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

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.

A genome-wide association study for age-related hearing impairment in the Saami

“…Intriguingly, the SNP rs161927 (P-value 0.000149), that ranked eighth for PC1, was positioned immediately downstream from the metabotropic GRM7 gene. A previous GWAS of a European and a Finnish sample set, which was based on an age-and gendercorrected Z-score highly correlated with our PC1, 9,11,28,42 already suggested a role for GRM7 in ARHI. 9 GRM7 encodes a metabotropic glutamate receptor that can be activated by L-glutamate, the primary excitatory neurotransmitter in the cochlear hair cell.…”

“…8 In addition, several association studies based on a candidate gene approach and two genome-wide association studies (GWAS) 8,9 have been conducted. Early candidate gene-based association studies are reviewed by Van Eyken et al 10 Recently, based on a candidate gene approach, we reported associations between ARHI and variants in GRHL2, 11 encoding a transcription factor that is also involved in monogenic hearing loss. In addition, based on a pooling GWAS, we reported association with variants in the glutamate receptor-7 gene (GRM7), 9 encoding a metabotropic glutamate receptor assumed to modulate hair cell excitability and synaptic efficacy.…”

Genome-wide association analysis demonstrates the highly polygenic character of age-related hearing impairment

“…9 Phenotypes were described using Principal component (PC) scores, as described in Supplementary data. In total, PC scores were obtained for 2161 individuals.…”

Downregulation of GRHL2 inhibits the proliferation of colorectal cancer cells by targeting ZEB1

“…4,5 This protein expressed in epithelial structures acts as a transcriptional activator, regulating epidermal development. 6,7 GRHL2 is associated with age-related hearing impairment, 8 neural tube closure, 9 epidermal integrity, 10 wound healing, 11 and the regulation of many physiological functions of human airway epithelium. 12 In the context of cancer, GRHL2 has been reported to function as a tumor suppressor.…”