Tinnitus: Audiological measures and genetic susceptibility

项目总结/摘要 耳鸣是一种在没有外部声源的情况下对声音的幻觉， disorder.目前，耳鸣的确切神经和分子机制尚不清楚。耳鸣是 耳鸣是一种常见的耳科疾病，也是一种常见的耳科疾病。 不能归因于任何已知的原因（Stouffer &泰勒，1990）。耳鸣的病因有哪些？ (Sand等人，2007）。知识基础中的一个关键空白是如何在临床上识别那些遗传上 在他们获得这种听力健康问题之前就容易耳鸣。R21的短期目标 职业研究PAR 16-057申请，题为“耳鸣：听力测量和遗传易感性”， 是确定详细的表型和基因型档案慢性耳鸣在年轻人。应用程序 PI是Ishan Bhatt，Ph.D.在听力学（CCC-A，FAAA），谁是工作 与合作伙伴的杰森怀尔德博士在遗传学方面，王进博士和Raquel Dias博士在 生物信息学。本项目将通过识别与下列因素相关的关键变量来填补知识的差距： CT的遗传易感性这项调查将包括大学年龄的年轻参与者，以控制年龄- 相关的混杂变量，如系统性疾病和听力损失。根据PI的初步研究， （Bhatt，2017 a），慢性耳鸣（CT）、急性耳鸣（AT）和无耳鸣（NT）的估计患病率为 分别为8%、13%和79%左右。为了实现我们的短期目标，我们将进行病例对照- 对照外显子全基因组关联研究（GWAS）（N = 300），其中受试者将分为三组 组：（1）CT（耳鸣> 1年; n=100），（2）AT（耳鸣≤ 1年，可能是由于急性 环境暴露; n=100）;和（3）NT（一生中没有耳鸣经历; n=100）。具体目标 主要有：（1）确定外显子单核苷酸多态性（SNPs）与耳鸣之间的关系 表型根据初步研究中规定的标准（Bhatt，2017 a; Bhatt等人，2016;菲利普等 例如，2015），我们的工作假设是，因果SNP将表现出更高频率的特定基因型， 与AT和NT受试者相比，CT受试者。(2)为了鉴定在一个基因组中选择的SNP之间的关联， 在CT、AT和NT受试者中的候选基因集和听力学测量，基于我们的 初步研究（Bhatt等人，2016年，菲利普斯等人，2015），我们的工作假设是，具有因果关系的主体 CT的等位基因将在听力测量中表现出病理生理学变化。意义：成功 本研究的完成将使我们能够鉴定CT的表型和基因型谱。这将有助于我们 实现我们的长期目标，这是发展一个遗传风险概况，可用于卫生保健 提供者和教育者（例如，卫生专业人员、音乐和工艺美术教师） 在遗传上有CT的风险。

PROJECT SUMMARY/ABSTRACT Tinnitus, the phantom perception of sound in absence of an external sound source, is a prevalent hearing disorder. To date, the exact neural and molecular mechanisms underlying tinnitus are not known. Tinnitus is associated with a number of otological diseases and clinical conditions; however, almost 50% of tinnitus cases are not attributable to any known cause (Stouffer & Tyler, 1990). There is likely a genetic component to tinnitus (Sand et al, 2007). A critical gap in the knowledge base is how to clinically identify those who are genetically predisposed to tinnitus well before they acquire this hearing health issue. The short-term goal of this R21 Early Career Research PAR 16-057 application, entitled “Tinnitus: Audiological measures and genetic susceptibility,” is to identify detailed phenotypic and genotypic profiles of chronic tinnitus in young adults. The application is proposed by a team of researchers: The PI is Ishan Bhatt, Ph.D. in audiology (CCC-A, FAAA), who is working with Co-PI’s Jason Wilder, Ph.D. in genetics, Jin Wang, Ph.D. in statistics, and Raquel Dias, Ph.D. in Bioinformatics. This project will fill the gap in knowledge by identifying the critical variables associated with a genetic predisposition to CT. This investigation will include college-aged young participants to control for age- related confounding variables such as systemic diseases and hearing loss. According to the PI’s pilot study (Bhatt, 2017a), the estimated prevalence of chronic tinnitus (CT), acute tinnitus (AT) and no tinnitus (NT) is around 8%, 13% and 79%, respectively. To accomplish our short-term goal, we will conduct a case-control- control exonic genome-wide association study (GWAS) (N = 300) in which subjects will be divided into three groups: those with (1) CT (tinnitus for > 1 year; n=100), (2) AT (tinnitus for ≤ 1 year, presumably due to acute environmental exposure; n=100); and (3) NT (no experience of tinnitus in a lifetime; n=100). The Specific Aims are: (1) to identify associations between exonic Single Nucleotide Polymorhisms (SNPs) and tinnitus phenotype. Based on the criteria laid out in the preliminary studies (Bhatt, 2017a; Bhatt et al., 2016; Phillip et al., 2015), our working hypothesis is that causal SNPs will exhibit a higher frequency of a specific genotype for subjects with CT compared to subjects with AT and NT. (2) To identify association between selected SNPs in a candidate set of genes and audiologic measures among subjects with CT, AT and NT, Based on our preliminary studies (Bhatt et al., 2016, Phillips et al., 2015), our working hypothesis is that subjects with causal alleles for CT will exhibit pathophysiological variation in the audiometric measures. Significance: Successful completion of this project will enable us to identify phenotypic and genotypic profiles of CT. This will help us to achieve our long term goal, which is to develop a genetic Risk Profile that can be used by health-care providers, and educators (e.g., health professionals, music and industrial arts teachers) to identify individuals genetically at risk for CT.