Mutation screen and association analysis of the glucocorticoid receptor gene NR3C1 in childhoodonset mood disorders COMDPlease cite this article as follows: Mill J, Wigg K, Burcescu I, Vetró Á, Kiss E, Kapornai K, Tamás Z, Baji I, Gádoros J, Kennedy JL, Kovacs M, Barr CL, The International Consortium for ChildhoodOnset Mood Disorders. 2009. Mutation screen and association analysis of the glucocorticoid receptor gene NR3C1 in childhoodonset mood disorders COMD. Am J Med Genet Part B 150B:866–873.

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 GRmediated negative feedback. Given the role of GRmediated 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 NGF1A transcription factor bindingsite 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 NR3C1to identify conserved promoter sequences and predicted transcription factor binding sites. These regions were screened with denaturing highperformance liquid chromatography DHPLC and direct resequencing, and several novel polymorphic variants were identified. We genotyped nine polymorphisms across NR3C1in a large sample of Hungarian nuclear families ascertained through affected probands with a diagnosis of childhoodonset mood disorders COMD. Singlemarker analysis provided little evidence for an association of this gene with COMD, but multimarker analysis across a region of high linkage disequilibrium revealed modest evidence for the biased transmission of several haplotypes. © 2008 WileyLiss, Inc.