title: Evidence for the involvement of the glucocorticoid receptor gene in bipolar disorder in an isolated northern Swedish population.
abstract: OBJECTIVE
  Dysfunction of the hypothalamus-pituitary-adrenal (HPA) axis is one of the most consistent findings in the pathophysiology of mood disorders. The potential role of genes related to HPA axis function has been investigated extensively in major depression. However, in bipolar disorder (BPD) such studies are scarce. We performed a systematic HapMap-based association study of six genes crucial for HPA axis function in relation to BPD.
  
  
  METHODS
  Haplotype tagging single nucleotide polymorphisms (htSNPs) were selected in order to identify all haplotypes with a frequency of more than 1% in the genes encoding the glucocorticoid receptor (GR), mineralocorticoid receptor (MR), corticotrophin releasing hormone receptor 1 (CRH-R1) and 2 (CRH-R2), CRH binding protein (CRH-BP), and FK binding protein 5 (FKBP5). This resulted in a total selection of 225 SNPs that were genotyped and analyzed in 309 BPD patients and 364 matched control individuals all originating from an isolated northern Swedish population.
  
  
  RESULTS
  Consistent evidence for an association with BPD was found for NR3C1, the gene encoding GR. Almost all SNPs in two adjacent haplotype blocks contributed to the positive signal, comprised of significant single marker, sliding window, and haplotype-specific p-values. All these results point to a moderately frequent (10-15%) susceptibility haplotype covering the entire coding region and 3' untranslated region (UTR) of NR3C1.
  
  
  CONCLUSIONS
  This study contributes to the growing evidence for a role of the glucocorticoid receptor gene (NR3C1) in vulnerability to mood disorders, and BPD in particular, and warrants further in vitro investigation of the at-risk haplotypes with respect to disease etiology. However, this association might be restricted to this specific population, as it is observed in a rather small sample from an isolated population without replication, and data from large meta-analyses for genome-wide association studies in BPD do not show the GR as a very strong candidate.
authors.affiliation: Applied Molecular Genomics Group, Department of Molecular Genetics, VIB, Belgium.
authors.forename: Shana
authors.initials: S
authors.lastname: Ceulemans
authors.forename: Sonia
authors.initials: S
authors.lastname: De Zutter
authors.forename: Lien
authors.initials: L
authors.lastname: Heyrman
authors.forename: Karl-Fredrik
authors.initials: KF
authors.lastname: Norrback
authors.forename: Annelie
authors.initials: A
authors.lastname: Nordin
authors.forename: Lars-Göran
authors.initials: LG
authors.lastname: Nilsson
authors.forename: Rolf
authors.initials: R
authors.lastname: Adolfsson
authors.forename: Jurgen
authors.initials: J
authors.lastname: Del-Favero
authors.forename: Stephan
authors.initials: S
authors.lastname: Claes
mesh_terms: D000328:Adult; D001714:Bipolar Disorder / Q000453:epidemiology / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D018161:Receptors, Mineralocorticoid / Q000235:genetics; D013548:Sweden / Q000453:epidemiology; D022021:Tacrolimus Binding Proteins / Q000235:genetics; D000099052:CRF Receptor, Type 1; D000099159:Tacrolimus Binding Protein 5
chemical_list: D002352:Carrier Proteins; D018019:Receptors, Corticotropin-Releasing Hormone; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D022021:Tacrolimus Binding Proteins; D000099052:CRF Receptor, Type 1; D000099159:Tacrolimus Binding Protein 5; C497713:NR3C1 protein, human; C561839:NR3C2 protein, human; C067133:corticotropin releasing factor-binding protein