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

作者：Almli Lynn M; Stevens Jennifer S; Smith Alicia K; Kilaru Varun; Meng Qian; Flory Janine; Abu Amara Duna; Hammamieh Rasha; Yang Ruoting; Mercer Kristina B; Binder Elizabeth B; Bradley Bekh; Hamilton Steven; Jett Marti; Yehuda Rachel; Marmar Charles R; Ressler Kerry J^*

来源：American Journal of Medical Genetics Part B-Neuropsychiatric Genetics, 2015, 168(5): 327-336.

DOI：10.1002/ajmg.b.32315

• GWAS
• PTSD
• fMRI
• meQTL
• epigenetic

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.

• 出版日期2015-7