Genome-wide SNP-Based Linkage Scan Identifies a Locus on 8q24 for an Age-Related Hearing Impairment Trait

Department of Medical Genetics, University of Antwerp, B-2610 Antwerp, Belgium.
The American Journal of Human Genetics (Impact Factor: 10.93). 09/2008; 83(3):401-7. DOI: 10.1016/j.ajhg.2008.08.002
Source: PubMed


Age-related hearing impairment (ARHI), or presbycusis, is a very common multifactorial disorder. Despite the knowledge that genetics play an important role in the etiology of human ARHI as revealed by heritability studies, to date, its precise genetic determinants remain elusive. Here we report the results of a cross-sectional family-based genetic study employing audiometric data. By using principal component analysis, we were able to reduce the dimensionality of this multivariate phenotype while capturing most of the variation and retaining biologically important features of the audiograms. We conducted a genome-wide association as well as a linkage scan with high-density SNP microarrays. Because of the presence of genetic population substructure, association testing was stratified after which evidence was combined by meta-analysis. No association signals reaching genome-wide significance were detected. Linkage analysis identified a linkage peak on 8q24.13-q24.22 for a trait correlated to audiogram shape. The signal reached genome-wide significance, as assessed by simulations. This finding represents the first locus for an ARHI trait.

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Available from: Elina Mäki-Torkko, Oct 08, 2015
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    • "Variance in PTA was summarised using principal component analysis, where PC1 represented the threshold shift over all frequencies (0.125–8.0 kHz) and captured 54.25% of the variance. A high PC1 score thus corresponded to reduced hearing ability [27]. "
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    ABSTRACT: Epigenetic regulation of gene expression has been shown to change over time and may be associated with environmental exposures in common complex traits. Age-related hearing impairment is a complex disorder, known to be heritable, with heritability estimates of 57-70%. Epigenetic regulation might explain the observed difference in age of onset and magnitude of hearing impairment with age. Epigenetic epidemiology studies using unrelated samples can be limited in their ability to detect small effects, and recent epigenetic findings in twins underscore the power of this well matched study design. We investigated the association between venous blood DNA methylation epigenome-wide and hearing ability. Pure-tone audiometry (PTA) and Illumina HumanMethylation array data were obtained from female twin volunteers enrolled in the TwinsUK register. Two study groups were explored: first, an epigenome-wide association scan (EWAS) was performed in a discovery sample (n = 115 subjects, age range: 47-83 years, Illumina 27 k array), then replication of the top ten associated probes from the discovery EWAS was attempted in a second unrelated sample (n = 203, age range: 41-86 years, Illumina 450 k array). Finally, a set of monozygotic (MZ) twin pairs (n = 21 pairs) within the discovery sample (Illumina 27 k array) was investigated in more detail in an MZ discordance analysis. Hearing ability was strongly associated with DNA methylation levels in the promoter regions of several genes, including TCF25 (cg01161216, p = 6.6×10-6), FGFR1 (cg15791248, p = 5.7×10-5) and POLE (cg18877514, p = 6.3×10-5). Replication of these results in a second sample confirmed the presence of differential methylation at TCF25 (p(replication) = 6×10-5) and POLE (p(replication) = 0.016). In the MZ discordance analysis, twins' intrapair difference in hearing ability correlated with DNA methylation differences at ACP6 (cg01377755, r = -0.75, p = 1.2×10-4) and MEF2D (cg08156349, r = -0.75, p = 1.4×10-4). Examination of gene expression in skin, suggests an influence of differential methylation on expression, which may account for the variation in hearing ability with age.
    PLoS ONE 09/2014; 9(9):e105729. DOI:10.1371/journal.pone.0105729 · 3.23 Impact Factor
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    • "Compared to candidate genes association studies, the genome-wide association study (GWAS) might provide the most convincing evidence for genetic susceptibility to complex diseases. Three GWASs of ARHI have been published recently [14,27,28]. Research done by Friedman et al. [27] provided convincing evidence that variations in glutamate metabotrophic receptor 7 (GRM7, OMIM ID: 604101) was associated with ARHI in older European adults. "
