Tinnitus: Audiological measures and genetic susceptibility

项目摘要/摘要 耳鸣，在没有外部声源的情况下对声音的幻觉，是一种普遍的听力 无序。到目前为止，耳鸣的确切神经和分子机制尚不清楚。耳鸣是 与许多耳科疾病和临床情况有关；然而，几乎50%的耳鸣病例 不能归因于任何已知的原因(Stouffer&Tyler，1990)。耳鸣可能有遗传因素。 (Sand等人，2007年)。知识库中的一个关键差距是如何在临床上识别哪些人是遗传病患者 在他们出现听力健康问题之前就有耳鸣的倾向。这款R21的短期目标是提早 职业研究标准杆16-057号申请，题为“耳鸣：听力测量和遗传易感性”， 目的是确定年轻人慢性耳鸣的详细表型和基因图谱。该应用程序是 由一组研究人员推荐：PI是正在工作的听力学(CCC-A，FAAA)博士伊珊·巴特 与Co-Pi的遗传学博士Jason Wilder、统计学博士王进和博士Raquel Dias一起， 生物信息学。该项目将通过确定与以下各项相关的关键变量来填补知识空白 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。根据国际和平研究所的初步研究 (Bhatt，2017a)，慢性耳鸣(CT)、急性耳鸣(AT)和非耳鸣(NT)的估计患病率为 分别在8%、13%和79%左右。为了实现我们的短期目标，我们将进行病例控制- 对照外显子全基因组关联研究(GWAS)(N=300)，其中受试者将被分为三组 组：(1)CT(耳鸣1年；n=100)，(2)AT(≤耳鸣1年，可能是由于急性耳鸣) 环境暴露；(n=100)；(3)NT(一生无耳鸣经验；n=100)。具体目标 目的：(1)确定外显子单核苷酸多态(SNPs)与耳鸣的关系 表型。根据初步研究中提出的标准(Bhatt，2017a；Bhatt等人，2016；Phillip等人 Al.，2015)，我们的工作假设是，因果SNPs将显示出特定基因的更高频率 CT检查的受试者与AT和NT受试者比较。(2)识别选定的SNP之间的关联 基于OUR的CT、AT和NT受试者的候选基因集和听力测量 初步研究(Bhatt等人，2016，Phillips等人，2015)，我们的工作假设是有因果关系的受试者 CT的等位基因将在听力测量中表现出病理生理变化。意义：成功 该项目的完成将使我们能够确定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，即开发一种可用于医疗保健的遗传风险概况 提供者和教育工作者(例如，卫生专业人员、音乐和工艺美术教师)以确定个人 CT有遗传风险。

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.