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: 10.99). 09/2008; 83(3):401-7. DOI: 10.1016/j.ajhg.2008.08.002
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Elina Mäki-Torkko, Aug 27, 2015
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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 · 2.85 Impact Factor
  • Source
    • "es show that progres - sive and age - related hearing loss depends on genetic predisposition , where disease onset and progression are determined by complex interactions between genetic and environmental factors , further underscoring our lack of understanding of the full spectrum of genetic variants leading to deafness ( Friedman et al . , 2009 ; Huyghe et al . , 2008 ; Van Eyken et al . , 2007a , b ; Van Laer et al . , 2008 ) . The genomic technologies described above are being translated into high - throughout pipelines to accelerate the pace of gene discovery , functional annotation , and analysis of disease mecha - nisms . The first example of targeted genomic capture and MPS to identify a Mendel"
    [Show abstract] [Hide abstract]
    ABSTRACT: Our understanding of hereditary hearing loss has greatly improved since the discovery of the first human deafness gene. These discoveries have only accelerated due to the great strides in DNA sequencing technology since the completion of the human genome project. Here, we review the immense impact that these developments have had in both deafness research and clinical arenas. We review commonly used genomic technologies as well as the application of these technologies to the genetic diagnosis of hereditary hearing loss and to the discovery of novel deafness genes.
    Hearing research 12/2011; 282(1-2):1-9. DOI:10.1016/j.heares.2011.10.001 · 2.85 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Altersschwerhörigkeit (ASH), auch Presbyakusis genannt, ist die häufgste sensorische Beeinträchtigung von älteren Personen. 37 % der 61–70-Jährigen haben einen signifkanten Hörverlust von wenigstens 25 dB[9] Von ASH Betroffene gewöhnen sich nur schwer an diese Einschränkung. Deshalb hat Schwerhörigkeit (SH) großen Einfuss auf die Lebensqualität und das psychologische Befnden der Betroffenen. Kommunikationsprobleme führen zu psychosozialer Dysfunktion mit sozialer Isolation als Folge. Betroffene verlieren ihre Unabhängigkeit; Depressionen, Angstzustände, Lethargie, soziale Unzufriedenheit und möglicherweise kognitive Defzite, ähnlich der Demenz, folgen daraus[8], [18].
Show more