HPA axis dysfunction is a key neurobiological finding in major depression (MDD) and in a number of other stress related psychiatric disorders. Hyperdrive of corticotropin releasing hormone (CRH) is at the core of HPA axis dysregulation in MDD. The liability to develop CRH hyperdrive is a complex trait, partially determined by genetic factors. A main functional candidate gene for the regulation of the HPA axis is the gene encoding for the glucocorticoid receptor (GR). Transgenic mice with functional GR gene impairment show profound behavioral changes and elevated plasma corticotropin responses to stress. In humans, several GR polymorphisms were shown to influence HPA axis function. Recently, our group published a positive association finding between polymorphisms in the 5' region of the GR gene and recurrent MDD in two separate populations [1].

The action of the glucocorticoid receptor is tightly regulated by a number of co-chaperones. Binder et al. [2] found significant associations of response to antidepressants and polymorphisms in the FKBP5 gene, a glucocorticoid receptor−regulating co-chaperone of hsp-90.

Several other candidate genes are of interest, such as the CRH receptor 1 and CRH receptor 2 genes, the CRH binding protein gene [3], the AVP receptor gene and the mineralocorticoid receptor gene. These and other genetic determinants of HPA axis function, from our own studies and from the literature, will be discussed.