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
Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia.
Department of Psychiatry, University Medical Center, New York, New York.
Am J Med Genet B Neuropsychiatr Genet. 2015 Jul;168B(5):327-36. doi: 10.1002/ajmg.b.32315. Epub 2015 May 18.
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.
遗传因素似乎与预测创伤后应激障碍（PTSD）发展的差异风险高度相关。在一个发现样本中，我们对一小群军人（系统生物学PTSD生物标志物联盟；SBPBC，N = 147）进行了PTSD的全基因组关联研究（GWAS），该样本被设计为近期返回的、有或无与战斗相关PTSD的高暴露退伍军人的病例对照样本。在4号染色体p15处发现了一个全基因组显著的单核苷酸多态性（SNP），rs717947（N = 147，β = 31.34，P = 1.28×10^(-8)），它与PTSD的金标准诊断指标（临床医生管理的PTSD量表）相关。我们在一个外部样本，即一个更大的城市社区队列（格雷迪创伤项目，GTP，N = 2006）中进行了重复和后续研究，以确定这种风险变异的稳健性和假定功能。在GTP重复样本中，SNP rs717947与女性的PTSD诊断相关（N = 2006，P = 0.005），但与男性无关。在GTP重复样本（N = 157，P = 0.002）中，还发现SNP rs717947是一个甲基化数量性状位点（meQTL）。此外，在GTP重复样本中，rs717947的风险等位基因与对恐惧面孔的内侧和背外侧皮质激活减少相关（N = 53，P < 0.05）。这些数据确定了一个全基因组显著的多态性，它赋予了PTSD风险，在重复样本中，该多态性与差异表观遗传调控以及对恐惧的差异皮质反应相关。这些结果可能为理解PTSD的遗传和表观遗传调控以及导致该疾病的中间表型提供新的见解。
