The hypothalamic-pituitary-adrenal (HPA)-axis regulates the response to stressful events and is expected to be involved in the pathogenesis of depression. The glucocorticoid receptor (GR) regulates the activity of the HPA-axis. Both GR gene polymorphisms and childhood adversity are known to be associated with increased risk for depression. In the Longitudinal Aging Study Amsterdam, a large population based sample of older men and women, 906 subjects were genotyped. An association study was performed to determine the relationship between GR gene polymorphisms, childhood adversity, HPA-axis markers and depressive symptoms. A gene-environment interaction between the GR polymorphisms 22/23EK and 9beta and childhood adversity resulted in an increased risk of clinically relevant depressive symptoms. Without childhood adversity no increased risk was present. The 22/23EK variant was also associated with a lower Free Cortisol Index in the presence of childhood adversity. Persons that are heterozygous for the BclI variant, in contrast with wild-type and BclI-homozygotes, had lower serum levels of cortisol binding globulin and had no increased risk of recurrent depressive symptoms in the presence of childhood adversity. We found a gene-environment (G x E) interaction between common variants of the GR gene and childhood adversity, demonstrating a vulnerable phenotype for developing clinically relevant depressive symptoms at old age. This G x E interaction also influencedHPA-axismarkers providing support for the involvement of theHPA-axis in both stress regulation and the pathogenesis of depression.

Childhood adversity, Depression, Depressive symptoms, Glucocorticoid receptor gene, HPA-axis,
American Journal of Medical Genetics. Part B: Neuropsychiatric Genetics
Erasmus MC: University Medical Center Rotterdam

Bet, P.M, Penninx, B.W.J.H, Bochdanovits, Z, Uitterlinden, A.G, Beekman, A.T.F, van Schoor, N.M, … Hoogendijk, W.J.G. (2009). Glucocorticoid receptor gene polymorphisms and childhood adversity are associated with depression: New evidence for a gene-environment interaction. American Journal of Medical Genetics. Part B: Neuropsychiatric Genetics, 150(5), 660–669. doi:10.1002/ajmg.b.30886