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 本研究的目标是表征退伍军人群体中耳鸣的表型 并识别基因和基因与环境（GxE）的相互作用来预测发育 耳鸣。耳鸣，或者没有外部来源的耳鸣，一直是排名第一的残疾 自 2006 年起在 VA 进行补偿诊断，目前 MVP 中超过 30% 都有报告 人口。除了伤残津贴外，退伍军人管理局的费用还包括治疗其合并症、 包括抑郁症和焦虑症、睡眠不足、自杀倾向、认知障碍 疾病、创伤后应激综合症和听力损失，包括听力检查和 助听器的费用。然而，迄今为止，还没有客观的表型、客观的生物标志物或 与这种疾病相关的明确治疗。 尽管与听力损失高度相关，但继发于年龄、噪音和脑部创伤 损伤（TBI）时，耳鸣是一种单独且独特的症状，并且有大量证据 表明耳鸣是由大脑引起的。同时，耳蜗是听觉的来源 因此，耳鸣和听力损失将具有不同的遗传结构。迄今为止，有 还没有足够大的全基因组关联研究（GWAS）来分离基因 与这些不同的病因相关，也不能表明为什么有些人会持续耳鸣和 有些则不然。当前 MVP 队伍由超过 350,000 名退伍军人组成，他们有足够的力量来帮助 耳鸣不同病因的遗传描述，包括年龄、创伤性脑损伤、爆炸、 以及噪音引起的耳鸣。 对候选基因的建议包括与氧化应激有关的途径， 炎症、钾通道受体和神经修复等。然而，所有的 这些研究是在小群体中进行的，功效不足。我们的 GWAS 平均年龄 22 岁的现役海洋复原力研究 (MRS) 队列表明了几个基因 在大脑中表达，参与发育和神经修复中的轴突生长 与 TBI 相关。另一方面，MVP 包含超过 107,000 个自我报告的受试者 耳鸣的平均年龄为 68 岁，而我们的越南时代双胞胎衰老研究 (VETSA) 的平均年龄为 55 岁数。这些具有耳鸣、听力和环境暴露数据的不同群体将 可以将与年龄相关的耳鸣与噪声引起的耳鸣和与 TBI 相关的耳鸣区分开来。不同的表型 将通过自我报告、电子健康记录数据和标准化模式来确定 听力图数据。 我们对 VETSA 数据的遗传力研究表明基因与环境相互作用 (GxE) 包括责任阈值模型而不是假设附加遗传因素的模型， 与其他研究一致。利用双胞胎研究的力量，有证据表明存在一个阈值 超过该程度的伤害，易感人群就会出现耳鸣。 该研究的总体假设是不同的基因组变异会导致 容易出现耳鸣。不同的基因组图谱在触发时可能会导致耳鸣 环境刺激，例如噪音、爆炸或头部外伤。另一方面，对于那些 由于年龄的原因导致耳鸣持续存在，可能还有其他遗传因素参与。迄今为止，研究 规模太小，无法剖析与不同病因相关的基因。 MVP 群体 提供了将耳鸣分为病因的能力，以便识别不同的表型。 ！