The genetic basis for age-related hearing loss in outbred mice

项目总结/摘要 听力损失的主要原因是听力损失的严重程度。 影响全球老年人的最常见疾病。双胞胎和家庭研究显示，25-75% ARHI遗传性（Momi等，2015）。据估计，大约三分之二的人年龄超过 70在美国的经验ARHI，到2020年，超过一半的人在美国与 听力损失的年龄将超过70岁（班布里奇和沃勒，2014）。ARHI已被证明是 与认知能力下降、痴呆、抑郁和孤独独立相关，并导致 估计每年的经济负担超过30亿美元（Deal等人，2017; Deal等人，2018; Lin和Albert，2014）。 我们的总体假设得到了小鼠和人类的初步数据的支持，即ARHI是一种 具有许多可能相关基因的复杂性状（Fransen等，2015; Friedman等人，2009; Kalra等人，二〇一九年; 威尔斯等人，2019年）。已经鉴定出100多个单基因耳聋基因;然而， 很大一部分ARHI患者在任何已知的耳聋基因中没有可识别的突变，这表明 还有更多的基因有待发现（Bowl和Dawson，2018）。 小鼠仍然是听力研究的主要生物体。听觉结构的相似性 以及小鼠和人类之间的生理学，基因组的密切进化关系（大多数基因在 小鼠具有人类同源物），相对较低的住房成本，遗传标准化和可用的 基因工具包使小鼠成为研究听觉功能基因组学的重要模型系统 系统（Bowl和Dawson，2015）。我们建议通过执行第一个 在CFW小鼠中进行ARHI的全基因组关联研究（GWAS）， 内耳尽管包括我们在内的几个实验室已经使用人类受试者进行GWAS，但迄今为止还没有 具有充分把握度的综合特征队列，因此存在有限的复制 候选基因的研究在目标1中，我们将测量听性脑干反应和畸变产物 2,000只1岁CFW小鼠的耳声发射阈值，雌雄各半。 我们将对每只小鼠进行超过1，000，000个单核苷酸多态性标记的基因分型，并在目标2中进行基因分型。 进行GWAS以鉴定数量性状基因座（QTL）。在目标3中，我们将使用RNAseq来评估 从CFW队列中随机选择100只小鼠的内耳中的基因表达， CFW小鼠内的遗传变异提供了一个独特的机会，以阐明分子遗传变异的机制。 ARHI的基础机制为药物开发提供了新的靶点，并提供了一种方法， 识别有风险的患者。

Project Summary / Abstract Age-related hearing impairment (ARHI) is the most common cause of hearing loss, is heritable, and is one of the most prevalent conditions affecting the elderly globally. Twin and family studies reveal 25-75% heritability for ARHI (Momi et al., 2015). Estimates suggest approximately two‐thirds of people over the age of 70 in the United States experience ARHI, and that by 2020, over half of all people in the United States with hearing loss will be over 70 years of age (Bainbridge and Wallhagen, 2014). ARHI has been shown to be independently associated with cognitive decline, dementia, depression, and loneliness and results in an estimated annual economic burden of over $3 billion (Deal et al., 2017; Deal et al., 2018; Lin and Albert, 2014). Our overarching hypothesis, supported by preliminary data in both mice and humans, is that ARHI is a complex trait with many likely genes associated (Fransen et al., 2015; Friedman et al., 2009; Kalra et al., 2019; Wells et al., 2019). Greater than 100 genes have been identified for monogenic deafness; however, a substantial fraction of patients with ARHI have no identifiable mutation in any known deafness gene suggesting that there remain additional genes to discover (Bowl and Dawson, 2018). Mice continue to be the predominant organism for hearing research. Similarities in the auditory structure and physiology between mice and humans, the close evolutionary relationship of genomes (most genes in mice have a human homologue), relatively low housing costs, genetic standardization and the available genetic toolkit make the mouse a crucial model system for the study of the functional genomics of the auditory system (Bowl and Dawson, 2015). We are proposing to identify candidate genes by performing the first complete genome-wide association study (GWAS) of ARHI in CFW mice and examining gene expression in the inner ear. Although several labs including ours have used human subjects for GWAS, to date there exist no comprehensively characterized cohorts with sufficient power and therefore there exist limited replication studies of candidate genes. In Aim 1, we will measure auditory brainstem response and distortion product otoacoustic emission thresholds in 2,000 one-year-old CFW mice equally divided among males and females. We will genotype each mouse at more than 1,000,000 single nucleotide polymorphism markers and in Aim 2 perform GWAS to identify quantitative trait loci (QTL). In Aim 3, we will use RNAseq to assess differences in gene expression in the inner ears of 100 randomly selected mice from the CFW cohort and define expressed QTLs (eQTLs).The genetic variation within CFW mice presents a unique opportunity to elucidate the molecular mechanisms that underlie ARHI providing novel targets for drug development and providing a means for identifying patients at risk.