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Characterization of a glucocorticoid receptor gene ( GR , NR3C1 ) promoter polymorphism reveals functionality and extends a haplotype with putative clinical relevance
Author(s) -
Kumsta Robert,
Moser Dirk,
Streit Fabian,
Koper Jan Willem,
Meyer Jobst,
Wüst Stefan
Publication year - 2008
Publication title -
american journal of medical genetics part b: neuropsychiatric genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.393
H-Index - 126
eISSN - 1552-485X
pISSN - 1552-4841
DOI - 10.1002/ajmg.b.30837
Subject(s) - glucocorticoid receptor , linkage disequilibrium , single nucleotide polymorphism , biology , haplotype , snp , genetics , allele , glucocorticoid , endocrinology , gene , genotype
Hyperactivity of the hypothalamus–pituitary–adrenal (HPA) axis has been associated with the etiology of major depression. One of the factors underlying altered glucocorticoid signaling might be variability of the glucocorticoid receptor gene ( GR , NR3C1 ). GR polymorphisms have been associated with variability in glucocorticoid sensitivity and endocrine responses to psychosocial stress. Furthermore, a common GR SNP (rs10482605), located in the promoter region, has been associated with major depression. We performed functional characterization of this SNP in vitro using a reporter gene assay under different stimulation conditions. Furthermore, we genotyped 219 subjects previously genotyped for four common GR SNPs to further characterize GR haplotype structure. The minor C allele of the rs10482605 SNP showed reduced transcriptional activity under unstimulated conditions and under different stimulation conditions in two brain derived cell lines. Linkage analyses revealed that the rs10482605 SNP is in high linkage disequilibrium with a A/G SNP in exon 9beta (rs6198), associated with relative glucocorticoid resistance and increased GRbeta mRNA stability. We provide evidence that two functional GR SNPs in linkage disequilibrium are responsible for both regulation of GR expression and mRNA stability. This newly characterized haplotype could increase the risk for the development of stress related disorders, including major depression. © 2008 Wiley‐Liss, Inc.