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Original Investigation |

Interaction of the ADRB2 Gene Polymorphism With Childhood Trauma in Predicting Adult Symptoms of Posttraumatic Stress Disorder

Israel Liberzon, MD1,2; Anthony P. King, PhD1,2; Kerry J. Ressler, MD, PhD3; Lynn M. Almli, PhD3; Peng Zhang, PhD4; Sean T. Ma, PhD1; Gregory H. Cohen, MPH5; Marijo B. Tamburrino, MD6; Joseph R. Calabrese, MD7; Sandro Galea, MD, MPH5
[+] Author Affiliations
1Department of Psychiatry, University of Michigan, Ann Arbor
2Veterans Affairs Ann Arbor Health System, Ann Arbor, Michigan
3Emory University, Atlanta, Georgia
4The Johns Hopkins University, Baltimore, Maryland
5Columbia University, New York, New York
6University of Toledo, Toledo, Ohio
7Case Western University, Cleveland, Ohio
JAMA Psychiatry. 2014;71(10):1174-1182. doi:10.1001/jamapsychiatry.2014.999.
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Importance  Posttraumatic stress disorder (PTSD), while highly prevalent (7.6% over a lifetime), develops only in a subset of trauma-exposed individuals. Genetic risk factors in interaction with trauma exposure have been implicated in PTSD vulnerability.

Objective  To examine the association of 3755 candidate gene single-nucleotide polymorphisms with PTSD development in interaction with a history of childhood trauma.

Design, Setting, and Participants  Genetic association study in an Ohio National Guard longitudinal cohort (n = 810) of predominantly male soldiers of European ancestry, with replication in an independent Grady Trauma Project (Atlanta, Georgia) cohort (n = 2083) of predominantly female African American civilians.

Main Outcomes and Measures  Continuous measures of PTSD severity, with a modified (interview) PTSD checklist in the discovery cohort and the PTSD Symptom Scale in the replication cohort.

Results  Controlling for the level of lifetime adult trauma exposure, we identified the novel association of a single-nucleotide polymorphism within the promoter region of the ADRB2 (Online Mendelian Inheritance in Man 109690) gene with PTSD symptoms in interaction with childhood trauma (rs2400707, P = 1.02 × 10−5, significant after correction for multiple comparisons). The rs2400707 A allele was associated with relative resilience to childhood adversity. An rs2400707 × childhood trauma interaction predicting adult PTSD symptoms was replicated in the independent predominantly female African American cohort.

Conclusions and Relevance  Altered adrenergic and noradrenergic function has been long believed to have a key etiologic role in PTSD development; however, direct evidence of this link has been missing. The rs2400707 polymorphism has been linked to function of the adrenergic system, but, to our knowledge, this is the first study to date linking the ADRB2 gene to PTSD or any psychiatric disorders. These findings have important implications for PTSD etiology, chronic pain, and stress-related comorbidity, as well as for both primary prevention and treatment strategies.

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Figure 1.
Interaction of ADRB2 Single-Nucleotide Polymorphism rs2400707 With Childhood Adversity in Adult Posttraumatic Stress Disorder

Exposure to childhood adversity is coded 0 for no reported abuse (521 in the discovery cohort and 1370 in the replication cohort), 1 for 1 category reported (101 in the discovery cohort and 516 in the replication cohort), or 2 for 2 or more forms of child abuse reported (93 in the discovery cohort and 197 in the replication cohort). The PTSD Checklist (PCL) and PTSD Symptom Scale (PSS) scores are continuous measures of posttraumatic stress disorder. A, Discovery cohort (n = 715, P = 1.02 × 10−5 for interaction). B, Replication cohort (n = 2083, P = .0009 for interaction).

Graphic Jump Location
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Figure 2.
Linkage Disequilibrium and Haplotype Analysis of the ADRB2 Locus

A, ADRB2 locus linkage disequilibrium map demonstrating the physical location (lines) and linkage disequilibrium pattern of the selected ADRB2 single-nucleotide polymorphisms within the region in proximity to the most significant SNP (rs2400707), a 47-kilobase region in chromosome 5. The x-axis shows the position on chromosome 5. The lower part shows a linkage disequilibrium plot generated with Haploview (http://www.broadinstitute.org/scientific-community/science/programs/medical-and-population-genetics/haploview/haploview) using R2 as the measure of linkage disequilibrium. B, Three common haplotypes in the ADRB2 promoter region and the observed frequency in the discovery cohort.

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