PTSDgene database

Pathway Enrichment Analysis Protein-Protein Interaction Analysis

Study Report

Study Information

Basic Info

Reference	Liberzon, I.,2014 PMID: 25162199
Citation	Liberzon, I., et al. (2014). "Interaction of the ADRB2 gene polymorphism with childhood trauma in predicting adult symptoms of posttraumatic stress disorder." JAMA Psychiatry 71(10): 1174-1182.
Phenotype	PTSD symptoms, Intrusive symptoms, Hyperarousal symptoms, Avoidance symptoms
Trauma	Various
Study Design	Case-control
Study Type	Candidate gene association study, Gene-environment interaction study
Sample Size	810 soldiers
SNP/Marker Size	3,755 SNPs
Predominant Ethnicity	Black, Caucasian
Population	European ancestry, African American
Gender	Discovery cohort: 84.3% male. Replication cohort: 30.1% male.
Age	18 years or older

Detail Info

Sample Diagnosis	DSM-IV
Related Diagnostic Tools	Adverse Childhood Events (ACEs), the PTSD Checklist (PCL), Clinician-Administered PTSD Scale, PTSD Symptom Scale
Sample Status	The discovery cohort included 810 active duty Ohio National Guard soldiers. Participants of non-European ancestry by principal components analysis (PCA) (n = 38) or with no lifetime trauma exposure (n = 57) were excluded, leaving 715 trauma-exposed soldiers. The replication cohort included 2083 trauma-exposed persons, primarily African American women with low levels of income and education, enrolled in the Grady Trauma Project at Emory University.
Controls Exposed	NA
Replication Size	2,083 civilians
Result Summary	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-value = 1.02 x 10?5, significant after correction for multiple comparisons). The rs2400707 A allele was associated with relative resilience to childhood adversity. An rs2400707 x childhood trauma interaction predicting adult PTSD symptoms was replicated in the independent predominantly female African American cohort. 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.
Potential Biomarker	None

Genetic result reported by this study

Gene * Environment result reported by this study (count: 4)

Marker	Phenotype	Related Gene	Environment	Statistical Values	Author Comments	Marker's Category
rs2400707	Avoidance symptoms	ADRB2	Adverse childhood event (ACE)	Subscales of PTSD symptoms, avoidance symptoms: mean B=0.82, SD=0.24, t=3.43, P-value=.0006.	All 3 subscales of PTSD symptoms showed rs2400707 x ACE inte...... All 3 subscales of PTSD symptoms showed rs2400707 x ACE interaction, including intrusive and hyperarousal; however, the subscale for avoidance symptoms had the most robust interaction. More...	Significant
rs2400707	Hyperarousal symptoms	ADRB2	Adverse childhood event (ACE)	Subscales of PTSD symptoms, hyperarousal: mean B=0.61, SD=0.20, t=3.07, P-value=.002.	All 3 subscales of PTSD symptoms showed rs2400707 x ACE inte...... All 3 subscales of PTSD symptoms showed rs2400707 x ACE interaction, including intrusive and hyperarousal; however, the subscale for avoidance symptoms had the most robust interaction. More...	Significant
rs2400707	PTSD symptoms	ADRB2	Adverse childhood event (ACE)	Linear regression model controlling for adult trauma exposure, the SNP x ACE interaction: mean unstandardized estimate B= 3.07, SD=0.69, beta=0.243, t=4.48, P-value=1.02-5e. Stratification of the sample by ACEs in persons with 2 or more reported categories of ACEs:n=93, mean B =?6.44, SD=2.08, t=?3.10, P-value=.003. Secondary analysis of binary logistic regression of PTSD caseness: rs2400707 x ACE interaction: OR=0.54, P-value=5.16-4e. Addition of PCs of rs2400707: P-value=1.11-5e. The rs2407007 x ACE interaction in the association with PTSD symptoms in the Grady Trauma Project: mean B=1.80, SD=0.54, t=3.328, P-value=.0009; when using robust standard errors: mean B=1.81, SD=0.60, t=3.02, P-value=.0026 after controlling for sex and adult trauma exposure: mean B=1.58, SD=0.50, t=3.15, P-value=.0017 and after controlling for the 10 PCs: mean B=1.55, SD=0.51, t=3.06, P-value=.0022. In persons with 2 or more reported ACEs: n=197, mean B=?5.34, SD=1.35, t=3.95, P-value=.00011).	Significant associations were detected for the SNP x ACE int...... Significant associations were detected for the SNP x ACE interaction term in rs2400707. Permutation analysis of the SNP x ACE interaction term further confirmed a significant association with rs2400707 (P-value < .05 corrected for multiple comparisons). As shown in Figure 1A, rs2400707 AA homozygotes demonstrated lower levels of PTSD symptoms in the presence of 2 or more categories of reported childhood adversity in the discovery cohort. Stratification of the sample by ACEs showed an effect of rs2400707 only in persons with 2 or more reported categories of ACEs. Although our primary focus was on continuous measures of PTSD severity, a secondary analysis of binary logistic regression of PTSD caseness confirmed an rs2400707 x ACE interaction, indicating that the A allele is protective in terms of adult PTSD symptoms on categorical PTSD diagnosis. Addition of PCs did not alter the significant association of rs2400707. The rs2407007 x ACE interaction in the association with PTSD symptoms in the Grady Trauma Project remained significant when using robust standard errors after controlling for sex and adult trauma exposure and after controlling for the 10 PCs. Again, an effect of rs2400707 was found only in persons with 2 or more reported ACEs. We tested the same model (linear regression of SNP, ACEs, adult trauma, and SNP x ACE and SNP x adult trauma interaction terms) in the combined data set (adjusting symptom severity measures to the same scale) of both the discovery and replication cohorts. We found that the rs2400707 x ACE interaction term had a mean. More...	Significant
rs2400707	Intrusive symptoms	ADRB2	Adverse childhood event (ACE)	Subscales of PTSD symptoms, intrusive: mean B=0.47, SD=0.17, t=2.79, P-value=.005.	All 3 subscales of PTSD symptoms showed rs2400707 x ACE inte...... All 3 subscales of PTSD symptoms showed rs2400707 x ACE interaction, including intrusive and hyperarousal; however, the subscale for avoidance symptoms had the most robust interaction. More...	Significant