A Large Genome-Wide Association Study of Age-Related Hearing Impairment Using Electronic Health Records

Age-related hearing impairment (ARHI), one of the most common sensory disorders, can be mitigated, but not cured or eliminated. To identify genetic influences underlying ARHI, we conducted a genome-wide association study of ARHI in 6,527 cases and 45,882 controls among the non-Hispanic whites from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. We identified two novel genome-wide significant SNPs: rs4932196 (odds ratio = 1.185, p = 4.0x10-11), 52Kb 3’ of ISG20, which replicated in a meta-analysis of the other GERA race/ethnicity groups (1,025 cases, 12,388 controls, p = 0.00094) and in a UK Biobank case-control analysis (30,802 self-reported cases, 78,586 controls, p = 0.015); and rs58389158 (odds ratio = 1.132, p = 1.8x10-9), which replicated in the UK Biobank (p = 0.00021). The latter SNP lies just outside exon 8 and is highly correlated (r2 = 0.96) with the missense SNP rs5756795 in exon 7 of TRIOBP, a gene previously associated with prelingual nonsyndromic hearing loss. We further tested these SNPs in phenotypes from audiologist notes available on a subset of GERA (4,903 individuals), stratified by case/control status, to construct an independent replication test, and found a significant effect of rs58389158 on speech reception threshold (SRT; overall GERA meta-analysis p = 1.9x10-6). We also tested variants within exons of 132 other previously-identified hearing loss genes, and identified two common additional significant SNPs: rs2877561 (synonymous change in ILDR1, p = 6.2x10-5), which replicated in the UK Biobank (p = 0.00057), and had a significant GERA SRT (p = 0.00019) and speech discrimination score (SDS; p = 0.0019); and rs9493627 (missense change in EYA4, p = 0.00011) which replicated in the UK Biobank (p = 0.0095), other GERA groups (p = 0.0080), and had a consistent significant result for SRT (p = 0.041) and suggestive result for SDS (p = 0.081). Large cohorts with GWAS data and electronic health records may be a useful method to characterize the genetic architecture of ARHI.年龄相关性听力损伤（Age-related hearing impairment, ARHI）是最常见的感觉障碍之一，目前仅可缓解，无法根治或彻底消除。为明确ARHI的遗传影响因素，我们针对成人健康与衰老遗传流行病学研究（Genetic Epidemiology Research on Adult Health and Aging, GERA）队列中的非西班牙裔白人群体，开展了ARHI的全基因组关联研究，共纳入6527例病例与45882例对照。本研究鉴定出两个全新的全基因组显著性单核苷酸多态性（Single Nucleotide Polymorphism, SNP）：rs4932196（优势比=1.185，p=4.0×10^-11），位于ISG20基因3'端下游52kb处。该位点在其他GERA种族/族裔群体的荟萃分析（纳入1025例病例、12388例对照，p=0.00094）以及英国生物库（UK Biobank）的病例对照研究（纳入30802例自我报告病例、78586例对照，p=0.015）中均得到了重复验证；另一个为rs58389158（优势比=1.132，p=1.8×10^-9），该位点在英国生物库中得到了重复验证（p=0.00021）。后一个SNP恰好位于第8号外显子外侧，与TRIOBP基因第7号外显子上的错义SNP rs5756795存在高度连锁不平衡（r²=0.96）；TRIOBP基因此前已被报道与语前非综合征性听力损失相关。我们进一步基于GERA队列中4903名受试者的听力学医师笔记表型数据，按病例/对照状态进行分层，构建了独立的重复验证检验，并发现rs58389158对言语接受阈（speech reception threshold, SRT）存在显著影响（GERA整体荟萃分析p=1.9×10^-6）。我们还对此前已报道的132个听力损失相关基因的外显子区域内的变异进行了检测，鉴定出另外两个常见的显著性SNP：rs2877561（位于ILDR1基因的同义突变位点，p=6.2×10^-5），该位点在英国生物库中得到重复验证（p=0.00057），且在GERA队列中对SRT（p=0.00019）与言语识别率（speech discrimination score, SDS）均存在显著影响（p=0.0019）；以及rs9493627（位于EYA4基因的错义突变位点，p=0.00011），该位点在英国生物库（p=0.0095）与其他GERA亚组（p=0.0080）中均得到重复验证，且对SRT存在显著影响（p=0.041），对SDS则呈现出潜在的关联趋势（p=0.081）。整合全基因组关联研究数据与电子健康档案的大型队列，可为阐明ARHI的遗传结构提供有效的研究途径。