Genetic Analysis of Age Related Hearing Impairment

年龄相关性听力障碍(ARHI；也称为老年性耳聋)损害了超过5亿人的感官输入[1，2]，世界卫生组织预测，随着人口年龄中位数的稳步增加，对公共健康的影响只会增加(http://www.who.int/en/).许多研究表明，AHRI对生活质量有负面影响[2-5]。一项针对131,535名加拿大人的横断面调查报告称，听力受损的人患抑郁症的几率更高[6]，而一项针对1140名老年人的研究表明，听力障碍与男性死亡风险的显著增加有关[7]。ARHI的发病年龄差异很大；随着年龄的增长，总的患病率稳步上升，因此70岁至80岁的人中有60%表现出明显的听力障碍[8，9]。我们的团队最近完成了第一项全基因组关联研究，确定了几个ARHI的易感等位基因[10] 这项提议的一个主要优势在于我们召集了一组调查人员。每个中心都带来了独特的优势和能力。来自众议院耳朵研究所和安特卫普大学的研究人员在听力损失的遗传学、GWA和耳蜗组织的外科手术方面拥有专业知识。翻译基因组学(TGen)在基因分型和拷贝数变异(CNV)分析方面拥有世界知名的专业知识。这个团队的成功最好的例证是我们发现并发表了GRM7，这是在GWAS中发现的第一个ARHI易感变种[10]。利用这些优势，我们可以极大地促进我们对使人类易患ARHI的潜在遗传结构的理解。我们的长期目标是全面了解导致ARHI的特定遗传因素。作为实现这一目标的第一步，我们将有条不紊地建立在我们的GWAS结果的基础上，通过分析已经收集并通过下一代测序(NGS)进行测序的全面的人类成年耳蜗组。这个耳蜗转录组，以及小鼠现有的转录组数据，将为我们提供机会，以增加我们的GWA中包含在耳蜗中表达的基因的相关基因组区域的权重。这种方法将增强我们研究的力量，提供更具成本效益的设计。我们提出了以下具体目标： 目的1：编制成人耳蜗组转录组的精确表达。假说：与ARHI相关的基因变异存在于耳蜗组织中正常表达的基因中。对耳蜗组转录组的深入描述已经开始。分子生物学已经完成，我们正在开始生物信息学分析。存在几种分析方法，允许根据生物学标准对单个SNPs进行加权。我们将使用新的和现有的耳蜗基因列表来先验地在分析我们的AIM 2数据时赋予特定的SNPs额外的权重。 目的2：使用GWAS设计阐明与ARHI相关的新基因和生化网络。假设：ARHI是一种由多个基因的等位基因变异引起的复杂疾病。最近，我们基于一种汇集方法证实了遗传变异在GWAARHI中的作用，该方法证明了包括GRM7在内的几个基因的等位基因关联。使用假设无关的基因发现模型的适当的研究已经证明了在识别与复杂疾病相关的基因组变异方面的巨大作用。一种循序渐进的方法，通过增加包含在耳蜗中表达的基因的基因组区域的权重，并考虑到已知的协变，进一步增加了我们研究的能力，导致了一个具有成本效益的设计。 我们建议的研究不仅将提高我们对ARHI的遗传基础的理解，而且将为开展假说驱动的研究提供理论基础，这将反过来促进我们对ARHI的遗传、分子和细胞原因的理解。 可以预期，这一改进的知识库将构成开发新的以证据为基础的预防和治疗ARHI方法的肥沃土壤。

Age-related hearing impairment (ARHI; also called presbycusis) impairs sensory input in more than a half of a billion people [1, 2], and the WHO predicts that the impact on public health will only increase as the median age of the population steadily increases (http://www.who.int/en/). A number of studies indicate that AHRI negatively impacts quality of life [2-5]. A cross-sectional survey of 131,535 Canadians reported that subjects with hearing impairment suffer higher rates of depression [6], while a study of 1140 elderly, linked hearing deficits with a significant increase in mortality risk in men [7]. The age of onset for ARHI varies markedly; with overall prevalence increasing steadily with age, so that 60% of individuals aged 70 to 80 demonstrate significant hearing impairment [8, 9]. Our team has recently completed the first genome-wide association study (GWAS) identifying several susceptibility alleles for ARHI [10] A major strength of this proposal lies in the group of investigators we have assembled. Each of the centers brings unique strengths and capabilities. The investigators from the House Ear Institute and the University of Antwerp have expertise in the genetics of hearing loss, GWAS and surgical access to cochlear tissue. Translational Genomics (TGen) has world-renowned expertise in genotyping and copy number variant (CNV) analysis. The success of this team is best illustrated by our discovery and publication of GRM7, the first susceptibility variant for ARHI found in a GWAS [10]. Leveraging these strengths uniquely positions us to dramatically advance our understanding of the underlying genetic architecture that predisposes humans to ARHI. Our LONG-TERM GOAL is to develop a comprehensive understanding of the specific genetic factors that contribute to ARHI. As an initial step towards that objective, we will build methodically upon results from our GWAS by analyzing a comprehensive human adult cochlear transcriptome that has been collected and sequenced by next generation sequencing (NGS). This cochlear transcriptome, and the existing transcriptome data in the mouse, will provide us with the opportunity to up weight genomic regions of association in our GWAS that contain genes expressed in the cochlea. This approach will enhance the power of our study providing a more cost-effective design. We propose the following SPECIFIC AIMS: AIM 1: Compile an accurate representation of the adult human cochlear transcriptome. Hypothesis: Genetic variants associated with ARHI reside within genes that are normally expressed in the cochlea. An in-depth characterization of the cochlear transcriptome has been initiated. The molecular biology has been completed and we are beginning the bioinformatics analysis. Several analytical methods exist that allow for weighting of individual SNPs due to biological criteria. We will use the new and existing cochlear gene list to a priori assign specific SNPs additional weight in the analysis of our Aim 2 data. AIM 2: Elucidate novel genes and biochemical networks associated with ARHI using a GWAS design. Hypothesis: ARHI is a complex disease resulting from allelic variation in multiple genes. We have recently confirmed the role of genetic variants in ARHI in a GWAS based on a pooling approach that demonstrated allelic association in several genes, including GRM7. Properly powered studies using hypothesis independent models of gene discovery have demonstrated great utility in identifying genomic variation associated with complex diseases. A stepwise approach, with up weighting of genomic regions containing genes expressed in the cochlea, and accounting for known covariant, further increases the power of our study, resulting in a cost-effective design. Our proposed investigation will not only improve our understanding of the genetic bases of ARHI, but will provide a rationale to pursue hypothesis-driven investigations that will in turn advance our understanding of the genetic, molecular, and cellular causes of ARHI. This improved knowledge base can be anticipated to constitute fertile ground for developing new evidence-based preventive and therapeutic approaches to treating ARHI.