Influence of child abuse on adult depression: moderation by the corticotropin-releasing hormone receptor gene

Abstract

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.

Figure 1

Main and interaction effects of CRHR1 single-nucleotide polymorphisms (SNPs) with child abuse on adult depression. A, CRHR1 linkage disequilibrium (LD) map demonstrating the physical location (arrows) and LD pattern of the selected CRHR1 SNPs. For initial genotyping, we selected 15 SNPs covering the gene from the promoter region to the 3′ end of the gene, with an average intermarker distance of 4.1 kilobases (kb) over a total region of 57 kb. The x-axis shows the position on chromosome 17. Ten of these SNPs had a minor allele frequency greater than 5.0% and were thus included in the analysis. The lower part shows an LD plot generated with Haploview using r as the measure of LD, which ranges from 1 (or complete LD, indicated by black squares) to 0 (or absence of LD, indicated by white squares). In our population, we observed moderate LD in this gene, especially in the part containing the coding regions with 2 separate blocks of LD according to the confidence interval method. B, Main genetic effects. The P values (log scale) for the main genetic effect (for a model containing SNP genotype, Childhood Trauma Questionnaire scores, age, and sex as independent variables and Beck Depression Inventory scores as outcome) for all of the genotyped subjects (n=422), subjects with no to mild child abuse (n=262), and subjects with moderate to severe child abuse (n=160). Concordant with a gene × environment interaction effect, the main genetic effect is carried by individuals with moderate to severe child abuse and is stronger than in the whole sample, whereas no SNPs significant in the whole sample remain significant in the group with no to mild child abuse. C, Interaction effects. The y-axis shows the P value (log scale) for the interaction effect of the 10 SNPs that were present with a minor allele frequency greater than 5.0%. Horizontal lines indicate P=.05 (nominally significant) and P=.0094 (significance level after correction for multiple testing as described in the text).

Figure 2

Child abuse interacts with the CRHR1 genotype to enhance risk for depression in adults. A, Mean Beck Depression Inventory (BDI) scores (n = 476) are predicted by continuous scores on the Childhood Trauma Questionnaire (CTQ) physical, sexual, and emotional abuse scales divided into quartiles (quartile 1: CTQ score = 15.0–17.5 [n = 117]; quartile 2: CTQ score = 17.5–22.0 [n = 112]; quartile 3: CTQ score = 22.0–31.0 [n = 123]; quartile 4: CTQ score > 31 [n = 124]). The error bars indicate SEM. The overall analysis of variance comparing the 4 groups on the BDI was significant (F_3,472 = 37.12; P <.001). Post hoc analysis indicated significant differences (P <.001) between all pairs of groups except for between groups 2 and 3. Effect of rs7209436 (B), rs110402 (C), and rs242924 (D) genotypes and child abuse on adult depression. Error bars indicate SEM. The sample sizes for no to mild child abuse and moderate to severe child abuse are as follows: rs7209436: CC, 110 and 84, respectively; CT, 115 and 61, respectively; TT, 23 and 9, respectively (B); rs110402: GG, 108 and 84, respectively; AG, 114 and 61, respectively; AA, 23 and 9, respectively (C); and rs242924: GG, 112 and 87, respectively; GT, 111 and 60, respectively; TT, 24 and 10, respectively (D). P values of significance (based on conservative linear permutation analyses) for the main effect of genotype in the moderate to severe abuse group are shown.

Figure 3

Effect of rs242940 (A), rs173365 (B), rs4792887 (C), and rs242948 (D) genotypes and child abuse on adult depression. Error bars indicate SEM. The sample sizes for no to mild child abuse and moderate to severe child abuse are as follows: rs242940: AA, 98 and 74, respectively; AG, 113 and 69, respectively; GG, 31 and 13 respectively (A); rs173365: GG, 79 and 56, respectively; AG, 114 and 78, respectively; AA, 51 and 21, respectively (B); rs4792887: CC, 107 and 58, respectively; CT, 105 and 70, respectively; TT, 29 and 26, respectively (C); and rs242948: GG, 84 and 57, respectively; GT, 107 and 79, respectively; TT, 64 and 22, respectively (D). P values of significance for the main effect of genotype in the moderate to severe abuse group are shown.

Figure 4

Effect of estimated CRHR1 haplotypes and child abuse on adult depressive symptoms. The frequencies of the estimated individual haplotypes within the first linkage disequilibrium block (A) and of the 3 most significant single-nucleotide polymorphisms (SNPs) (B). C, The effects of the estimated copy numbers of specific haplotypes on adult depression in the presence or absence of moderate to severe child abuse. Error bars indicate SEM. Only haplotypes with an estimation likelihood greater than 95.0% were included in the analysis. The sample sizes for no to mild child abuse and moderate to severe child abuse were as follows: TCA haplotype: 0 copies, 107 and 82, respectively; 1 copy, 109 and 60, respectively; 2 copies, 21 and 9, respectively; TAT haplotype: 0 copies, 118 and 91, respectively; 1 copy, 106 and 54, respectively; 2 copies, 19 and 9, respectively. P values of significance for the interaction effect of haplotype in the moderate to severe abuse group are shown. D, A graphical representation of the number of copies of the TAT haplotype in a smaller but ethnically and socioeconomically separate sample. In this separate sample, the best SNP haplotype frequencies were 41.6% for TAT and 56.0% for CGG. The frequencies of TAT haplotypes are shown within child abuse groups for those with no history of major depressive disorder (MDD) and those with a lifetime history of MDD. The protective alleles appear to be present at a higher rate in those with moderate to severe child abuse who have no lifetime MDD compared with those with a lifetime history of MDD.