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Genome-wide association analysis demonstrates the highly polygenic character of age-related hearing impairment.

ABSTRACT: We performed a genome-wide association study (GWAS) to identify the genes responsible for age-related hearing impairment (ARHI), the most common form of hearing impairment in the elderly. Analysis of common variants, with and without adjustment for stratification and environmental covariates, rare variants and interactions, as well as gene-set enrichment analysis, showed no variants with genome-wide significance. No evidence for replication of any previously reported genes was found. A study of the genetic architecture indicates for the first time that ARHI is highly polygenic in nature, with probably no major genes involved. The phenotype depends on the aggregated effect of a large number of SNPs, of which the individual effects are undetectable in a modestly powered GWAS. We estimated that 22% of the variance in our data set can be explained by the collective effect of all genotyped SNPs. A score analysis showed a modest enrichment in causative SNPs among the SNPs with a P-value below 0.01.

SUBMITTER: Fransen E

PROVIDER: S-EPMC4266741 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Genome-wide association analysis demonstrates the highly polygenic character of age-related hearing impairment.

Fransen Erik E Bonneux Sarah S Corneveaux Jason J JJ Schrauwen Isabelle I Di Berardino Federica F White Cory H CH Ohmen Jeffrey D JD Van de Heyning Paul P Ambrosetti Umberto U Huentelman Matthew J MJ Van Camp Guy G Friedman Rick A RA

European journal of human genetics : EJHG 20140618 1

We performed a genome-wide association study (GWAS) to identify the genes responsible for age-related hearing impairment (ARHI), the most common form of hearing impairment in the elderly. Analysis of common variants, with and without adjustment for stratification and environmental covariates, rare variants and interactions, as well as gene-set enrichment analysis, showed no variants with genome-wide significance. No evidence for replication of any previously reported genes was found. A study of ...[more]

PMID: 24939585

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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.

Project description:Importance:Evidence has linked age-related hearing impairment (ARHI) with cognitive decline; however, very few studies (none in the United Kingdom) explore this link in large well-characterized groups of community-dwelling individuals. Objective:To investigate the link between ARHI and cognitive decline using a cohort of elderly individuals from the United Kingdom and explore untreated hearing loss and social isolation as potential explanations for the observed link. Design, Setting, and Participants:This cross-sectional analysis of wave 7 (June 2014 through May 2015) of the English Longitudinal Study of Ageing (ELSA) sampled men and women 50 years or older and living in the United Kingdom in a community setting. Those with a diagnosis of dementia, Alzheimer disease, or Parkinson disease or with ear infections and cochlear implants were excluded. Data were analyzed from August 1, 2017, through May 25, 2018. Main Outcomes and Measures:Memory and executive function as measures of cognitive function and hearing acuity derived from the HearCheck screener device (Siemens). Results:Of a cohort of 9666 members in wave 7 of ELSA, 7385 were eligible for analysis after applying exclusion criteria (55.1% women; mean [SD] age, 67.4 [9.4] years). Of these, 3056 (41.4%) had mild hearing loss and 755 (10.2%) had severe hearing loss; 834 (11.3%) used a hearing aid; and 7155 (96.9%) were white. Hearing loss had a negative association with cognition; for those with moderate to severe loss, the score on memory assessment was a full 1 point less (-1.00; 95% CI, -1.24 to -0.76), ceteris paribus, relative to those with no hearing loss. However, this association was seen only in the individuals with untreated hearing loss (ie, those who did not use hearing aids) (-1.16; 95% CI, -1.45 to -0.87). Evidence suggests that social isolation acts as a mediating factor. Conclusions and Relevance:Although hearing loss and cognition are linked, untreated hearing loss drives the association. Social isolation is a mediating factor in the link for those who have untreated hearing loss. Cognitive decline associated with ARHI is probably preventable by early rehabilitation and increased opportunistic screening for the elderly.

Dataset Information

Genome-wide association analysis demonstrates the highly polygenic character of age-related hearing impairment.

Publications

Genome-wide association analysis demonstrates the highly polygenic character of age-related hearing impairment.

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