Expression and Replication Studies to Identify New Candidate Genes Involved in Normal Hearing Function

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2014 Jan 24

PMID 24454846

Citations 26

Authors

Giorgia Girotto

Dragana Vuckovic

Annalisa Buniello

Beatriz Lorente-Canovas

Morag Lewis

Paolo Gasparini

Karen P Steel

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

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References

Wang K, Abbott D . A principal components regression approach to multilocus genetic association studies. Genet Epidemiol. 2007; 32(2):108-18. DOI: 10.1002/gepi.20266. View

Tannenbaum J, Slepecky N . Localization of microtubules containing posttranslationally modified tubulin in cochlear epithelial cells during development. Cell Motil Cytoskeleton. 1997; 38(2):146-62. DOI: 10.1002/(SICI)1097-0169(1997)38:2<146::AID-CM4>3.0.CO;2-5. View

Abecasis G, Altshuler D, Auton A, Brooks L, Durbin R, Gibbs R . A map of human genome variation from population-scale sequencing. Nature. 2010; 467(7319):1061-73. PMC: 3042601. DOI: 10.1038/nature09534. View

Baig S, Koschak A, Lieb A, Gebhart M, Dafinger C, Nurnberg G . Loss of Ca(v)1.3 (CACNA1D) function in a human channelopathy with bradycardia and congenital deafness. Nat Neurosci. 2010; 14(1):77-84. DOI: 10.1038/nn.2694. View

Howie B, Fuchsberger C, Stephens M, Marchini J, Abecasis G . Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. Nat Genet. 2012; 44(8):955-9. PMC: 3696580. DOI: 10.1038/ng.2354. View

Dror A, Avraham K . Hearing impairment: a panoply of genes and functions. Neuron. 2010; 68(2):293-308. DOI: 10.1016/j.neuron.2010.10.011. View

Liu X, Ouyang X, Xia X, Zheng J, Pandya A, Li F . Prestin, a cochlear motor protein, is defective in non-syndromic hearing loss. Hum Mol Genet. 2003; 12(10):1155-62. DOI: 10.1093/hmg/ddg127. View

Goodyear R, Legan P, Wright M, Marcotti W, Oganesian A, Coats S . A receptor-like inositol lipid phosphatase is required for the maturation of developing cochlear hair bundles. J Neurosci. 2003; 23(27):9208-19. PMC: 6740823. View

Lin P, Gleeson J, Corbo J, Flanagan L, Walsh C . DCAMKL1 encodes a protein kinase with homology to doublecortin that regulates microtubule polymerization. J Neurosci. 2000; 20(24):9152-61. PMC: 6773030. View

10.

Bryant E, Dressen A, Bunker C, Hokanson J, Hamman R, Kamboh M . A multiethnic replication study of plasma lipoprotein levels-associated SNPs identified in recent GWAS. PLoS One. 2013; 8(5):e63469. PMC: 3661596. DOI: 10.1371/journal.pone.0063469. View

11.

Aulchenko Y, Ripke S, Isaacs A, Van Duijn C . GenABEL: an R library for genome-wide association analysis. Bioinformatics. 2007; 23(10):1294-6. DOI: 10.1093/bioinformatics/btm108. View

12.

Schulz H, Stohr H, Weber B . Characterization of three novel isoforms of the metabotrobic glutamate receptor 7 (GRM7). Neurosci Lett. 2002; 326(1):37-40. DOI: 10.1016/s0304-3940(02)00306-3. View

13.

Parsons M, Lester K, Barclay N, Nolan P, Eley T, Gregory A . Replication of Genome-Wide Association Studies (GWAS) loci for sleep in the British G1219 cohort. Am J Med Genet B Neuropsychiatr Genet. 2013; 162B(5):431-8. DOI: 10.1002/ajmg.b.32106. View

14.

Gaudet R . A primer on ankyrin repeat function in TRP channels and beyond. Mol Biosyst. 2008; 4(5):372-9. PMC: 3006086. DOI: 10.1039/b801481g. View

15.

El-Amraoui A, Petit C . Cadherin defects in inherited human diseases. Prog Mol Biol Transl Sci. 2013; 116:361-84. DOI: 10.1016/B978-0-12-394311-8.00016-9. View

16.

Cartmell J, Schoepp D . Regulation of neurotransmitter release by metabotropic glutamate receptors. J Neurochem. 2000; 75(3):889-907. DOI: 10.1046/j.1471-4159.2000.0750889.x. View

17.

Dumitrescu L, Carty C, Taylor K, Schumacher F, Hindorff L, Ambite J . Genetic determinants of lipid traits in diverse populations from the population architecture using genomics and epidemiology (PAGE) study. PLoS Genet. 2011; 7(6):e1002138. PMC: 3128106. DOI: 10.1371/journal.pgen.1002138. View

18.

Shahin H, Rahil M, Abu Rayan A, Avraham K, King M, Kanaan M . Nonsense mutation of the stereociliar membrane protein gene PTPRQ in human hearing loss DFNB84. J Med Genet. 2010; 47(9):643-5. DOI: 10.1136/jmg.2009.075697. View

19.

Girotto G, Pirastu N, Sorice R, Biino G, Campbell H, DAdamo A . Hearing function and thresholds: a genome-wide association study in European isolated populations identifies new loci and pathways. J Med Genet. 2011; 48(6):369-74. DOI: 10.1136/jmg.2010.088310. View

20.

Kraus D, Elliott G, Chute H, Horan T, Pfenninger K, Sanford S . CSMD1 is a novel multiple domain complement-regulatory protein highly expressed in the central nervous system and epithelial tissues. J Immunol. 2006; 176(7):4419-30. DOI: 10.4049/jimmunol.176.7.4419. View