Analysis of RORA and other candidate genes in PTSD

RORA和PTSD其他候选基因分析

• 批准号: 8774542
• 负责人: MARK W MILLER
• 金额: --
• 依托单位: VA BOSTON HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8774542
• 关键词: Accidents; Address; Affect; American Psychiatric Association; Attention deficit hyperactivity disorder; Autistic Disorder; Behavioral; Binding; Biochemical; Bioinformatics; Bipolar Disorder; Blood; Candidate Disease Gene; Circadian Rhythms; Cognitive; Collection; Comorbidity; Complement; DNA Sequence; DSM-IV; Data; Development; Diagnosis; Disasters; Disease; Emotional; Emotions; Event; Exposure to; Forcible intercourse; Fright; Gene Expression Profile; Gene Expression Profiling; General Population; Genes; Genetic; Genetic Variation; Genetic study; Genotype; Heredity; Heritability; Individual; Injury; Life; Light; Lymphocyte; Mental Depression; Mental disorders; Military Personnel; Molecular; Molecular Genetics; NR1 gene; Nightmare; Nuclear Hormone Receptors; Orphan; Paper; Pathway interactions; Phenotype; Physiological; Play; Post-Traumatic Stress Disorders; Probability; Process; Proteins; Psychophysiology; Publishing; RNA; Reporting; Research; Retinoids; Risk Factors; Role; Single Nucleotide Polymorphism; Sleep; Stimulus; Stress; Symptoms; Thinking; Trauma; Twin Multiple Birth; Twin Studies; Variant; Veterans; Violence; base; brain cell; combat; disorder risk; experience; follow-up; functional genomics; gene interaction; genetic analysis; genetic risk factor; genetic variant; genome wide association study; genome-wide; hormone regulation; hormone response element; meetings; member; neuroprotection; novel; physical assault; public health relevance; receptor; response; risk variant; sexual assault; traumatic event

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.

描述（由申请人提供）： 创伤后应激障碍 (PTSD) 是一种精神疾病，其特征是在经历心理创伤事件后发生的认知、行为和生理功能严重紊乱。接触后，一般人群患 PTSD 的概率约为 10%，但在退伍军人中观察到更高的比率（即接近 25%）。许多因素都会影响患这种疾病的可能性，其中包括遗传。双胞胎研究表明，30-70% 的 PTSD 风险变异是由遗传因素造成的。在最近的一篇论文中（Logue 等人，2012 年）；我们报告了首次发表的针对 PTSD 的全基因组关联研究 (GWAS) 的结果。我们发现，类维生素A相关孤儿受体α（RORA）基因中的单核苷酸多态性（SNP）显示出全基因组范围内与创伤后应激障碍（PTSD）的显着关联，表明该基因是该疾病的重要风险位点。 RORA 与先前的精神科 GWAS 相关，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。该基因还可以影响昼夜节律、激素调节和神经保护。基于此，我们相信，我们的发现表明 RORA 与 PTSD 的发展有关，可能为未来对该疾病的研究指出一条新的、潜在的重要途径。因此，该提案的目的是对 RORA 和 PTSD 进行更详细的遗传分析。具体来说，我们建议对 RORA（以及其他几个 PTSD 候选基因）进行广泛测序，以确定这些与 PTSD 风险相关的基因的完整遗传变异，然后使用血液淋巴细胞 RNA 进行全基因组表达分析。我们还旨在通过分析其他 PTSD 相关共病表型并检查可能的基因间相互作用来跟踪 GWAS 的发现。研究结果有望为 RORA 和其他候选基因在 PTSD 发展中的作用提供新的线索。

项目成果

Traumatic stress, oxidative stress and post-traumatic stress disorder: neurodegeneration and the accelerated-aging hypothesis.

• DOI: 10.1038/mp.2014.111
• 发表时间: 2014-11
• 期刊: MOLECULAR PSYCHIATRY
• 影响因子: 11
• 作者: Miller, M. W.;Sadeh, N.
• 通讯作者: Sadeh, N.

Dichlorido(methanol-κO)[2-(2-pyridyl-meth-oxy)-1,10-phenanthroline-κN,N',N'']manganese(II).

二氯(甲醇-γO)[2-(2-吡啶基甲氧基)-1,10-菲咯啉-γN,N,N]锰(II)。

• DOI: 10.1107/s1600536808018631
• 发表时间: 2008
• 期刊: Acta crystallographica. Section E, Structure reports online
• 作者: Li,HongLiang;Chao,Hou
• 通讯作者: Chao,Hou

An analysis of gene expression in PTSD implicates genes involved in the glucocorticoid receptor pathway and neural responses to stress.

对 PTSD 基因表达的分析表明，基因涉及糖皮质激素受体途径和应激神经反应。

• DOI: 10.1016/j.psyneuen.2015.03.016
• 发表时间: 2015
• 期刊: Psychoneuroendocrinology
• 影响因子: 3.7
• 作者: Logue,MarkW;Smith,AliciaK;Baldwin,Clinton;Wolf,ErikaJ;Guffanti,Guia;Ratanatharathorn,Andrew;Stone,Annjanette;Schichman,StevenA;Humphries,Donald;Binder,ElisabethB;Arloth,Janine;Menke,Andreas;Uddin,Monica;Wildman,Derek;Galea
• 通讯作者: Galea