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.

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

“…We have previously reported an association of a common variant in the GRM7 gene, rs11928865, with hearing ability based on a pooling-based GWAS of a European sample set. 9 Therefore, we also genotyped this SNP in the Saami population and analysed these data using the mixed-model approach. This resulted in a P-value of 0.045.…”

“…Hitherto, three linkage studies have been performed, [6][7][8] but only one region on chromosome 8q24.13-q24.22 reached genomewide significance. 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.…”

“…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. Acquired mitochondrial mutations have also been proposed as a cause of ARHI in humans.…”

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

“…For the GWAS on the Saami, we checked all SNPs with a P-value below 1.0e À4. For the study by Friedman et al, 3 we selected the SNPs that were significant in the GRM7 gene and compared these with our PC1 results. The results are shown in Supplementary Table 2.…”

“…This gene encodes the metabotropic glutamate receptor type7, which is activated through L-glutamate, the primary excitatory neurotransmitter in the cochlear hair cell. 3 A GWAS in 352 samples from the Saami, an isolated population originating from northern Finland, revealed no genome-wide significant associations for ARHI, although the authors noted one SNP immediately downstream of the GRM7 gene among the most significant association signals. 4 In a study on normal hearing function in 3417 persons over age 18, Girotto et al 5 performed a GWAS in 6 isolated European populations using a meta-analysis approach.…”