A Genome-Wide Identified Risk Variant for PTSD is a Methylation Quantitative Trait Locus and Confers Decreased Cortical Activation to Fearful Faces
ARMY CENTER FOR ENVIRONMENTAL HEALTH RESEARCH FORT DETRICK MD
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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, N147 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 N147, b31.34, P1.2810 -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, N2006, to determine the robustness and putative functionality of this risk variant. In the GTP replication sample, SNP rs717947 associated with PTSD diagnosis in females N2006, P0.005, but not males. SNP rs717947 was also found to be a methylation quantitative trait locus meQTL in the GTP replication sample N157, P0.002. Further, the risk allele of rs717947 was associated with decreased medial and dorsolateral cortical activation to fearful faces N53, P0.05 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.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research