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Mutation screen and association analysis of the glucocorticoid receptor gene ( NR3C1 ) in childhood‐onset mood disorders (COMD)
Author(s) -
Mill J.,
Wigg K.,
Burcescu I.,
Vetró Á.,
Kiss E.,
Kapornai K.,
Tamás Z.,
Baji I.,
Gádoros J.,
Kennedy J.L.,
Kovacs M.,
Barr C.L.
Publication year - 2009
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.30909
Subject(s) - glucocorticoid receptor , genetics , biology , linkage disequilibrium , transcription factor , gene , promoter , mood disorders , haplotype , genotype , gene expression , anxiety , psychology , psychiatry
Depressive disorders are highly heterogeneous psychiatric disorders involving deficits to cognitive, psychomotor, and emotional processing. Considerable evidence links disruption to the hypothalamic–pituitary–adrenal (HPA) axis to the etiology of depression, with specific deficits reported in glucocorticoid receptor (GR)‐mediated negative feedback. Given the role of GR‐mediated negative feedback in mediating response to stress, and the clear link between stress and depression, it is plausible that polymorphisms in the GR gene ( NR3C1 ) act to increase susceptibility. Maternal behavior in rats epigenetically alters a NGF1‐A transcription factor binding‐site in the promoter region of the GR gene, providing a mechanism by which environmental cues can regulate GR expression and thus response to stress. The analogous region of the human GR gene ( NR3C1 ) has not been studied, but it is possible that polymorphisms in this region may alter the binding of transcription factors known to regulate GR expression. In this study, we have performed bioinformatic analyses on the promoter region of NR3C1 to identify conserved promoter sequences and predicted transcription factor binding sites. These regions were screened with denaturing high‐performance liquid chromatography (DHPLC) and direct re‐sequencing, and several novel polymorphic variants were identified. We genotyped nine polymorphisms across NR3C1 in a large sample of Hungarian nuclear families ascertained through affected probands with a diagnosis of childhood‐onset mood disorders (COMD). Single‐marker analysis provided little evidence for an association of this gene with COMD, but multi‐marker analysis across a region of high linkage disequilibrium revealed modest evidence for the biased transmission of several haplotypes. © 2008 Wiley‐Liss, Inc.