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

Lut Van Laer, Els Van Eyken, Erik Fransen, Jeroen R. Huyghe, Vedat Topsakal, Jan Jaap Hendrickx, Samuli Hannula, Elina Mäki-Torkko, Mona Jensen, Kelly Demeester, Manuela Baur, Amanda Bonaconsa, Manuela Mazzoli, Angeles Espeso, Katia Verbruggen, Joke Huyghe, Patrick Huygen, Sylvia Kunst, Minna Manninen, Annelies KoningsAmalia N. Diaz-Lacava, Michael Steffens, Thomas F. Wienker, Ilmari Pyykkö, Cor W R J Cremers, Hannie Kremer, Ingeborg Dhooge, Dafydd Stephens, Eva Orzan, Markus Pfister, Michael Bille, Agnete Parving, Martti Sorri, Paul H. Van de Heyning, Guy Van Camp

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)159-169
Number of pages11
JournalHuman Molecular Genetics
Volume17
Issue number2
DOIs
Publication statusPublished - Jan 15 2008

ASJC Scopus subject areas

  • Genetics

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    Van Laer, L., Van Eyken, E., Fransen, E., Huyghe, J. R., Topsakal, V., Hendrickx, J. J., Hannula, S., Mäki-Torkko, E., Jensen, M., Demeester, K., Baur, M., Bonaconsa, A., Mazzoli, M., Espeso, A., Verbruggen, K., Huyghe, J., Huygen, P., Kunst, S., Manninen, M., ... Van Camp, G. (2008). The grainyhead like 2 gene (GRHL2), alias TFCP2L3, is associated with age-related hearing impairment. Human Molecular Genetics, 17(2), 159-169. https://doi.org/10.1093/hmg/ddm292