TY - JOUR T1 - Expression and replication studies to identify new candidate genes involved in normal hearing function. JF - PLoS One Y1 - 2014 A1 - Girotto, Giorgia A1 - Vuckovic, Dragana A1 - Buniello, Annalisa A1 - Lorente-Cánovas, Beatriz A1 - Lewis, Morag A1 - Gasparini, Paolo A1 - Steel, Karen P KW - Adult KW - Animals KW - DNA Replication KW - Gene Expression Profiling KW - Genome-Wide Association Study KW - Genotype KW - Hair Cells, Auditory KW - Hearing KW - Humans KW - Mice KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Stria Vascularis AB -

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.

VL - 9 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24454846?dopt=Abstract ER -