Genome-wide SNP-based linkage scan identifies a locus on 8q24 for an age-related hearing impairment trait

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.

Figure 1

Comparison of Audiograms between Subjects with High and Low Values for PC1, PC2, and PC3 Three subjects were randomly selected from the lower and upper 10% extremes of the distribution for each of the three traits. To show the extent of intrasubject variability, audiograms for both ears are given. Left and right ears correspond to filled and open circles, respectively. For PC1, on average, hearing loss is much less pronounced in individuals from higher extremes (top row) compared to the lower extremes (second row from the top). Subjects with low values for PC2 (fourth row from the top) tend to have a much more sloping audiogram, compared to subjects with high values for PC2 (third row from the top). Subjects with high values for PC3 (second row from the bottom) tend to have a more concave audiogram, compared to subjects in the lower extreme for PC3 (bottom row).

Figure 2

Chromosome 8 Multipoint and Singlepoint LOD Scores for PC3 together with Marker Informativities Gray and red dots represent singlepoint marker informativities and LOD scores, respectively. Gray and blue solid lines represent multipoint informativities and LOD scores, respectively.