Bradley, R.G., E.B. Binder, M.P. Epstein, et al. Influence of Child Abuse on Adult Depression: Moderation by the corticotropin-releasing hormone receptor gene. Arch Gen Psychiatry, 65(2), 190 (February, 2008).
The hypothalamus-pituitary-adrenal axis has long been implicated in the normal and pathological responses to stress. The present study takes the linkage a step further by examining the potential influence of genetic variability in the corticotropin-releasing hormone (CRH) receptor on susceptibility to depression in adulthood, following severe stress in childhood.
The gene for the CRH type 1 receptor was analyzed in samples from 422 low-income adults, primarily of African American ancestry who completed psychological evaluations for child abuse and depression. The results identified 10 single nucleotide polymorphisms (SNPs) of interest for a gene x environment analysis. That evaluation narrowed the field to seven SNPs that showed a significant interaction with child abuse for the prediction of adult depression. After correcting for multiple testing, two CRHR1 SNPs, rs110402 and rs7209436, continued to show a significant interaction with child abuse.
Further examination of the two SNPs found that they had a protective effect on the severity of adult depressive symptoms. Individuals who were homozygous for the common alleles had the highest scores (22.33 to 22.49) on the Beck Depression Inventory (BDI), indicating moderate depressive symptoms, while heterozygous individuals had significantly lower BDI scores (16.31 to 16.39). Individuals who were homozygous for the rare alleles had a mean BDI score of 10.22, indicating low-to-moderate levels of depressive symptoms, despite the presence of at least one type of moderate-to-severe child abuse. This average was comparable to that observed for individuals who were in the no/mild abuse group.
CRHR1 haplotypes showed a similar gene x environment interaction, with a specific haplotype (involving SNPs at rs7209436, rs4792887, and rs110402) exhibiting protection in a dose-dependent manner. Moreover, genetic ancestry was found not to correlate with either the extent of child abuse or the adult BDI scores.
The validity of the genetic analysis was supported by a similar evaluation of individuals with a different ethnic and socioeconomic background than the initial group. Five CRHR1 SNPs were examined, and two alleles, rs7209436 and rs242940, were found to occur in 35% of the individuals with child abuse, but no major depressive symptoms.
The results of this study are consistent with the hypothesis that hyperactivity of the hypothalamic-pituitary-adrenal axis, stemming from early life stress, may form the physiological basis for elevated risk of depression in adulthood. They even suggest heritable differences in CRH-mediated neurotransmission protect or predispose individuals to durable effects of stress in childhood. Thus, the data provides a compelling rationale for the use of CRH-related drug therapy for some patients suffering from depression.
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