School of Health Sciences, Division of Otolaryngology, University of California San Diego, La Jolla, San Diego, CA, USA.
Research Department, VA Hospitals San Diego, San Diego, CA, USA.
Hum Genet. 2022 Apr;141(3-4):981-990. doi: 10.1007/s00439-021-02317-9. Epub 2021 Jul 27.
Genome-wide association studies (GWAS) provide an unbiased first look at genetic loci involved in aging and noise-induced sensorineural hearing loss and tinnitus. The hearing phenotype, whether audiogram-based or self-report, is regressed against genotyped information at representative single nucleotide polymorphisms (SNPs) across the genome. Findings include the fact that both hearing loss and tinnitus are polygenic disorders, with up to thousands of genes, each of effect size of < 0.02. Smaller human GWAS' were able to use objective measures and identified a few loci; however, hundreds of thousands of participants have been required for the statistical power to identify significant variants, and GWAS is unable to assess rare variants with mean allele frequency < 1%. Animal studies are required as well because of inability to access the human cochlea. Mouse GWAS builds on linkage techniques and the known phenotypic differences in auditory function between inbred strains. With the advantage that the laboratory environment can be controlled for noise and aging, the Hybrid Mouse Diversity Panel (HDMP) combines 100 strains sequenced at high resolution. Lift-over regions between mice and humans have identified over 17,000 homologous genes. Since most significant SNPs are either intergenic or in introns, and binding sites between species are poorly preserved between species, expression quantitative trait locus information is required to bring humans and mice into agreement. Transcriptome-wide analysis studies (TWAS) can prioritize putative causal genes and tissues. Diverse species, each making a distinct contribution, carry a synergistic advantage in the quest for treatment and ultimate cure of sensorineural hearing difficulties.
全基因组关联研究 (GWAS) 为研究与衰老和噪声性感音神经性听力损失和耳鸣相关的遗传位点提供了一种无偏的初步方法。听力表型，无论是基于听力图还是自我报告，都与代表单核苷酸多态性 (SNP) 的基因组中基因分型信息进行回归。研究结果表明，听力损失和耳鸣都是多基因疾病，多达数千个基因，每个基因的效应大小都小于 0.02。较小的人类 GWAS 能够使用客观测量方法并确定少数几个位点；然而，需要数十万参与者才能具有识别显著变体的统计能力，并且 GWAS 无法评估平均等位基因频率 < 1%的罕见变体。由于无法接触人类耳蜗，因此也需要进行动物研究。小鼠 GWAS 建立在连锁技术和近交系之间听觉功能的已知表型差异的基础上。由于实验室环境可以控制噪声和衰老，杂交小鼠多样性面板 (HDMP) 结合了 100 个以高分辨率测序的品系。在小鼠和人类之间进行的基因定位区域鉴定出了超过 17000 个同源基因。由于大多数显著 SNP 要么位于基因间，要么位于内含子中，并且物种之间的结合位点保存不佳，因此需要表达数量性状基因座信息来使人类和小鼠达成一致。全转录组分析研究 (TWAS) 可以优先考虑假定的因果基因和组织。不同的物种，每个物种都有独特的贡献，在寻求治疗和最终治愈感音神经性听力困难方面具有协同优势。
