division of Psychiatry, Regional Center for Clinical Psychosis Research, Stavanger, Norway; the Department of Clinical Medicine, Section Psychiatry, University of Bergen, Norway; and Sørlandet Hospital HF, Kristiansand, Norway.
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Ole A. Andreassen, M.D., Ph.D.
From the Division of Mental Health and Addiction, Oslo University Hospital Ullevål, Oslo, Norway; KG Jebsen Center for Psychosis Research, the Institute of Clinical Medicine, University of Oslo, Oslo; the Department of Psychiatry, Østfold Hospital, Fredrikstad, Norway; the Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo; the Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo; the Faculty of Medicine, University of Oslo, Oslo; the Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Norway; the Department of Medical Genetics, Oslo University Hospital Ullevål, Oslo; Stavanger University Hospital, Division of Psychiatry, Regional Center for Clinical Psychosis Research, Stavanger, Norway; the Department of Clinical Medicine, Section Psychiatry, University of Bergen, Norway; and Sørlandet Hospital HF, Kristiansand, Norway.
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Thor Ueland, Ph.D.
From the Division of Mental Health and Addiction, Oslo University Hospital Ullevål, Oslo, Norway; KG Jebsen Center for Psychosis Research, the Institute of Clinical Medicine, University of Oslo, Oslo; the Department of Psychiatry, Østfold Hospital, Fredrikstad, Norway; the Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo; the Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo; the Faculty of Medicine, University of Oslo, Oslo; the Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Norway; the Department of Medical Genetics, Oslo University Hospital Ullevål, Oslo; Stavanger University Hospital, Division of Psychiatry, Regional Center for Clinical Psychosis Research, Stavanger, Norway; the Department of Clinical Medicine, Section Psychiatry, University of Bergen, Norway; and Sørlandet Hospital HF, Kristiansand, Norway.
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Notes

Address correspondence to Dr. Dieset ([email protected]).

Funding Information

Dr. Dieset has received a research award from Lundbeck. Drs. Dieset, Hope, and Tesli have received travel expenses from Astra Zeneca for a Scandinavian College of Neuropsychopharmacology research conference. Dr. Melle and Dr. Andreassen have received speaker’s honorarium from Janssen and AstraZeneca, and Dr. Andreassen has also received speaker’s honorarium from Bristol-Myers Squibb and GlaxoSmithKline. The other authors report no financial relationships with commercial interests.
Supplementary Material
Supported by the Research Council of Norway (grants 167153/V50, 163070/V50, 175345/V50), South-Eastern and Western Norway Health Authority (123-2004), and Oslo University Hospital Ullevål and the University of Oslo for the Thematic Organized Psychosis Research Study group.

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