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

摘要/摘要 这项研究的目的是描述退伍军人人群中耳鸣的表型。 并确定预测疾病发展的基因和基因与环境(GxE)的相互作用 耳鸣。耳鸣，即没有外部来源的耳鸣，一直是头号残疾 自2006年以来在退伍军人管理局进行了补偿诊断，目前超过30%的MVP报告了这一问题 人口。除了伤残费，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，自杀联想，认知 精神障碍、创伤后应激综合征和听力损失，包括听力检查和 助听器的费用。然而，到目前为止，还没有客观的表型、客观的生物标记物或 与这种疾病相关的明确治疗。 虽然与听力损失高度相关，但继发于年龄、噪音和创伤性脑损伤 损伤(TBI)，耳鸣是一种独立的、独特的症状，也是证据的优势。 表明耳鸣是在大脑中引起的。随之而来的是，耳蜗是听觉的来源 因此，耳鸣和听力损失将有不同的遗传结构。到目前为止，有 还没有大到足以分离基因的全基因组关联研究 与这些不同的病因有关，也不能说明为什么有些人会持续耳鸣和 有些人则不这么认为。目前超过350,000名退伍军人的MVP队列有足够的力量来帮助 耳鸣的不同病因的遗传描述，包括年龄，创伤性脑损伤，冲击波， 以及噪音引起的耳鸣。 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 这些研究是在动力不足的小群体中进行的。我们的GWA在 平均年龄22岁的现役海洋适应性研究(MRS)队列显示了几个基因 在大脑中表达，参与轴突发育和神经修复 与颅脑损伤相关。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，我们越南时代的双胞胎衰老研究(Vetsa)平均55岁 几年前。这些具有耳鸣、听力和环境暴露数据的不同队列将 允许将与年龄有关的耳鸣与噪音引起的和脑损伤相关的耳鸣分开。不同的表型 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，而不是假设可加遗传因素的模型，在 与其他研究结果一致。利用双胞胎研究的力量，有证据表明存在门槛 超过此范围易受伤害的人会引起耳鸣。 这项研究的主要假设是不同的基因组变异会导致 对耳鸣易感性。不同的基因组图谱可能导致耳鸣，当触发 环境刺激，如噪音、冲击波或头部创伤。另一方面，对于那些 持续耳鸣由于年龄的原因，可能还有其他遗传因素参与其中。到目前为止，研究 已经太小了，无法剖析出与不同病因相关的基因。MVP队列 提供了将耳鸣分离为病因的能力，以便识别不同的表型。 好了！

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. !