Polymorphisms in CRHR1 and the serotonin transporter loci: gene x gene x environment interactions on depressive symptoms

Abstract

Gene x environment (G x E) interactions mediating depressive symptoms have been separately identified in the stress-sensitive serotonergic (5-HTTLPR) and corticotropin-releasing hormone (CRHR1) systems. Our objective was to examine whether the effects of child abuse are moderated by gene x gene (G x G) interactions between CRHR1 and 5-HTTLPR polymorphisms. We used an association study examining G x G x E interactions of CRHR1 and 5-HTTLPR polymorphisms and measures of child abuse on adult depressive symptomatology. The participant population (N = 1,392) was African-American, of low socioeconomic status (60% with <$1,000/month family income), and with high rates of childhood and lifetime trauma. Depressive symptoms were measured with Beck Depression Inventory (BDI) and history of Major Depression by Structure Clinical Interview based on DSM-IV (SCID). We first replicated an interaction of child abuse and 5-HTTLPR on lifetime SCID diagnosis of major depression in a subsample (N = 236) of the study population-the largest African-American 5-HTTLPR cohort reported to date. We then extended our previously reported interaction with both a CRHR1 SNP (rs110402) and TCA haplotype interacting with child abuse to predict current symptoms (N = 1,059; P = 0.0089). We found that the 5-HTTLPR S allele interacted with CRHR1 haplotypes and child abuse to predict current depressive symptoms (N = 856, P = 0.016). These data suggest that G x E interactions predictive of depressive symptoms may be differentially sensitive to levels of childhood trauma, and the effects of child abuse are moderated by genetic variation at both the CRHR1 and 5-HTTLPR loci and by their G x G interaction.

FIG. 1

Interaction of 5-HTTLLPR S-allele carrier status and CRHR1 TCA haplotype with child abuse to predict adult depression. A: Depression symptoms using the Beck Depression Inventory (BDI) are graphed as a function of 5-HTTLPR SS, SL versus LL carrier status, as a function of level of moderate-to-severe child abuse. We find no significant main or interaction effects. B: Depression symptoms using the BDI are graphed as a function of TCA haplotype (rs7209436, rs4792887, and rs110402) of the CRHR1 gene, as a function of level of moderate-to-severe child abuse, demonstrating a significant interaction effect (P < 0.05). C: Depression symptoms using the BDI are graphed as a function of CRHR1 rs110402 (A-carrier model), as a function of level of moderate-to-severe child abuse, demonstrating a significant interaction effect (P = 0.009).

FIG. 2

Interaction of CRHR1 rs110402 with replicate samples. Depression symptoms using the BDI are graphed as a function of theCRHR1 rs110402 SNP, GG versus AA, AG as a function of level of moderate-to-severe child abuse in the sample reported in Bradley et al. (old) and additional samples reported in this manuscript (new).

FIG. 3

Interaction between 5-HTTLPR S-allele carrier status and CRHR1 TCA haplotype carriers and child abuse on adult depressive symptoms. Panel A: Depression symptoms using the BDI are graphed as a function of 5-HTTLPR and CRHR1 genotype. Left panel: Individuals with 5-HTTLPR LL genotypes are represented with lines representing one or copies versus no copies of the protective TCA CRHR1 haplotype. Right panel: Individuals with 5-HTTLPR SS or SL genotypes are represented with lines representing one or copies versus no copies of the protective TCA CRHR1 haplotype. An overall gene × gene × environment interaction is seen (N = 856, P = .016). Panel B: Representation of the same interaction but grouping the individuals by number of risk variants. No abuse group: N = 159 no risk alleles, N = 115 only 5-HTTLPR s-allele, N = 148 only CRHR1 risk, N = 102 both risk alleles. One type of abuse group: N = 44 no risk alleles, N = 39 only 5-HTTLPR s-allele, N = 69 only CRHR1 risk, N = 44 both risk alleles. Two types of abuse: N = 42 no risk alleles, N = 36 only 5-HTTLPR s-allele, N = 46 only CRHR1 risk, and N = 30 both risk alleles.