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Human Molecular Genetics Advance Access published online on October 6, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm292
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The grainyhead like 2 gene (GRHL2), alias TFCP2L3, is associated with age-related hearing impairment

Lut Van Laer1,{dagger}, Els Van Eyken1,{dagger}, Erik Fransen1, Jeroen R. Huyghe1, Vedat Topsakal2, Jan-Jaap Hendrickx2,3, Samuli Hannula4, Elina Mäki-Torkko4, Mona Jensen5, Kelly Demeester2, Manuela Baur6, Amanda Bonaconsa7, Manuela Mazzoli7, Angeles Espeso8, Katia Verbruggen9, Joke Huyghe9, Patrick Huygen3, Sylvia Kunst3, Minna Manninen10, Annelies Konings1, Amalia N. Diaz-Lacava11, Michael Steffens11, Thomas Wienker11, Ilmari Pyykkö10, Cor W.R.J. Cremers3, Hannie Kremer3, Ingeborg Dhooge9, Dafydd Stephens8, Eva Orzan7, Markus Pfister6, Michael Bille5, Agnete Parving5, Martti Sorri4, Paul H. Van de Heyning2 and Guy Van Camp1,*

1 Department of Medical Genetics, University of Antwerp, B-2610 Antwerp, Belgium 2 Department of Otorhinolaryngology, University Hospital of Antwerp, B-2650 Antwerp, Belgium 3 Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands 4 Department of Otorhinolaryngology, University of Oulu, FIN 90220 Oulu, Finland 5 Department of Audiology, Bispebjerg Hospital, 2400 Copenhagen, Denmark 6 Department of Otorhinolaryngology, University of Tübingen, 72074 Tübingen, Germany 7 Department of Oto-surgery, University Hospital Padova, 35128 Padova, Italy 8 Welsh Hearing Institute, Cardiff University, Cardiff CF4 4XW, UK 9 Department of Otorhinolaryngology, University Hospital of Ghent, B-9000 Ghent, Belgium 10 Department of Otorhinolaryngology, University of Tampere, FIN 33014 Tampere, Finland 11 Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, D-53105 Bonn, Germany

* To whom correspondence should be addressed at: Dr. Guy Van Camp, Department of Medical Genetics, University of Antwerp, Campus Drie Eiken, Universiteitsplein 1, B-2610 Antwerp, Belgium. Tel.: +323/820.24.91, Fax: +323/820.25.66, Email: guy.vancamp{at}ua.ac.be

Received September 13, 2007; Revised October 1, 2007; Accepted October 1, 2007

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 9 centers from 7 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 on 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.

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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