title: Genome-wide association analysis on normal hearing function identifies PCDH20 and SLC28A3 as candidates for hearing function and loss.
abstract: Hearing loss and individual differences in normal hearing both have a substantial genetic basis. Although many new genes contributing to deafness have been identified, very little is known about genes/variants modulating the normal range of hearing ability. To fill this gap, we performed a two-stage meta-analysis on hearing thresholds (tested at 0.25, 0.5, 1, 2, 4, 8 kHz) and on pure-tone averages (low-, medium- and high-frequency thresholds grouped) in several isolated populations from Italy and Central Asia (total N = 2636). Here, we detected two genome-wide significant loci close to PCDH20 and SLC28A3 (top hits: rs78043697, P = 4.71E-10 and rs7032430, P = 2.39E-09, respectively). For both loci, we sought replication in two independent cohorts: B58C from the UK (N = 5892) and FITSA from Finland (N = 270). Both loci were successfully replicated at a nominal level of significance (P < 0.05). In order to confirm our quantitative findings, we carried out RT-PCR and reported RNA-Seq data, which showed that both genes are expressed in mouse inner ear, especially in hair cells, further suggesting them as good candidates for modulatory genes in the auditory system. Sequencing data revealed no functional variants in the coding region of PCDH20 or SLC28A3, suggesting that variation in regulatory sequences may affect expression. Overall, these results contribute to a better understanding of the complex mechanisms underlying human hearing function.
authors.affiliation: Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste 34100, Italy.
authors.forename: Dragana
authors.initials: D
authors.lastname: Vuckovic
authors.affiliation: UCL Ear Institute, University College London, London WC1X 8EE, UK.
authors.forename: Sally
authors.initials: S
authors.lastname: Dawson
authors.affiliation: Howard Hughes Medical Institute and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Deborah I
authors.initials: DI
authors.lastname: Scheffer
authors.affiliation: Gerontology Research Center and Department of Health Sciences, University of Jyväskylä, Jyväskylä FI-40014, Finland.
authors.forename: Taina
authors.initials: T
authors.lastname: Rantanen
authors.affiliation: Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste 34100, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Morgan
authors.affiliation: Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste 34100, Italy.
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Di Stazio
authors.affiliation: Institute for Maternal and Child Health IRCCS 'Burlo Garofolo', Trieste 34100, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Vozzi
authors.affiliation: Institute of Genetics and Biophysics 'A. Buzzati-Traverso', CNR, Naples 80131, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Nutile
authors.affiliation: Institute of Population Genetics, National Research Council of Italy, Sassari 07100, Italy.
authors.forename: Maria P
authors.initials: MP
authors.lastname: Concas
authors.affiliation: Institute of Molecular Genetics, National Research Council of Italy, Pavia 27100, Italy.
authors.forename: Ginevra
authors.initials: G
authors.lastname: Biino
authors.affiliation: UCL Ear Institute, University College London, London WC1X 8EE, UK.
authors.forename: Lisa
authors.initials: L
authors.lastname: Nolan
authors.affiliation: Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki FI-00014, Finland and.
authors.forename: Aileen
authors.initials: A
authors.lastname: Bahl
authors.affiliation: Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki FI-00014, Finland and.
authors.forename: Anu
authors.initials: A
authors.lastname: Loukola
authors.affiliation: Gerontology Research Center and Department of Health Sciences, University of Jyväskylä, Jyväskylä FI-40014, Finland.
authors.forename: Anne
authors.initials: A
authors.lastname: Viljanen
authors.affiliation: UCL Ear Institute, University College London, London WC1X 8EE, UK.
authors.forename: Adrian
authors.initials: A
authors.lastname: Davis
authors.affiliation: Institute of Genetics and Biophysics 'A. Buzzati-Traverso', CNR, Naples 80131, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Ciullo
authors.affiliation: Howard Hughes Medical Institute and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Corey
authors.affiliation: Institute of Population Genetics, National Research Council of Italy, Sassari 07100, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Pirastu
authors.affiliation: Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste 34100, Italy, Institute for Maternal and Child Health IRCCS 'Burlo Garofolo', Trieste 34100, Italy, Experimental Genetics Division, Sidra, Doha, Qatar.
authors.forename: Paolo
authors.initials: P
authors.lastname: Gasparini
authors.affiliation: Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste 34100, Italy, giorgia.girotto@burlo.trieste.it.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Girotto
mesh_terms: D000818:Animals; D001209:Asia, Central; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D003638:Deafness / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods*; D006199:Hair Cells, Auditory, Inner / Q000378:metabolism; D006309:Hearing / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007558:Italy; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D000091363:Protocadherins; D017423:Sequence Analysis, RNA / Q000379:methods
chemical_list: D015820:Cadherins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C000601912:PCDH20 protein, human; D000091363:Protocadherins; C065171:cif nucleoside transporter