Interaction of the ADRB2 gene polymorphism with childhood trauma in predicting adult symptoms of posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is a debilitating and highly prevalent (7.6% over a lifetime) consequence of trauma exposure.1,2 Recent large-scale military deployments and high-profile traumatic events have contributed to greater recognition of the PTSD burden both among health professionals3 and the general public.4 Trauma exposure is presumed to constitute a key etiologic factor in PTSD5; however, only a subset of trauma-exposed individuals develops PTSD,2 suggesting that vulnerability and resilience factors might have an important role in PTSD development. Heritable factors and trauma exposure have been implicated in PTSD by twin and family studies,6–8 suggesting that both genetic and environmental factors are involved; however, larger-scale efforts to identify specific genetic factors are relatively nascent. A recent review of the candidate gene studies of PTSD (approximately 40 to date) addressed 18 gene variants9; however, the majority (10 of 18) were based on a single, relatively small discovery cohort each. Only a few (eg, the FKBP5 gene10–14 and the SLC6A4 gene15,16) had more than 1 positive association, showed no reported negative findings, and involved relatively large cohorts. Beyond candidate gene studies, a small genome-wide association study17 (GWAS) identified a single-nucleotide polymorphism (SNP) within the retinoid-related orphan receptor alpha gene (RORA) as associated with PTSD, and a larger GWAS18 identified SNPs near the Tolloid-like 1 gene (TLL1) as associated with PTSD. Given that expected variance contributed by any single genetic factor is small19 and that the likelihood of pleiotropic and polygenic effects in psychiatric disorders is high,20 major effort is required to both replicate the reported findings and to identify novel risk genes if the goal of identifying genetic risk factors for PTSD is to be accomplished. Given the centrality of trauma exposure to the etiology of PTSD, a broad range of environmental exposures has been examined in this context, with early childhood trauma emerging as a risk factor linked to both the incident PTSD and the course of PTSD over time.21,22 Importantly, childhood trauma has been shown to act in interaction with the 2 most consistently replicated PTSD risk alleles in the SLC6A4 and FKBP5 genes,10,13,15,16 suggesting that gene × environment (G × E) approaches utilizing continuous measures of adult PTSD severity might be particularly useful in the study of PTSD pathogenesis. Finally, on the physiological level, while adrenergic and noradrenergic abnormalities have long been believed to have a key etiologic role in PTSD development,23,24 contributing to exaggerated physiological reactivity and hyperarousal symptoms,25–27 direct evidence of genetic variance in noradrenergic and adrenergic function in PTSD has been missing. The PTSD genetic findings so far have mainly implicated serotonin, dopamine, and hypothalamic-pituitary-adrenal axis genes. To address key open questions listed above, we have conducted a candidate gene study in PTSD-relevant pathways, including the adrenergic and noradrenergic systems, using independent discovery and confirmation cohorts and G × E models.