title: GRM7 variants confer susceptibility to age-related hearing impairment.
abstract: Age-related hearing impairment (ARHI), or presbycusis, is the most prevalent sensory impairment in the elderly. ARHI is a complex disease caused by an interaction between environmental and genetic factors. Here we describe the results of the first whole genome association study for ARHI. The study was performed using 846 cases and 846 controls selected from 3434 individuals collected by eight centers in six European countries. DNA pools for cases and controls were allelotyped on the Affymetrix 500K GeneChip for each center separately. The 252 top-ranked single nucleotide polymorphisms (SNPs) identified in a non-Finnish European sample group (1332 samples) and the 177 top-ranked SNPs from a Finnish sample group (360 samples) were confirmed using individual genotyping. Subsequently, the 23 most interesting SNPs were individually genotyped in an independent European replication group (138 samples). This resulted in the identification of a highly significant and replicated SNP located in GRM7, the gene encoding metabotropic glutamate receptor type 7. Also in the Finnish sample group, two GRM7 SNPs were significant, albeit in a different region of the gene. As the Finnish are genetically distinct from the rest of the European population, this may be due to allelic heterogeneity. We performed histochemical studies in human and mouse and showed that mGluR7 is expressed in hair cells and in spiral ganglion cells of the inner ear. Together these data indicate that common alleles of GRM7 contribute to an individual's risk of developing ARHI, possibly through a mechanism of altered susceptibility to glutamate excitotoxicity.
authors.affiliation: House Ear Institute, Gonda Research Center for Cell and Molecular Biology, Los Angeles, CA, USA. rfriedman@hei.org
authors.forename: Rick A
authors.initials: RA
authors.lastname: Friedman
authors.forename: Lut
authors.initials: L
authors.lastname: Van Laer
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Huentelman
authors.forename: Sonal S
authors.initials: SS
authors.lastname: Sheth
authors.forename: Els
authors.initials: E
authors.lastname: Van Eyken
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Corneveaux
authors.forename: Waibhav D
authors.initials: WD
authors.lastname: Tembe
authors.forename: Rebecca F
authors.initials: RF
authors.lastname: Halperin
authors.forename: Ashley Q
authors.initials: AQ
authors.lastname: Thorburn
authors.forename: Sofie
authors.initials: S
authors.lastname: Thys
authors.forename: Sarah
authors.initials: S
authors.lastname: Bonneux
authors.forename: Erik
authors.initials: E
authors.lastname: Fransen
authors.forename: Jeroen
authors.initials: J
authors.lastname: Huyghe
authors.forename: Ilmari
authors.initials: I
authors.lastname: Pyykkö
authors.forename: Cor W R J
authors.initials: CW
authors.lastname: Cremers
authors.forename: Hannie
authors.initials: H
authors.lastname: Kremer
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Dhooge
authors.forename: Dafydd
authors.initials: D
authors.lastname: Stephens
authors.forename: Eva
authors.initials: E
authors.lastname: Orzan
authors.forename: Markus
authors.initials: M
authors.lastname: Pfister
authors.forename: Michael
authors.initials: M
authors.lastname: Bille
authors.forename: Agnete
authors.initials: A
authors.lastname: Parving
authors.forename: Martti
authors.initials: M
authors.lastname: Sorri
authors.forename: Paul H
authors.initials: PH
authors.lastname: Van de Heyning
authors.forename: Linna
authors.initials: L
authors.lastname: Makmura
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Ohmen
authors.forename: Frederick H
authors.initials: FH
authors.lastname: Linthicum
authors.forename: Jose N
authors.initials: JN
authors.lastname: Fayad
authors.forename: John V
authors.initials: JV
authors.lastname: Pearson
authors.forename: David W
authors.initials: DW
authors.lastname: Craig
authors.forename: Dietrich A
authors.initials: DA
authors.lastname: Stephan
authors.forename: Guy
authors.initials: G
authors.lastname: Van Camp
mesh_terms: D000367:Age Factors; D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D007758:Ear, Inner / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011304:Presbycusis / Q000235:genetics* / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000235:genetics* / Q000378:metabolism; D044465:White People / Q000235:genetics; D000097808:GluK3 Kainate Receptor
chemical_list: D018092:Kainic Acid Receptors; D000097808:GluK3 Kainate Receptor