Up-Regulation of NOTCH4 Gene Expression in Bipolar Disorder

• Published in: The American journal of psychiatry 2012-12, Vol.169 (12), p.1292-1300
• Main Authors: Dieset, Ingrid, Djurovic, Srdjan, Tesli, Martin, Hope, Sigrun, Mattingsdal, Morten, Michelsen, Annika, Joa, Inge, Larsen, Tor Ketil, Agartz, Ingrid, Melle, Ingrid, Røssberg, Jan Ivar, Aukrust, Pål, Andreassen, Ole A., Ueland, Thor
• Format: Article
• Language: English
• Subjects: Adult; Adult and adolescent clinical studies; Biological and medical sciences; Bipolar disorder; Bipolar Disorder - genetics; Bipolar Disorder - physiopathology; Bipolar disorders; Case-Control Studies; Female; Gene expression; Gene Expression Regulation - genetics; Gene Expression Regulation - physiology; Genetic markers; Genotype; Humans; Male; Medical sciences; Mood disorders; Oligonucleotide Array Sequence Analysis; Polymorphism; Polymorphism, Single Nucleotide - genetics; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - physiology; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Quantitative Trait Loci - genetics; Receptor, Notch4; Receptors, Notch - genetics; Receptors, Notch - physiology; RNA, Messenger - genetics; Schizophrenia - genetics; Schizophrenia - physiopathology; Up-Regulation
• ISSN: 0002-953X; 1535-7228
• DOI: 10.1176/appi.ajp.2012.11091431

ObjectiveImmunopathogenic 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.MethodThe 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.ResultsThe 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).ConclusionsThe 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.