%0 Journal Article %J PLoS One %D 2014 %T Expression and replication studies to identify new candidate genes involved in normal hearing function. %A Girotto, Giorgia %A Vuckovic, Dragana %A Buniello, Annalisa %A Lorente-Cánovas, Beatriz %A Lewis, Morag %A Gasparini, Paolo %A Steel, Karen P %K Adult %K Animals %K DNA Replication %K Gene Expression Profiling %K Genome-Wide Association Study %K Genotype %K Hair Cells, Auditory %K Hearing %K Humans %K Mice %K Phenotype %K Polymorphism, Single Nucleotide %K Stria Vascularis %X

Considerable progress has been made in identifying deafness genes, but still little is known about the genetic basis of normal variation in hearing function. We recently carried out a Genome Wide Association Study (GWAS) of quantitative hearing traits in southern European populations and found several SNPs with suggestive but none with significant association. In the current study, we followed up these SNPs to investigate which of them might show a genuine association with auditory function using alternative approaches. Firstly, we generated a shortlist of 19 genes from the published GWAS results. Secondly, we carried out immunocytochemistry to examine expression of these 19 genes in the mouse inner ear. Twelve of them showed distinctive cochlear expression patterns. Four showed expression restricted to sensory hair cells (Csmd1, Arsg, Slc16a6 and Gabrg3), one only in marginal cells of the stria vascularis (Dclk1) while the others (Ptprd, Grm8, GlyBP, Evi5, Rimbp2, Ank2, Cdh13) in multiple cochlear cell types. In the third step, we tested these 12 genes for replication of association in an independent set of samples from the Caucasus and Central Asia. Nine out of them showed nominally significant association (p<0.05). In particular, 4 were replicated at the same SNP and with the same effect direction while the remaining 5 showed a significant association in a gene-based test. Finally, to look for genotype-phenotype relationship, the audiometric profiles of the three genotypes of the most strongly associated gene variants were analyzed. Seven out of the 9 replicated genes (CDH13, GRM8, ANK2, SLC16A6, ARSG, RIMBP2 and DCLK1) showed an audiometric pattern with differences between different genotypes further supporting their role in hearing function. These data demonstrate the usefulness of this multistep approach in providing new insights into the molecular basis of hearing and may suggest new targets for treatment and prevention of hearing impairment.

%B PLoS One %V 9 %P e85352 %8 2014 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/24454846?dopt=Abstract %R 10.1371/journal.pone.0085352 %0 Journal Article %J Hum Mol Genet %D 2014 %T Salt-inducible kinase 3, SIK3, is a new gene associated with hearing. %A Wolber, Lisa E %A Girotto, Giorgia %A Buniello, Annalisa %A Vuckovic, Dragana %A Pirastu, Nicola %A Lorente-Cánovas, Beatriz %A Rudan, Igor %A Hayward, Caroline %A Polasek, Ozren %A Ciullo, Marina %A Mangino, Massimo %A Steves, Claire %A Concas, Maria Pina %A Cocca, Massilimiliano %A Spector, Tim D %A Gasparini, Paolo %A Steel, Karen P %A Williams, Frances M K %K Age Factors %K Animals %K Cochlea %K European Continental Ancestry Group %K Genome-Wide Association Study %K Hearing %K Humans %K Mice, Inbred C57BL %K Polymorphism, Single Nucleotide %K Protein Kinases %X

Hearing function is known to be heritable, but few significant and reproducible associations of genetic variants have been identified to date in the adult population. In this study, genome-wide association results of hearing function from the G-EAR consortium and TwinsUK were used for meta-analysis. Hearing ability in eight population samples of Northern and Southern European ancestry (n = 4591) and the Silk Road (n = 348) was measured using pure-tone audiometry and summarized using principal component (PC) analysis. Genome-wide association analyses for PC1-3 were conducted separately in each sample assuming an additive model adjusted for age, sex and relatedness of subjects. Meta-analysis was performed using 2.3 million single-nucleotide polymorphisms (SNPs) tested against each of the three PCs of hearing ability in 4939 individuals. A single SNP lying in intron 6 of the salt-inducible kinase 3 (SIK3) gene was found to be associated with hearing PC2 (P = 3.7×10(-8)) and further supported by whole-genome sequence in a subset. To determine the relevance of this gene in the ear, expression of the Sik3 protein was studied in mouse cochlea of different ages. Sik3 was expressed in murine hair cells during early development and in cells of the spiral ganglion during early development and adulthood. Our results suggest a developmental role of Sik3 in hearing and may be required for the maintenance of adult auditory function.

%B Hum Mol Genet %V 23 %P 6407-18 %8 2014 Dec 1 %G eng %N 23 %1 http://www.ncbi.nlm.nih.gov/pubmed/25060954?dopt=Abstract %R 10.1093/hmg/ddu346