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

项目摘要/摘要 年龄相关性听力障碍(ARHI)是导致听力损失的最常见的原因，是可遗传的，也是 影响全球老年人的最普遍的疾病之一。双胞胎和家庭研究显示25%-75% ARHI的遗传性(Momi等人，2015年)。据估计，大约三分之二的人年龄在 70的美国人经历了ARHI，到2020年，超过一半的美国人患有ARHI 听力损失的年龄将超过70岁(Bainbridge和Wallhgen，2014)。ARHI已经被证明是 独立地与认知衰退、痴呆症、抑郁症和孤独感相关，并导致 估计每年的经济负担超过30亿美元(Deal等人，2017年；Deal等人，2018年；Lin和Albert，2014年)。 我们的主要假设是，在小鼠和人类身上都有初步数据支持，即ARHI是一种 与许多可能基因相关的复杂性状(Fransen等人，2015；Friedman等人，2009；Kalra等人，2019； Wells等人，2019年)。超过100个基因已经被确定为单基因耳聋；然而，一个 大部分ARHI患者在任何已知的耳聋基因中都没有可识别的突变，这表明 还有更多的基因有待发现(Bowl和Dawson，2018)。 老鼠仍然是听力研究的主要生物。听觉结构上的相似性 以及老鼠和人之间的生理，基因组之间的密切进化关系(大多数基因在 老鼠有人类同源物)，相对较低的居住成本，基因标准化和可用 遗传工具箱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基因识别候选基因 CFW小鼠ARHI全基因组关联研究及基因表达检测 内耳。尽管包括我们在内的几个实验室已经将人类受试者用于GWAS，但到目前为止还没有 具有足够能力的全面表征的队列，因此存在有限的复制 对候选基因的研究。在目标1中，我们将测量听觉脑干反应和失真产物 2,000只一岁的CFW小鼠的耳声发射阈值被平均分配给雄性和雌性。 我们将在100多万个单核苷酸多态标记上对每只小鼠进行基因分型，并在Aim 2中进行 用广义遗传算法确定数量性状基因座(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只小鼠的内耳基因表达和定义表达 Cfw小鼠体内的遗传变异为阐明该分子提供了独特的机会。 ARHI的基础机制为药物开发提供了新的靶点，并提供了一种 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.