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Genome-wide association meta-analysis identifies five novel loci for age-related hearing impairment.

ABSTRACT: Previous research has shown that genes play a substantial role in determining a person's susceptibility to age-related hearing impairment. The existing studies on this subject have different results, which may be caused by difficulties in determining the phenotype or the limited number of participants involved. Here, we have gathered the largest sample to date (discovery n?=?9,675; replication n?=?10,963; validation n?=?356,141), and examined phenotypes that represented low/mid and high frequency hearing loss on the pure tone audiogram. We identified 7 loci that were either replicated and/or validated, of which 5 loci are novel in hearing. Especially the ILDR1 gene is a high profile candidate, as it contains our top SNP, is a known hearing loss gene, has been linked to age-related hearing impairment before, and in addition is preferentially expressed within hair cells of the inner ear. By verifying all previously published SNPs, we can present a paper that combines all new and existing findings to date, giving a complete overview of the genetic architecture of age-related hearing impairment. This is of importance as age-related hearing impairment is highly prevalent in our ageing society and represents a large socio-economic burden.

SUBMITTER: Nagtegaal AP

PROVIDER: S-EPMC6811684 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Genome-wide association meta-analysis identifies five novel loci for age-related hearing impairment.

Nagtegaal Andries Paul AP Broer Linda L Zilhao Nuno R NR Jakobsdottir Johanna J Bishop Charles E CE Brumat Marco M Christiansen Mark W MW Cocca Massimiliano M Gao Yan Y Heard-Costa Nancy L NL Evans Daniel S DS Pankratz Nathan N Pratt Sheila R SR Price T Ryan TR Spankovich Christopher C Stimson Mary R MR Valle Karen K Vuckovic Dragana D Wells Helena H Eiriksdottir Gudny G Fransen Erik E Ikram Mohammad Arfan MA Li Chuang-Ming CM Longstreth W T WT Steves Claire C Van Camp Guy G Correa Adolfo A Cruickshanks Karen J KJ Gasparini Paolo P Girotto Giorgia G Kaplan Robert C RC Nalls Michael M Schweinfurth John M JM Seshadri Sudha S Sotoodehnia Nona N Tranah Gregory J GJ Uitterlinden André G AG Wilson James G JG Gudnason Vilmundur V Hoffman Howard J HJ Williams Frances M K FMK Goedegebure André A

Scientific reports 20191023 1

Previous research has shown that genes play a substantial role in determining a person's susceptibility to age-related hearing impairment. The existing studies on this subject have different results, which may be caused by difficulties in determining the phenotype or the limited number of participants involved. Here, we have gathered the largest sample to date (discovery n = 9,675; replication n = 10,963; validation n = 356,141), and examined phenotypes that represented low/mid and high frequenc ...[more]

PMID: 31645637

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Project description: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.

Dataset Information

Genome-wide association meta-analysis identifies five novel loci for age-related hearing impairment.

Publications

Genome-wide association meta-analysis identifies five novel loci for age-related hearing impairment.

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