Glucocorticoid receptor gene-based SNP analysis in patients with recurrent major depression.

Dysregulation of the hypothalamic-pituitary-adrenal axis, one of the stress-response systems, is one of the key neurobiological features of major depression (MDD). Data supporting the notion that glucocorticoid-mediated feedback inhibition is impaired in MDD come from a multitude of studies demonstrating nonsuppression of cortisol secretion following administration of the synthetic glucocorticoid dexamethasone. We examined whether genetic variations in the glucocorticoid receptor gene (Nuclear Receptor Subfamily 3, Group C, Member 1; NR3C1) could be associated with increased susceptibility for MDD using a whole gene-based association analysis of single nucleotide polymorphisms (SNPs). Four SNPs were identified in NR3C1 and genotyped in two well-diagnosed samples of patients with MDD ascertained in Belgium and northern Sweden, and matched control samples. In total, 314 MDD patients and 354 control individuals were included in the study. In the Belgian sample, we observed significant allele (p=0.02) and genotype (p=0.02) association with an SNP in the promoter region (NR3C1-1); in the Swedish sample, we observed significant allele (p=0.02) and genotype (p=0.02) association with the R23K SNP. The haplotype association studies showed modest evidence for an involvement of the 5' region of the NR3C1 gene in the genetic vulnerability for MDD. This study suggests that polymorphisms in the 5' region of the NR3C1 gene may play a role in the genetic vulnerability for MDD.

The corticotropin-releasing hormone binding protein is associated with major depression in a population from Northern Sweden.

BACKGROUND: Recent research suggests that central corticotropin releasing hormone hyperdrive is an important neurobiological risk factor for developing major depression. The availability of free corticotropin releasing hormone in the central nervous system is tightly regulated by the expression of corticotropin releasing hormone binding protein. Therefore, the gene encoding for corticotropin releasing hormone binding protein is a functional candidate gene for major depression. METHODS: We present a systematic study of single nucleotide polymorphisms in the corticotropin releasing hormone binding protein gene and their role in the liability for major depression. Seven single nucleotide polymorphisms were genotyped in a well-diagnosed sample of 89 patients with recurrent major depressions and matched controls. RESULTS: Two single nucleotide polymorphisms within the corticotropin releasing hormone binding protein gene were significantly associated with the disease (p <.05). An expectation-maximization algorithm estimated a specific haplotype to have a frequency of 53% in patients and 35% in controls (p <.001). CONCLUSIONS: The corticotropin releasing hormone binding protein gene is likely to be involved in the genetic vulnerability for major depression.