Genome-wide association study of tinnitus in the Million Veterans Program with emphasis on traumatic brain injury

百万退伍军人计划中耳鸣的全基因组关联研究，重点是创伤性脑损伤

• 批准号: 10247446
• 负责人: Allen F. Ryan
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10247446
• 关键词: Age; Age-Years; Aging; Agreement; Anxiety; Anxiety Disorders; Audiology; Auditory; Biological Markers; Brain; Candidate Disease Gene; Cochlea; Cognition Disorders; Cognitive; Cognitive Therapy; Cohort Studies; Collection; Craniocerebral Trauma; Data; Data Set; Development; Diagnosis; Diffuse; Disease; Dizygotic Twins; Ear; Electronic Health Record; Environmental Exposure; Etiology; European; Exposure to; Family Study; Financial compensation; Framingham Heart Study; Future; Genes; Genetic; Genetic Variation; Genotype; Goals; Hearing; Hearing Aids; Hearing Tests; Heritability; Impaired cognition; Individual; Inflammation; Injury; Lead; Major Depressive Disorder; Mental Depression; Mental disorders; Military Personnel; Modeling; Monozygotic twins; Neurologic; Noise; Noise Induced Tinnitus; Other Genetics; Oxidative Stress; Pathway interactions; Patient Self-Report; Pattern; Pharmacologic Substance; Phenotype; Population; Post-Traumatic Stress Disorders; Potassium Channel; Predisposition; Prospective cohort; Reporting; Research Design; Risk; Sampling; Secondary to; Services; Sleep Deprivation; Sleep Disorders; Source; Stimulus; Stratification; Suggestion; Symptoms; Syndrome; Testing; Tinnitus; Traumatic Brain Injury; Twin Studies; Validation; Variant; Veterans; Vietnam; Visit; War; Work; active duty; age related; axon growth; axon injury; base; blast trauma; cohort; comorbidity; cost; curative treatments; data standards; disability; disability payment; gene environment interaction; gene therapy; genetic architecture; genetic association; genome wide association study; genome-wide; genomic profiles; genomic variation; hearing impairment; male; military veteran; nerve repair; noise trauma; novel; post-traumatic stress; programs; receptor; relating to nervous system; repaired; resilience; suicidal; suicidal risk; trait

SUMMARY/ABSTRACT The goals of this study are to characterize a phenotype for tinnitus in a Veteran population and to identify genes and gene-by-environment (GxE) interactions that predict development of tinnitus. Tinnitus, or ringing in the ears with no external source, has been the #1 disability compensation diagnosis at the VA since 2006 and is reported in over 30% of the current MVP population. Besides disability payments, costs to the VA include treatment for its comorbidities, including depression and anxiety disorders, sleep deprivation, suicidal association, cognitive disorders, post-traumatic stress syndrome, and hearing loss, comprising audiologic visits and costs of hearing aids. Yet, to date, there is no objective phenotype, objective biomarker, or definitive treatment associated with this disorder. Although highly correlated with hearing loss, secondary to age, noise, and traumatic brain injury (TBI), tinnitus is a separate and distinct symptom, and a preponderance of evidence indicates that tinnitus is elicited in the brain. Concomitantly, the cochlea is the source of hearing loss, and tinnitus and hearing loss will thus have separate genetic architecture. To date, there have been no genome-wide association studies (GWAS) large enough to separate genes associated with these different etiologies, nor to indicate why some people sustain tinnitus and some do not. The current MVP cohort of over 350,000 Veterans has sufficient power to aid in genetic delineation of disparate etiologies of tinnitus, including age, traumatic brain injury, blast, and noise-induced tinnitus. Suggestions for candidate genes have included pathways involved with oxidative stress, inflammation, potassium-channel receptors, and nerve repair, among others. However, all of these studies were performed in small cohorts with less than adequate power. Our GWAS on the active-duty Marine Resiliency Study (MRS) cohort of average age 22 suggests several genes expressed in the brain that are involved in axonal growth in development and neural repair correlated to TBI. On the other hand, MVP contains over 107,000 subjects with self-reported tinnitus of average age 68, and our Vietnam Era Twin Study on Aging (VETSA) averages 55 years of age. These different cohorts with tinnitus, hearing, and environmental exposure data will allow separation of age-related from noise-induced and TBI-related tinnitus. Distinct phenotypes will be determined by self-report, electronic health record data, and standardized patterns of audiogram data. Our heritability studies on VETSA data indicate a gene by environment interaction (GxE) including a liability threshold model rather than a model that postulates additive genetic factors, in agreement with other studies. Utilizing the power of a twin study, there is evidence for a threshold of injury beyond which susceptible individuals will incur tinnitus. The study's overarching hypothesis is that different genomic variations give rise to susceptibility to tinnitus. Diverse genomic profiles may lead to tinnitus when triggered by environmental stimuli, such as noise, blast, or head trauma. On the other hand, for those who sustain tinnitus as a result of age, there may be other genetic factors involved. To date, studies have been too small to dissect out genes associated with the different etiologies. The MVP cohort provides the power to separate tinnitus into etiologies in order to identify separate phenotypes. !

