PTSDgene database

Pathway Enrichment Analysis Protein-Protein Interaction Analysis

Study Report

Study Information

Basic Info

Reference	Almli, L. M.,2015 PMID: 25988933
Citation	Almli, L. M., et al. (2015). "A genome-wide identified risk variant for PTSD is a methylation quantitative trait locus and confers decreased cortical activation to fearful faces." Am J Med Genet B Neuropsychiatr Genet 168B(5): 327-336.
Phenotype	PTSD Symptoms as measured by the quantitave CAPS scores
Trauma	Combat veterans
Study Design	Case-control
Study Type	Genome-wide association study
Sample Size	63 PTSD and 84 controls
SNP/Marker Size	557,423 SNPs
Predominant Ethnicity	Caucasian, Black
Population	SBPBC Cohort: 38.8%Hispanic, 4.1% Non-hispanic Asian, 23.8% Non-hispanic black, 30.6% Non-hispanic white, 2.7% Non-hispanic other. Replication Cohort: African-American.
Gender	SBPBC Cohort(N=147):130 (88.4%) male. Replication Cohort: 2006 female and 862 male.
Age	SBPBC Cohort: mean age=32.8 years, SD=8.0. Replication Cohort:adults.

Detail Info

Sample Diagnosis	DSM, DSM-IV
Related Diagnostic Tools	Doctoral level clinical psychologists conducted structured diagnostic interviews. The Clinician-Administered PTSD Scale (CAPS). The Structured Clinical Interview for DSM-IV Diagnosis (Ventura et al., 1998). The military version of the PTSD Checklist (PCL-M) (Weathers et al., 2013), and the Beck depression index (BDI) (Beck et al., 1961). Modified PTSD Symptom Scale (PSS) (Falsetti et al., 1993).
Sample Status	Discovery Cohort:Participants were recruited at New York University Langone Medical Center and Icahn School of Medicine at Mount Sinai and from New York City Veteran Affairs medical centers at Manhattan and Bronx, as well as other veteran service organizations and the community. General inclusion criteria include being a US veteran who served in Operation Enduring Freedom in Afghanistan and/or Operation Iraqi Freedom, between the age of 20 and 60 years, being able to understand the protocol and willing to provide written informed consent. Consistent with the goal of having extreme phenotypes, with PTSD being the primary difference between groups, exclusion criteria included loss of consciousness for more than 10?min, neurological disorders, current alcohol and substance abuse disorders, suicidality, lifetime history of any psychiatric disorder with psychotic features, bipolar disorder or obsessive-compulsive disorder. After clinical screening, subjects who met the diagnosis criteria for PTSD with CAPS score >40 were included in the PTSD group and those with CAPS score <20 were included in the control group. These cut-offs were chosen to ensure clinically significant levels of symptomatology in the cases, and to exclude sub-threshold cases in the control group. Because of the nature of warzone trauma and the recruitment feasibility of combat veterans, PTSD subjects in the present study were chronic cases, and both groups had undergone prolonged warzone exposure. Replication Cohort:The replication cohort consisted of study participants from Grady Memorial Hospital (Atlanta, Georgia) as part of the GTP. As previously shown [Ressler et al., 2011], these participants were adult, primarily female, highly traumatized and impoverished, with high rates of PTSD.
Controls Exposed	Yes
Replication Size	urban community cohort (Grady Trauma Project, GTP):N=2868
Result Summary	In a discovery sample, we conducted a genome-wide association study (GWAS) for PTSD using a small military cohort (Systems Biology PTSD Biomarkers Consortium; SBPBC, N=147) that was designed as a case-controlled sample of highly exposed, recently returning veterans with and without combat-related PTSD. A genome-wide significant single nucleotide polymorphism (SNP), rs717947, at chromosome 4p15 (N=147,B=31.34, P-value=1.28E-08) was found to associate with the gold-standard diagnostic measure for PTSD (the Clinician Administered PTSD Scale). We conducted replication and follow-up studies in an external sample, a larger urban community cohort (Grady Trauma Project, GTP, N=2006), to determine the robustness and putative functionality of this risk variant. In the GTP replication sample, SNP rs717947 associated with PTSD diagnosis in females (N=2006, P-value=0.005), but not males. SNP rs717947 was also found to be a methylation quantitative trait locus (meQTL) in the GTP replication sample (N=157, P-value=0.002). Further, the risk allele of rs717947 was associated with decreased medial and dorsolateral cortical activation to fearful faces (N=53, P-value<0.05) in the GTP replication sample. These data identify a genome-wide significant polymorphism conferring risk for PTSD, which was associated with differential epigenetic regulation and with differential cortical responses to fear in a replication sample. These results may provide new insight into understanding genetic and epigenetic regulation of PTSD and intermediate phenotypes that contribute to this disorder.
Potential Biomarker	These results may provide new insight into understanding genetic and epigenetic regulation of PTSD and intermediate phenotypes that contribute to this disorder.