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    ABSTRACT: Several single nucleotide polymorphisms (SNPs) of the Glutamate metabotrophic receptor 7 gene (GRM7) have recently been identified by the genome-wide association study (GWAS) as potentially playing a role in susceptibility to age-related hearing impairment (ARHI), however this has not been validated in the Han Chinese population. The aim of this study was to determine if these SNPs are also associated with ARHI in an elderly male Han Chinese population. In this case-control candidate genes association study, a total of 982 men with ARHI and 324 normal-hearing controls subjects were studied. Using K-means cluster analysis, four audiogram shape subtypes of ARHI were identified in the case group: ''flat shape (FL)'', ''sloping shape (SL)'', ''2-4 kHz abrupt loss (AL) shape'' and ''8 kHz dip (8D) shape''. Results suggested that the SNP rs11928865 (A>T) of GRM7 was significantly associated with ARHI after adjusting for non-genetic factors (p= 0.000472, OR= 1.599, 95%CI= 1.229~2.081). Furthermore, frequency of TT genotype (rs11928865) were significant higher in the SL subgroup and AL subgroup with compared to controls group (p= 9.41E-05, OR= 1.945, 95%CI= 1.393~2.715; p= 0.000109, OR= 1.915, 95%CI= 1.378~2.661 adjusted, respectively) after Bonferroni correction. However, there wasn't significant difference in the frequency of the TT genotype between cases in the FL subgroup or the 8D subgroup with when compared with controls. Results of the current study suggest that, in an elderly male Han Chinese population, GRM7 SNP rs11928865 (TT) occurs more frequently in ARHI patients with SL and AL phenotype patterns.
    PLoS ONE 10/2013; 8(10):e77153. DOI:10.1371/journal.pone.0077153 · 3.23 Impact Factor
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    • "In one study, about 40 different candidate genes were tested based on their association with Mendelian forms of hearing loss; the most significant association was within an intron of the grainyhead-like 2 gene (GRHL2, OMIM ID: 608576) (Van Laer et al., 2008). Several linkage studies were attempted, but they either failed to identify any genome-wide significant peaks or exhibited such broad peaks that it was impossible to identify specific causative genes or mutations (DeStefano et al., 2003; Garringer et al., 2006; Huyghe et al., 2008). A 500K-single nucleotide polymorphism (SNP) genome-wide association study of a large European cohort of older adults (Study 1) resulted in the identification of one haplotype within the glutamate metabotrophic receptor 7 (GRM7, OMIM ID: 604101) as harboring a significant risk allele for ARHI (Friedman et al., 2009). "
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    ABSTRACT: Age-related hearing impairment (ARHI), or presbycusis, is a common condition of the elderly that results in significant communication difficulties in daily life. Clinically, it has been defined as a progressive loss of sensitivity to sound, starting at the high frequencies, inability to understand speech, lengthening of the minimum discernable temporal gap in sounds, and a decrease in the ability to filter out background noise. The causes of presbycusis are likely a combination of environmental and genetic factors. Previous research into the genetics of presbycusis has focused solely on hearing as measured by pure-tone thresholds. A few loci have been identified, based on a best ear pure-tone average phenotype, as having a likely role in susceptibility to this type of hearing loss; and GRM7 is the only gene that has achieved genome-wide significance. We examined the association of GRM7 variants identified from the previous study, which used an European cohort with Z-scores based on pure-tone thresholds, in a European-American population from Rochester, NY (N = 687), and used novel phenotypes of presbycusis. In the present study mixed modeling analyses were used to explore the relationship of GRM7 haplotype and SNP genotypes with various measures of auditory perception. Here we show that GRM7 alleles are associated primarily with peripheral measures of hearing loss, and particularly with speech detection in older adults.
    Hearing research 10/2012; 294(1-2). DOI:10.1016/j.heares.2012.08.016 · 2.97 Impact Factor
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