The grainyhead like 2 gene (GRHL2), alias TFCP2L3, is associated with age-related hearing impairment.
Age-related hearing impairment (ARHI) is the most prevalent sensory impairment in the elderly. ARHI is a complex disease caused by an interaction between environmental and genetic factors. The contribution of various environmental factors has been relatively extensively studied. In contrast, investigations to identify the genetic risk factors have only recently been initiated. In this paper we describe the results of an association study performed on 2418 ARHI samples derived from nine centers from seven European countries. In 70 candidate genes, a total of 768 tag single nucleotide polymorphisms (SNPs) were selected based on HAPMAP data. These genes were chosen among the monogenic hearing loss genes identified in mice and men in addition to several strong functional candidates. After genotyping and data polishing, statistical analysis of all samples combined resulted in a P-value that survived correction for multiple testing for one SNP in the GRHL2 gene. Other SNPs in this gene were also associated, albeit to a lesser degree. Subsequently, an analysis of the most significant GRHL2 SNP was performed separately for each center. The direction of the association was identical in all nine centers. Two centers showed significant associations and a third center showed a trend towards significance. Subsequent fine mapping of this locus demonstrated that the majority of the associated SNPs reside in intron 1. We hypothesize that the causative variant may change the expression levels of a GRHL2 isoform.
Van Laer
Lut
L
Department of Medical Genetics, University of Antwerp, B-2610 Antwerp, Belgium.
Van Eyken
Els
E
Fransen
Erik
E
Huyghe
Jeroen R
JR
Topsakal
Vedat
V
Hendrickx
Jan-Jaap
JJ
Hannula
Samuli
S
Mäki-Torkko
Elina
E
Jensen
Mona
M
Demeester
Kelly
K
Baur
Manuela
M
Bonaconsa
Amanda
A
Mazzoli
Manuela
M
Espeso
Angeles
A
Verbruggen
Katia
K
Huyghe
Joke
J
Huygen
Patrick
P
Kunst
Sylvia
S
Manninen
Minna
M
Konings
Annelies
A
Diaz-Lacava
Amalia N
AN
Steffens
Michael
M
Wienker
Thomas F
TF
Pyykkö
Ilmari
I
Cremers
Cor W R J
CW
Kremer
Hannie
H
Dhooge
Ingeborg
I
Stephens
Dafydd
D
Orzan
Eva
E
Pfister
Markus
M
Bille
Michael
M
Parving
Agnete
A
Sorri
Martti
M
Van de Heyning
Paul H
PH
Van Camp
Guy
G
D000368:Aged; D004268:DNA-Binding Proteins / Q000235:genetics*; D005060:Europe; D020022:Genetic Predisposition to Disease; D006801:Humans; D007438:Introns; D015810:Linkage Disequilibrium; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011304:Presbycusis / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*
D004268:DNA-Binding Proteins; C470830:GRHL2 protein, human; D020033:Protein Isoforms; D014157:Transcription Factors