Abstract
BackgroundThe genetic basis of hearing loss in humans is relatively poorly understood. In recent years, experimental approaches including laboratory studies of early onset hearing loss in inbred mouse strains, or proteomic analyses of hair cells or hair bundles, have suggested new candidate molecules involved in hearing function. However, the relevance of these genes/gene products to hearing function in humans remains unknown. We investigated whether single nucleotide polymorphisms (SNPs) in the human orthologues of genes of interest arising from the above-mentioned studies correlate with hearing function in children.Methods577 SNPs from 13 genes were each analysed by linear regression against averaged high (3, 4 and 8 kHz) or low frequency (0.5, 1 and 2 kHz) audiometry data from 4970 children in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth-cohort at age eleven years. Genes found to contain SNPs with low p-values were then investigated in 3417 adults in the G-EAR study of hearing.ResultsGenotypic data were available in ALSPAC for a total of 577 SNPs from 13 genes of interest. Two SNPs approached sample-wide significance (pre-specified at p = 0.00014): rs12959910 in CBP80/20-dependent translation initiation factor (CTIF) for averaged high frequency hearing (p = 0.00079, β = 0.61 dB per minor allele); and rs10492452 in L-plastin (LCP1) for averaged low frequency hearing (p = 0.00056, β = 0.45 dB). For low frequencies, rs9567638 in LCP1 also enhanced hearing in females (p = 0.0011, β = −1.76 dB; males p = 0.23, β = 0.61 dB, likelihood-ratio test p = 0.006). SNPs in LCP1 and CTIF were then examined against low and high frequency hearing data for adults in G-EAR. Although the ALSPAC results were not replicated, a SNP in LCP1, rs17601960, is in strong LD with rs9967638, and was associated with enhanced low frequency hearing in adult females in G-EAR (p = 0.00084).ConclusionsThere was evidence to suggest that multiple SNPs in CTIF may contribute a small detrimental effect to hearing, and that a sex-specific locus in LCP1 is protective of hearing. No individual SNPs reached sample-wide significance in both ALSPAC and G-EAR. This is the first report of a possible association between LCP1 and hearing function.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-015-0112-2) contains supplementary material, which is available to authorized users.
Highlights
The genetic basis of hearing loss in humans is relatively poorly understood
Identification of Single nucleotide polymorphism (SNP) in CBP80/20-dependent translation initiation factor (CTIF) and LCP1 that correlate with altered hearing in Avon Longitudinal Study of Parents and Children (ALSPAC) children For the 7082 children for whom hearing data had been obtained at 11 years of age, 4970 (70.2 %) were of white ethnicity and had full genotypic data. 49 % (n = 2445) of the children were male
This study demonstrates for the first time that SNPs in CTIF and LCP1 correlate with effects on hearing function in children at age 11
Summary
The genetic basis of hearing loss in humans is relatively poorly understood. In recent years, experimental approaches including laboratory studies of early onset hearing loss in inbred mouse strains, or proteomic analyses of hair cells or hair bundles, have suggested new candidate molecules involved in hearing function. Over the last 10–15 years, major advances have been made in understanding the molecular basis of mechanotransduction of sound waves in the mammalian inner ear, largely from the study of inherited forms of deafness [7, 8]. The auditory epithelium contains specialised hair cells with an elaborate morphology in which the apical surfaces are decorated with stereociliary or “hair” bundles. These make contact with the tectorial membrane, which is deflected by incoming sound waves. A protein complex, the tip link complex, is located at the tip of each stereocilium and makes contact with adjacent stereocilia such that the bundle is displaced in a coordinated way upon deflection of the tectorial membrane [7]. Mutations in multiple components of the tip link complex, for example, cadherin-23, are causal for the deafness/blindness syndrome, Usher syndrome type I [7, 8, 10,11,12]
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