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The genetic architecture of age-related hearing impairment revealed by genome-wide association analysis.

ABSTRACT: Age-related hearing impairment (ARHI) is the most common sensory disorder in older adults. We conducted a genome-wide association meta-analysis of 121,934 ARHI cases and 591,699 controls from Iceland and the UK. We identified 21 novel sequence variants, of which 13 are rare, under either additive or recessive models. Of special interest are a missense variant in LOXHD1 (MAF = 1.96%) and a tandem duplication in FBF1 covering 4 exons (MAF = 0.22%) associating with ARHI (OR = 3.7 for homozygotes, P = 1.7 × 10^-22 and OR = 4.2 for heterozygotes, P = 5.7 × 10^-27, respectively). We constructed an ARHI genetic risk score (GRS) using common variants and showed that a common variant GRS can identify individuals at risk comparable to carriers of rare high penetrance variants. Furthermore, we found that ARHI and tinnitus share genetic causes. This study sheds a new light on the genetic architecture of ARHI, through several rare variants in both Mendelian deafness genes and genes not previously linked to hearing.

SUBMITTER: Ivarsdottir EV

PROVIDER: S-EPMC8190123 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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The genetic architecture of age-related hearing impairment revealed by genome-wide association analysis.

Ivarsdottir Erna V EV Holm Hilma H Benonisdottir Stefania S Olafsdottir Thorhildur T Sveinbjornsson Gardar G Thorleifsson Gudmar G Eggertsson Hannes P HP Halldorsson Gisli H GH Hjorleifsson Kristjan E KE Melsted Pall P Gylfason Arnaldur A Arnadottir Gudny A GA Oddsson Asmundur A Jensson Brynjar O BO Jonasdottir Aslaug A Jonasdottir Adalbjorg A Juliusdottir Thorhildur T Stefansdottir Lilja L Tragante Vinicius V Halldorsson Bjarni V BV Petersen Hannes H Thorgeirsson Gudmundur G Thorsteinsdottir Unnur U Sulem Patrick P Hinriksdottir Ingibjorg I Jonsdottir Ingileif I Gudbjartsson Daniel F DF Stefansson Kari K

Communications biology 20210609 1

Age-related hearing impairment (ARHI) is the most common sensory disorder in older adults. We conducted a genome-wide association meta-analysis of 121,934 ARHI cases and 591,699 controls from Iceland and the UK. We identified 21 novel sequence variants, of which 13 are rare, under either additive or recessive models. Of special interest are a missense variant in LOXHD1 (MAF = 1.96%) and a tandem duplication in FBF1 covering 4 exons (MAF = 0.22%) associating with ARHI (OR = 3.7 for homozygotes, P ...[more]

PMID: 34108613

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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

The genetic architecture of age-related hearing impairment revealed by genome-wide association analysis.

Publications

The genetic architecture of age-related hearing impairment revealed by genome-wide association analysis.

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