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Am J Med Genet B Neuropsychiatr Genet. 2015 Jul;168B(5):327-36. doi: 10.1002/ajmg.b.32315. Epub 2015 May 18.

A genome-wide identified risk variant for PTSD is a methylation quantitative trait locus and confers decreased cortical activation to fearful faces.

Author information

1
Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia.
2
Department of Psychiatry, University Medical Center, New York, New York.
3
Mental Health Care Center, James J. Peters Veterans Affairs Medical Center, Bronx, New York/Traumatic Stress Studies Division, New York, New York.
4
Department of Psychiatry, New York University, Steven and Alexandra Cohen Veterans Center for Posttraumatic Stress and Traumatic Brain Injury, New York, New York.
5
Integrative Systems Biology, US Army Center for Environmental Health Research, Fort Detrick, Maryland.
6
Advanced Biomedical Computing Center, Frederick National Laboratory for Cancer Research/SAIC-Frederick Inc., Frederick, Maryland.
7
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
8
Department of Veterans Affairs Medical Center, Clinical Psychologist, Mental Health Service Line, Atlanta, Georgia.
9
Department of Psychiatry, University of California, San Francisco, California.
10
Howard Hughes Medical Institute, Chevy Chase, Maryland.

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.

KEYWORDS:

GWAS; PTSD; epigenetic; fMRI; meQTL

PMID:
25988933
PMCID:
PMC4844461
DOI:
10.1002/ajmg.b.32315
[Indexed for MEDLINE]
Free PMC Article

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