Genome-wide association study for age-related hearing loss (AHL) in the mouse: a meta-analysis

Abstract

Age-related hearing loss (AHL) is characterized by a symmetric sensorineural hearing loss primarily in high frequencies and individuals have different levels of susceptibility to AHL. Heritability studies have shown that the sources of this variance are both genetic and environmental, with approximately half of the variance attributable to hereditary factors as reported by Huag and Tang (Eur Arch Otorhinolaryngol 267(8):1179-1191, 2010). Only a limited number of large-scale association studies for AHL have been undertaken in humans, to date. An alternate and complementary approach to these human studies is through the use of mouse models. Advantages of mouse models include that the environment can be more carefully controlled, measurements can be replicated in genetically identical animals, and the proportion of the variability explained by genetic variation is increased. Complex traits in mouse strains have been shown to have higher heritability and genetic loci often have stronger effects on the trait compared to humans. Motivated by these advantages, we have performed the first genome-wide association study of its kind in the mouse by combining several data sets in a meta-analysis to identify loci associated with age-related hearing loss. We identified five genome-wide significant loci (<10(-6)). One of these loci confirmed a previously identified locus (ahl8) on distal chromosome 11 and greatly narrowed the candidate region. Specifically, the most significant associated SNP is located 450 kb upstream of Fscn2. These data confirm the utility of this approach and provide new high-resolution mapping information about variation within the mouse genome associated with hearing loss.

FIG. 1

The association result of three studies for 8 kHz mouse hearing. The gray horizontal line represents the genome-wide significance threshold 5.0 × 10⁻⁶.

FIG. 2

The association result of three studies for 16 kHz mouse hearing. The gray horizontal line represents the genome-wide significance threshold 5.0 × 10⁻⁶.

FIG. 3

The association result of three studies for 32 kHz mouse hearing. The gray horizontal line represents the genome-wide significance threshold 5.0 × 10⁻⁶.

FIG. 4

Mouse hearing association results from random effect meta-analysis. The gray horizontal line represents the genome-wide significance threshold 5.0 × 10⁻⁶.

FIG. 5

This figure highlights the differences in resolution of our meta-analysis GWAS and the backcross QTL mapping strategy of Johnson et al. The results are shown for distal chromosome 11 (112–122 Mb, NCBI build m37) the ahl8 locus. Both approaches successfully identify an association in this region. However, as shown in the figure, the significant association from the N2 cross (Johnson et al. (2008)) implicates a broad region spanning more than 2.5 Mb. In contrast, the meta-analysis identified a peak-associated SNP approximately 450 kb upstream of Fscn2, the implicated gene at this locus. The horizontal line represents the genome-wide significance threshold 5.0 × 10⁻⁶.

FIG. 6

(A) Forest plot and (B) PM plot for Chr11:120818214 locus (8 kHz). The Forest plot and PM plot shows the effect size estimates and m value from each study. The black square represents the effect size estimate and the size of the square represents the weights given to each study. The width of line in each study represents the confidence interval (CI) for effect size estimate. The diamond located at the bottom of the Forest plot shows the overall effect size estimate and the width of the diamond shows the confidence intervals for the overall effect estimate. The m value of the study represents the posterior probability that the effect of this locus exists for the phenotype. The horizontal dotted line in the PM plot denotes the genome-wide significance threshold (5.0 × 10⁻⁶). The two vertical dotted lines in the PM plot denote the posterior probability threshold for m value (0.1 and 0.9). The color dots for each study in the Forest plot and PM plot shows the posterior probability that a genetic effect exists for the study. Meta P denotes the P value obtained by the random effect meta-analysis.

FIG. 7

(A) Forest plot and (B) PM plot for Chr11:120818214 locus (16 kHz).

FIG. 8

(A) Forest plot and (B) PM plot for Chr11:120818214 locus (32 kHz).

FIG. 9

(A) Forest plot and (B) PM plot for Chr1:196270162 locus (8 kHz).

FIG. 10

(A) Forest plot and (B) PM plot for Chr8:130247700 locus (8 kHz).

FIG. 11

(A) Forest plot and (B) PM plot for Chr9:30287464 locus (16 kHz).

FIG. 12

(A) Forest plot and (B) PM plot for Chr18:24320393 locus (32 kHz).