Analysis of RORA and other candidate genes in PTSD

描述(由申请人提供)： 创伤后应激障碍(PTSD)是一种精神障碍，其特征是在暴露于心理创伤事件后发生严重的认知、行为和生理功能障碍。暴露后，在普通人群中患创伤后应激障碍的概率估计约为10%，尽管在作战退伍军人中观察到的比例更高(即接近25%)。包括遗传在内的许多因素都会导致这种疾病的发生。双胞胎研究表明，创伤后应激障碍风险的30%-70%的变化是由遗传因素造成的。在最近的一篇论文中(Logue等人，2012)；我们报告了第一个发表的关于创伤后应激障碍的全基因组关联研究的结果。我们发现视黄醇相关孤儿受体α(RORA)基因的单核苷酸多态性(SNPs)在全基因组范围内与创伤后应激障碍显著相关，提示该基因是创伤后应激障碍的重要危险基因。RORA曾被认为是注意力缺陷多动障碍、双相情感障碍、自闭症和抑郁症的危险因素。众所周知，该基因还影响昼夜节律、激素调节和神经保护。基于此，我们认为，我们的发现表明RORA参与了创伤后应激障碍的发展，这可能为未来对该疾病的研究指明了一条新的、潜在的重要途径。因此，建议的目的是对RORA和PTSD进行更详细的基因分析。具体地说，我们建议对RORA(以及其他几个PTSD候选基因)进行广泛的测序，以确定这些基因中与PTSD风险相关的完整遗传变异阵列，然后使用血淋巴细胞RNA进行全基因组表达分析。我们还打算通过分析其他与创伤后应激障碍相关的共病表型和检查可能的基因-基因相互作用来继续我们的GWAS发现。这些发现有望为RORA和其他候选基因在创伤后应激障碍的发展中所起的作用提供新的线索。

DESCRIPTION (provided by applicant): Posttraumatic Stress Disorder (PTSD) is a psychiatric disorder characterized by profound disturbances in cognitive, behavioral and physiological functioning that occurs following exposure to a psychologically traumatic event. After exposure, the probability of developing PTSD is estimated to be approximately 10% in the general population, although higher rates (i.e., closer to 25%) have been observed among combat Veterans. Numerous factors contribute to the probability of developing the disorder including heredity. Twin studies have shown that a 30-70% of variation in PTSD risk is explained by genetic factors. In a recent paper (Logue et al, 2012); we reported results from the first published genome-wide association study (GWAS) for PTSD. We found that single nucleotide polymorphisms (SNPs) in the retinoid-related orphan receptor alpha (RORA) gene showed genome-wide significant associations with PTSD suggesting that this gene is an important risk locus for the disorder. RORA has been implicated in prior psychiatric GWAS as a risk factor for attention-deficit hyperactivity disorder, bipolar disorder, autism, and depression. The gene is also known to influence circadian rhythms, hormone regulation, and neuroprotection. Based on this, we believe that our finding implicating RORA in the development PTSD may point to a new and potentially important avenue for future research on the disorder. Therefore, the aim of the proposal is to conduct a more detailed genetic analysis of RORA and PTSD. Specifically, we propose to conduct extensive sequencing of RORA (along with several other PTSD candidate genes) to identify the complete array of genetic variation in these genes associated with PTSD risk and then perform genome- wide expression analysis using blood lymphocyte RNA. We also aim to follow-up our GWAS finding with analysis of additional PTSD-related comorbidity phenotypes and examination of possible gene-gene interactions. Findings are expected to shed new light on the role of RORA and other candidate genes on the development of PTSD.