Glucocorticoid receptor gene polymorphisms and childhood adversity are associated with depression: New evidence for a gene-environment interaction.
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 influenced HPA-axis markers providing support for the involvement of the HPA-axis in both stress regulation and the pathogenesis of depression.
Bet
Pierre M
PM
Department of Clinical Pharmacology and Pharmacy, VU University Medical Center, Amsterdam, The Netherlands. pm.bet@vumc.nl
Penninx
Brenda W J H
BW
Bochdanovits
Zoltan
Z
Uitterlinden
André G
AG
Beekman
Aartjan T F
AT
van Schoor
Natasja M
NM
Deeg
Dorly J H
DJ
Hoogendijk
Witte J G
WJ
D054523:Adult Survivors of Child Abuse / Q000523:psychology; D000368:Aged; D000369:Aged, 80 and over; D003863:Depression / Q000209:etiology* / Q000235:genetics; D004198:Disease Susceptibility / Q000209:etiology; D004777:Environment; D004843:Epistasis, Genetic / Q000502:physiology; D005260:Female; D005787:Gene Frequency; D006801:Humans; D008016:Life Change Events; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D013315:Stress, Psychological / Q000150:complications / Q000235:genetics
D011965:Receptors, Glucocorticoid