title: 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.
authors.affiliation: 1] Center for Medical Genetics, University of Antwerp, Antwerp, Belgium [2] StatUa Center for Statistics, University of Antwerp, Antwerp, Belgium.
authors.forename: Erik
authors.initials: E
authors.lastname: Fransen
authors.affiliation: Center for Medical Genetics, University of Antwerp, Antwerp, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Bonneux
authors.affiliation: Neurogenomics Division, The Translational Genomics Research Institute, Phoenix, AZ, USA.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Corneveaux
authors.affiliation: 1] Center for Medical Genetics, University of Antwerp, Antwerp, Belgium [2] StatUa Center for Statistics, University of Antwerp, Antwerp, Belgium [3] Neurogenomics Division, The Translational Genomics Research Institute, Phoenix, AZ, USA.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Schrauwen
authors.affiliation: 1] Audiology Unit, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy [2] Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Di Berardino
authors.affiliation: Cell Biology and Genetics Division, House Research Institute, Los Angeles, CA, USA.
authors.forename: Cory H
authors.initials: CH
authors.lastname: White
authors.affiliation: Cell Biology and Genetics Division, House Research Institute, Los Angeles, CA, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Ohmen
authors.affiliation: Department of Otolaryngology, University Hospital of Antwerp, Edegem, Belgium.
authors.forename: Paul
authors.initials: P
authors.lastname: Van de Heyning
authors.affiliation: 1] Audiology Unit, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy [2] Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Umberto
authors.initials: U
authors.lastname: Ambrosetti
authors.affiliation: Neurogenomics Division, The Translational Genomics Research Institute, Phoenix, AZ, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Huentelman
authors.affiliation: Center for Medical Genetics, University of Antwerp, Antwerp, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Van Camp
authors.affiliation: Cell Biology and Genetics Division, House Research Institute, Los Angeles, CA, USA.
authors.forename: Rick A
authors.initials: RA
authors.lastname: Friedman
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D019295:Computational Biology; D030541:Databases, Genetic; D004777:Environment; D004843:Epistasis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D034381:Hearing Loss / Q000209:etiology* / Q000378:metabolism; D006801:Humans; D008297:Male; D020412:Multifactorial Inheritance; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D019655:Quantitative Trait, Heritable; D012307:Risk Factors; D015398:Signal Transduction