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, =31.34,
P=1.28x10(-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. (c) 2015 Wiley Periodicals, Inc.
