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Mol Psychiatry. Author manuscript; available in PMC Mar 1, 2012.
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PMCID: PMC3291097

Association of childhood trauma exposure and GABRA2 polymorphisms with risk of posttraumatic stress disorder in adults

Individuals who experience child abuse are at increased risk for developing posttraumatic stress disorder (PTSD) as a direct result of the abuse and upon exposure to subsequent trauma.1 A recent examination1 of PTSD symptoms in adults found evidence for a significant G × E interaction involving a quantitative measure of child abuse exposure and four single-nucleotide polymorphisms (SNPs) of FKBP5 including two SNPs for which an association of the same alleles with peritraumatic dissociative symptoms in medically ill children had been reported.2 A study3 of gene expression in the peripheral blood of trauma-exposed individuals found that FKBP5 is one of many genes whose upregulation immediately posttrauma is associated with risk for emergent PTSD at 4 months. Investigations46 using maternal care and separation in rodent models of child abuse have observed altered expression of genes encoding proteins involved in the stress response and, in work6 focusing on the glucocorticoid receptor (GR), have elegantly demonstrated that epigenetic mechanisms underlie these changes. Given FKBP5's role in the regulation of GR sensitivity, the G × E interaction associated with PTSD risk is likely a consequence of differential response to posttrauma alterations in gene expression resulting from one or more polymorphisms. Because animal4,5,7 and human3 studies have also found posttrauma changes in the expression of genes encoding GABAA (γ-aminobutyric acid) receptor subunits that affect ligand affinity at the benzodiazepine binding site, we examined whether risk for PTSD is associated with similar G × E interactions involving GABRA2 polymorphisms and childhood trauma exposure.

Interview data from twin and sibling participants (N=2594) in a recently completed family study of adult twins (only one twin from any monozygotic pair was included) with or without a history of childhood trauma were analyzed. These individuals completed a semi-structured diagnostic telephone interview modified from the SSAGA-II8 that assessed Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) PTSD and which included a separate detailed assessment of child abuse modified from the Christchurch Trauma Inventory.9 MPlus10 was used to create five first-order factors for which factor loadings were allowed to vary by gender, each representing a severe childhood stressor assessed in detail (that is, sexual abuse; physical abuse by mother, by father or by other adult household member; emotional and physical partner maltreatment by a parent) from which a single second-order childhood trauma factor was created. The prevalence of PTSD in the sample was 11.5%. In logistic regression analyses that corrected for the inclusion of multiple individuals from families, significant PTSD risk was found to be associated with childhood trauma factor score (CTFS): odds ratio 8.76 (95% confidence interval 6.53–11.75).

GABRA2 genotypic data ≤4 SNPs in any single participant) were available on a subset of 259 individuals (46 of whom met criteria for lifetime PTSD) who were also participants in a linkage study of nicotine use and dependence.11 SNPs were selected based on prior reports of association with alcohol12 and nicotine dependence.13 In preparation for analyses focusing on G × E interactions, logistic regression analyses were performed to evaluate main effects of SNP genotype coded either as number of risk-associated alleles or as separate variables for the presence of one and two alleles. No significant main effects were found for SNP genotype coded in either form, including when CTFS was added to these models. The results of logistic regression analyses that included G × E interactions involving CTFS and SNP genotype while controlling for main effects of CTFS and SNP genotype are displayed in Table 1. Findings across SNPs provide consistent support for G × E interactions involving CTFS and SNP genotype (those for rs279858 fell just below significance) coded as number of risk-associated alleles. When separate variables were coded for the presence of one or two risk-associated alleles, significant G × E interactions are only found for homozygous individuals. Further analyses controlling for DSM-IV nicotine and alcohol dependence diagnoses produced remarkably similar findings (Supplementary Table 1). To ensure that our results are specific to PTSD rather than major depressive disorder (MDD) with which PTSD has considerable comorbidity, we performed similar series of analyses focusing on MDD and found no evidence for significant G × E interactions (results not shown).

Table 1
Risk for PTSD associated with interaction terms involving childhood trauma factor score (CTFS) and GABRA2 SNP genotype ORs and 95% CIs are shown (controlling for main effects of CTFS and genotype)

The strength of our findings and their consistency with prior investigations are extremely encouraging. However, our results must be considered preliminary until they are replicated. Animal and human studies suggest that individuals who experience childhood trauma are likely to undergo epigenetic modifications that alter expression of GABAA receptor subunits affecting ligand affinity at the benzodiazepine receptor binding site.37 The G × E interactions that we observed may have resulted from one or more GABRA2 polymorphisms (the four SNPs are known to be in linkage disequilibrium with r2 values 0.86–0.97) that contributed to PTSD development in those experiencing childhood trauma exposure, perhaps by accentuating the postevent anxiogenic response4,5 and facilitating traumatic memory formation.14 Limitations that must be considered when interpreting our results include the limited number of individuals for whom both phenotypic data and DNAs (hence SNP genotype results) are available. Although their selection through participation in a linkage study of nicotine dependence may have introduced some bias, findings were unchanged in analyses controlling for nicotine dependence. The degree to which our results will be generalizable to samples not enriched for childhood trauma exposure is unclear. Similarly, as a minority of PTSD in our sample arose from traumatic events whose onset occurred after age 17 (28.3%), we do not have adequate power to determine whether our findings reflect risk for incident PTSD with subsequent trauma or primarily for emergent PTSD with childhood trauma. Additional research will be necessary to address these issues and to determine the polymorphism(s) underlying our findings. Our results suggest polymorphisms of genes for which posttrauma expression changes have been observed may provide fertile ground for future genetic studies of PTSD.

Supplementary Material

Supplement Table 1


Supplementary information is available at the Molecular Psychiatry website.


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