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Moderation by the Corticotropin-Releasing Hormone Receptor Gene

Rebekah G. Bradley, PhD; Elisabeth B. Binder, MD, PhD; Michael P. Epstein, PhD; Yilang Tang, PhD; Hemu P. Nair, PhD; Wei Liu, PhD; Charles F. Gillespie, MD, PhD; Tiina Berg, PhD; Mark Evces, PhD; D. Jeffrey Newport, MD; Zachary N. Stowe, MD; Christine M. Heim, PhD; Charles B. Nemeroff, MD, PhD; Ann Schwartz, MD; Joseph F. Cubells, MD, PhD; Kerry J. Ressler, MD, PhD

Arch Gen Psychiatry. 2008;65(2):190-200.

Context  Genetic inheritance and developmental life stress both contribute to major depressive disorder in adults. Child abuse and trauma alter the endogenous stress response, principally corticotropin-releasing hormone and its downstream effectors, suggesting that a gene x environment interaction at this locus may be important in depression.

Objective  To examine whether the effects of child abuse on adult depressive symptoms are moderated by genetic polymorphisms within the corticotropin-releasing hormone type 1 receptor (CRHR1) gene.

Design  Association study examining gene x environment interactions between genetic polymorphisms at the CRHR1 locus and measures of child abuse on adult depressive symptoms.

Setting  General medical clinics of a large, public, urban hospital and Emory University, Atlanta, Georgia.

Participants  The primary participant population was 97.4% African American, of low socioeconomic status, and with high rates of lifetime trauma (n = 422). A supportive independent sample (n = 199) was distinct both ethnically (87.7% Caucasian) and socioeconomically (less impoverished).

Main Outcome Measures  Beck Depression Inventory scores and history of major depressive disorder by the Structured Clinical Interview for DSM-IV Axis I Disorders.

Results  Fifteen single-nucleotide polymorphisms spanning 57 kilobases of the CRHR1 gene were examined. We found significant gene x environment interactions with multiple individual single-nucleotide polymorphisms (eg, rs110402, P = .008) as well as with a common haplotype spanning intron 1 (P < .001). Specific CRHR1 polymorphisms appeared to moderate the effect of child abuse on the risk for adult depressive symptoms. These protective effects were supported with similar findings in a second independent sample (n = 199).

Conclusions  These data support the corticotropin-releasing hormone hypothesis of depression and suggest that a gene x environment interaction is important for the expression of depressive symptoms in adults with CRHR1 risk or protective alleles who have a history of child abuse.

Author Affiliations: Atlanta VA Medical Center (Dr Bradley), and Departments of Psychiatry and Behavioral Sciences (Drs Bradley, Binder, Nair, Gillespie, Berg, Evces, Newport, Stowe, Heim, Nemeroff, Schwartz, Cubells, and Ressler) and Genetics (Drs Binder, Epstein, Tang, Liu, and Cubells) and Yerkes National Primate Research Center (Dr Ressler), Emory University School of Medicine, Atlanta, Georgia; and Beijing Institute of Microbiology and Epidemiology, Beijing, China (Dr Liu).

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