摘要/摘要 这项研究的目标是表征老兵人口的耳鸣表型 并确定预测的基因和基因 - 环境（GXE）相互作用 耳鸣。耳鸣或没有外部来源的耳朵响了，是＃1残疾 自2006年以来，VA的补偿诊断，当前30％以上的MVP报告 人口。除了残疾支付外，VA的费用还包括其合并症的治疗 包括抑郁症和焦虑症，睡眠剥夺，自杀关联，认知能力 疾病，创伤后压力综合征和听力丧失，包括听力学和 助听器的成本。但是，迄今为止，没有客观的表型，客观生物标志物或 与这种疾病相关的确定治疗方法。 虽然与听力损失高度相关，但继发于年龄，噪音和创伤性大脑 伤害（TBI），耳鸣是一种独立而独特的症状，有大量证据 表明耳鸣是在大脑中引起的。同时，耳蜗是听力的来源 因此，损失，耳鸣和听力损失将具有单独的遗传结构。迄今为止，那里 没有足够大的全基因组关联研究（GWAS）分离基因 与这些不同的病因相关，也没有说明为什么有些人维持耳鸣和 有些没有。当前由350,000多名退伍军人组成的MVP队列具有足够的能力来帮助 耳鸣的不同病因的遗传描述，包括年龄，创伤性脑损伤，爆炸， 和噪声引起的耳鸣。 候选基因的建议包括涉及氧化应激的途径， 炎症，钾通道受体和神经修复等。但是，全部 这些研究是在小队列中进行的，其功率不足。我们的gwas 现役海洋弹性研究（MRS）平均年龄22岁，表明几个基因 在发育和神经修复中参与轴突生长的大脑中表达 与TBI相关。另一方面，MVP包含超过107,000名自我报告的受试者 平均年龄68岁的耳鸣，以及我们的越南时代双胞胎衰老研究（VETSA）平均55 年龄。这些与耳鸣，听力和环境暴露数据不同的队列将 允许与年龄相关的与噪声引起的和TBI相关的耳鸣分离。独特的表型 将由自我报告，电子健康记录数据和标准化模式确定 听力图数据。 我们对VETSA数据的遗传性研究表明环境相互作用（GXE）的基因 包括责任阈值模型，而不是假设添加遗传因素的模型 与其他研究一致。利用双胞胎研究的力量，有阈值的证据 易感人士的伤害会导致耳鸣。 该研究的总体假设是不同的基因组变异引起 耳鸣的敏感性。当被不同的基因组谱可能导致耳鸣 环境刺激，例如噪声，爆炸或头部创伤。另一方面，对于那些 维持耳鸣，因为年龄，可能还涉及其他遗传因素。迄今为止，研究 太小了，无法剖析与不同病因相关的基因。 MVP队列 为了识别单独的表型，提供了将耳鸣分离为病因的力量。 呢