title: Up-regulation of NOTCH4 gene expression in bipolar disorder.
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.
  
  
  METHODS
  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.
authors.affiliation: Division of Mental Health and Addiction, Oslo University Hospital Ullevål, Oslo, Norway. ingrid.dieset@medisin.uio.no
authors.forename: Ingrid
authors.initials: I
authors.lastname: Dieset
authors.forename: Srdjan
authors.initials: S
authors.lastname: Djurovic
authors.forename: Martin
authors.initials: M
authors.lastname: Tesli
authors.forename: Sigrun
authors.initials: S
authors.lastname: Hope
authors.forename: Morten
authors.initials: M
authors.lastname: Mattingsdal
authors.forename: Annika
authors.initials: A
authors.lastname: Michelsen
authors.forename: Inge
authors.initials: I
authors.lastname: Joa
authors.forename: Tor Ketil
authors.initials: TK
authors.lastname: Larsen
authors.forename: Ingrid
authors.initials: I
authors.lastname: Agartz
authors.forename: Ingrid
authors.initials: I
authors.lastname: Melle
authors.forename: Jan Ivar
authors.initials: JI
authors.lastname: Røssberg
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
authors.forename: Ole A
authors.initials: OA
authors.lastname: Andreassen
authors.forename: Thor
authors.initials: T
authors.lastname: Ueland
mesh_terms: D000328:Adult; D001714:Bipolar Disorder / Q000235:genetics* / Q000503:physiopathology; D016022:Case-Control Studies; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D005838:Genotype; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D040641:Quantitative Trait Loci / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D000074562:Receptor, Notch4; D051880:Receptors, Notch / Q000235:genetics / Q000502:physiology*; D012559:Schizophrenia / Q000235:genetics / Q000503:physiopathology; D015854:Up-Regulation
chemical_list: C106075:NOTCH4 protein, human; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D000074562:Receptor, Notch4; D051880:Receptors, Notch