Genetic and Epigenetic Dissection of PTSD in African American Veterans

 描述(由申请人提供)： 创伤后应激障碍(PTSD)是一种复杂的焦虑障碍，在暴露于军事或平民创伤压力后发展起来。在美国，创伤后应激障碍影响着大约10%的女性和5%的男性，受影响的个人失业、抑郁、药物滥用和身体健康受损的风险增加。创伤后应激障碍在退伍军人中的比例过高。家庭和双胞胎研究表明，遗传和环境因素都与创伤后应激障碍的风险有关。病例/对照研究已经确定了创伤后应激障碍风险与一些候选基因变异之间的关联；然而，这种关联并没有在多个独立的数据集中一致地重复。我们假设，复制中的这种困难是由于之前的研究未能包括表观遗传变异，也就是未能完全解释基因和环境的相互作用。本申请将解决我们对增加创伤后应激障碍风险因素的认识上的这一差距。我们现有的全基因组关联数据集包括2500多例创伤后应激障碍病例和对照(包括1470名非裔美国人)，对超过250万个基因变异进行了基因分型。我们将在这个数据集中进行关联研究，并将环境影响纳入我们的遗传模型。我们将使用Illumina甲基化阵列测量1470名非裔美国人创伤后应激障碍患者和对照组的表观遗传变异，该阵列测量基因组中超过48万个位置的DNA甲基化水平。这些甲基化数据将被独立分析，并与遗传数据一起分析，以确定其在创伤后应激障碍风险中的作用。最后，我们将进行探索性的基因*环境和表观基因组*环境的交互作用分析。通过在我们的遗传变异分析中包括环境和表观遗传因素，我们将对增加创伤后应激障碍风险和严重性的多种因素有更清晰的理解。

 DESCRIPTION (provided by applicant): Posttraumatic stress disorder (PTSD) is a complex anxiety disorder that develops following exposure to either military or civilian traumatic stress. PTSD affects approximately 10% of women and 5% of men in the US, and affected individuals are at increased risk for unemployment, depression, substance abuse, and impaired physical health. PTSD is overrepresented in Veterans. Family and twin studies have implicated both genetic and environmental factors in PTSD risk. Case/control studies have identified associations between PTSD risk and variants in a number of candidate genes; however, such associations have not been consistently replicated in multiple independent datasets. We hypothesize that this difficulty in replication is the result of the failure of previous studies to include epigenetic variation, an to fully account for gene/environment interactions. The present application will address this gap in our knowledge of the factors that increase risk of PTSD. We have an existing genome-wide association dataset of more than 2500 PTSD cases and controls (including 1470 African Americans), genotyped at more than 2.5 million genetic variants. We will conduct association studies in this dataset, and incorporate environmental influences in our genetic models. We will measure epigenetic variation in 1470 African American PTSD patients and controls, using the Illumina methylation arrays that measure DNA methylation levels at more than 480,000 sites across the genome. This methylation data will be analyzed independently, as well as in conjunction with genetic data, to determine its role in PTSD risk. Finally, we will conduct an exploratory gene*environment and epigenome*environment interaction analysis. By including environmental and epigenetic factors in our analysis of genetic variants, we stand to gain a much clearer understanding of the multiple factors that increase both the risk and severity of PTSD.