Characterization of a glucocorticoid receptor gene promoter polymorphism reveals functionality and extends a haplotype with putative clinical relevance
Wüst, S.1,4, Kumsta, R.1,2, Moser, D. A.2, Streit, F.2, Koper, J. W.3, and Meyer, J.2
1Department of Psychobiology, University of Trier; 2Department of Neurobehavioral Genetics, University of Trier; 3Department of Internal Medicine, Erasmus MC, Rotterdam; 4Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim
Hyperactivity of the hypothalamus-pituitary-adrenal axis has been associated with the etiology of depression. One factor underlying altered glucocorticoid signaling might be variability of the glucocorticoid receptor gene (NR3C1). NR3C1 polymorphisms have been associated with endocrine stress responses. Furthermore, a NR3C1 promoter SNP (rs10482605) has been associated with depression.
We performed functional characterization of this SNP in vitro using a reporter gene assay. Furthermore, we genotyped 219 subjects previously genotyped for four NR3C1 SNPs to further characterize GR haplotype structure. The C allele of rs10482605 showed reduced transcriptional activity in two brain derived cell lines. Linkage analyses revealed that rs10482605 is in high linkage disequilibrium with a A/G SNP in exon 9beta, associated with relative glucocorticoid resistance and increased GRbeta mRNA stability.
Thus, two SNPs in linkage disequilibrium influence regulation of GR expression and mRNA stability. This newly characterized haplotype could increase the risk for stress related disorders.