Genetic result reported by this study

Normal genetic result reported by this study (count: 10)

Marker	Phenotype	Related Gene	Statistical Values	Author Comments	Marker's Category
rs4239715	PTSD Symptoms as measured by the quantitave CAPS scores	Intergenic (approx distance to downstream gene: 1069kb, PCSK2)	In (SBPBC cohort) discovery stage: (sex and top three principal components as covariates) B (SE)=18.00 (3.67), P-value=2.51E-06.	None None	Trend
rs4773155	PTSD Symptoms as measured by the quantitave CAPS scores	COL4A2	In (SBPBC cohort) discovery stage: (sex and top three principal components as covariates) B (SE)=20.03 (3.97), P-value=1.35E-06.	None None	Trend
rs17104851	PTSD Symptoms as measured by the quantitave CAPS scores	Intergenic (approx distance to downstream gene: 473kb, RAP1B)	In (SBPBC cohort) discovery stage: (sex and top three principal components as covariates) B (SE)=-23.74 (4.83), P-value=2.47E-06.	None None	Trend
rs3181035	PTSD Symptoms as measured by the quantitave CAPS scores	Intergenic (approx distance to downstream gene: 458kb, RAP1B)	In (SBPBC cohort) discovery stage: (sex and top three principal components as covariates) B (SE)=-23.74 (4.83), P-value=2.47E-06.	None None	Trend
rs717947	PTSD Symptoms as measured by the quantitave CAPS scores	Intergenic (approx distance to downstream gene: 2629kb, DTHD1)	In (SBPBC cohort) discovery stage: (sex and top three principal components as covariates) N=147, B (SE)=31.34 (5.19), P-value=1.28E-08; categorical PTSD diagnosis measure: OR=8.6, 95%CI=3.5-21.6, P-value=3.84E-06; self-reported PTSD symptoms: N=147, B (SE)=17.37 (3.10), P-value=1.203E-07. The main effect of rs717947 for CAPS scores after controlling for early childhood trauma exposure or overall negative life events: [Covariate: Early Trauma Inventory, N=146, B (SE)=31.5 (5.2), P-value=1.13E-08; Negative life events, N=146, B (SE)=24.9 (4.3), P-value=3.29E-08]. In (GTP cohort) replication stage: in female, N=2006, OR=1.25, CI=1.1-1.5, P-value=0.005; in male, N=862, P-value=0.37	The GWAS yielded one genome-wide significant SNP, rs717947 w...... The GWAS yielded one genome-wide significant SNP, rs717947 with current CAPS score. Sensitivity analysis covarying for self-reported race instead of the top three principal components showed similar results for the association between rs717947 and PTSD symptoms (data not shown). Follow-up analysis of SNP rs717947 showed that this SNP is robust to different measures of PTSD, both categorical and self-reported measures. In both cases, the main effect of rs717947 remained genome-wide significant for CAPS scores after controlling for early childhood trauma exposure or overall negative life events. In (GTP cohort) replication stage: in females, we found that carriers of the risk allele (T) had increased odds of PTSD diagnosis; in contrast, no association was found in males. More...	Significant
rs7684329	PTSD Symptoms as measured by the quantitave CAPS scores	Intergenic (approx distance to downstream gene: 2536kb, DTHD1)	In (SBPBC cohort) discovery stage: (sex and top three principal components as covariates) B (SE)=27.04 (5.38), P-value=1.47E-06.	None None	Trend
rs6080131	PTSD Symptoms as measured by the quantitave CAPS scores	Intergenic (approx distance to downstream gene: 1101kb, PCSK2)	In (SBPBC cohort) discovery stage: (sex and top three principal components as covariates) B (SE)=18.95 (3.85), P-value=3.48E-06.	None None	Trend
rs6080152	PTSD Symptoms as measured by the quantitave CAPS scores	Intergenic (approx distance to downstream gene: 1065kb, PCSK2)	In (SBPBC cohort) discovery stage: (sex and top three principal components as covariates) B (SE)=-18.95 (3.90), P-value=3.14E-06.	None None	Trend
rs13104973	PTSD Symptoms as measured by the quantitave CAPS scores	Intergenic (approx distance to downstream gene: 2472kb, DTHD1)	In (SBPBC cohort) discovery stage: (sex and top three principal components as covariates) B (SE)=29.04 (5.23), P-value=1.35E-07.	None None	Trend
rs13113036	PTSD Symptoms as measured by the quantitave CAPS scores	Intergenic (approx distance to downstream gene: 2148kb, DTHD1)	In (SBPBC cohort) discovery stage: (sex and top three principal components as covariates) B (SE)=23.19 (4.92), P-value=5.75E-06.	None None	Trend