title: A genome-wide identified risk variant for PTSD is a methylation quantitative trait locus and confers decreased cortical activation to fearful faces.
abstract: Genetic factors appear to be highly relevant to predicting differential risk for the development of post-traumatic stress disorder (PTSD). 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, β = 31.34, P = 1.28 × 10(-8) ) 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 = 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 = 0.002). Further, the risk allele of rs717947 was associated with decreased medial and dorsolateral cortical activation to fearful faces (N = 53, P < 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.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia.
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Almli
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Stevens
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia.
authors.forename: Alicia K
authors.initials: AK
authors.lastname: Smith
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia.
authors.forename: Varun
authors.initials: V
authors.lastname: Kilaru
authors.affiliation: Department of Psychiatry, University Medical Center, New York, New York.
authors.forename: Qian
authors.initials: Q
authors.lastname: Meng
authors.affiliation: Mental Health Care Center, James J. Peters Veterans Affairs Medical Center, Bronx, New York/Traumatic Stress Studies Division, New York, New York.
authors.forename: Janine
authors.initials: J
authors.lastname: Flory
authors.affiliation: Department of Psychiatry, New York University, Steven and Alexandra Cohen Veterans Center for Posttraumatic Stress and Traumatic Brain Injury, New York, New York.
authors.forename: Duna
authors.initials: D
authors.lastname: Abu-Amara
authors.affiliation: Integrative Systems Biology, US Army Center for Environmental Health Research, Fort Detrick, Maryland.
authors.forename: Rasha
authors.initials: R
authors.lastname: Hammamieh
authors.affiliation: Advanced Biomedical Computing Center, Frederick National Laboratory for Cancer Research/SAIC-Frederick Inc., Frederick, Maryland.
authors.forename: Ruoting
authors.initials: R
authors.lastname: Yang
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia.
authors.forename: Kristina B
authors.initials: KB
authors.lastname: Mercer
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia.|Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Binder
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia.|Department of Veterans Affairs Medical Center, Clinical Psychologist, Mental Health Service Line, Atlanta, Georgia.
authors.forename: Bekh
authors.initials: B
authors.lastname: Bradley
authors.affiliation: Department of Psychiatry, University of California, San Francisco, California.
authors.forename: Steven
authors.initials: S
authors.lastname: Hamilton
authors.affiliation: Integrative Systems Biology, US Army Center for Environmental Health Research, Fort Detrick, Maryland.
authors.forename: Marti
authors.initials: M
authors.lastname: Jett
authors.affiliation: Mental Health Care Center, James J. Peters Veterans Affairs Medical Center, Bronx, New York/Traumatic Stress Studies Division, New York, New York.
authors.forename: Rachel
authors.initials: R
authors.lastname: Yehuda
authors.affiliation: Department of Psychiatry, New York University, Steven and Alexandra Cohen Veterans Center for Posttraumatic Stress and Traumatic Brain Injury, New York, New York.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Marmar
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia.|Howard Hughes Medical Institute, Chevy Chase, Maryland.
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Ressler
mesh_terms: D000328:Adult; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000235:genetics*; D005145:Face / Q000502:physiology*; D005149:Facial Expression; D005239:Fear; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics; D012307:Risk Factors; D013313:Stress Disorders, Post-Traumatic / Q000235:genetics* / Q000523:psychology; D014728:Veterans / Q000523:psychology
keywords: GWAS; PTSD; epigenetic; fMRI; meQTL