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Am J Hum Genet. 2019 Oct 3;105(4):788-802. doi: 10.1016/j.ajhg.2019.09.008. Epub 2019 Sep 26.

GWAS Identifies 44 Independent Associated Genomic Loci for Self-Reported Adult Hearing Difficulty in UK Biobank.

Author information

1
Department of Twin Research and Genetic Epidemiology, School of Life Course Sciences, King's College London, London SE1 7EH, UK; UCL Ear Institute, University College London, London WC1X 8EE, UK.
2
Department of Twin Research and Genetic Epidemiology, School of Life Course Sciences, King's College London, London SE1 7EH, UK.
3
UCL Ear Institute, University College London, London WC1X 8EE, UK; Centre for Medical Image Computing, Department of Medical Physics and Biomedical Engineering, University College London, London, WC1E 7JE, UK.
4
Division of Informatics, Imaging & Data Sciences, The University of Manchester, Manchester M13 9PT, UK.
5
Manchester Centre for Audiology and Deafness, The University of Manchester, Manchester M13 9PL, UK.
6
Manchester Centre for Audiology and Deafness, The University of Manchester, Manchester M13 9PL, UK; Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, UK.
7
Manchester Centre for Audiology and Deafness, The University of Manchester, Manchester M13 9PL, UK; Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, UK; Departments of Obstetrics and Gynecology and of Pathology, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02115, USA.
8
Manchester Centre for Audiology and Deafness, The University of Manchester, Manchester M13 9PL, UK; Cincinnati Children's Hospital Medical Centre, Department of Otolaryngology, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
9
UCL Ear Institute, University College London, London WC1X 8EE, UK. Electronic address: sally.dawson@ucl.ac.uk.
10
Department of Twin Research and Genetic Epidemiology, School of Life Course Sciences, King's College London, London SE1 7EH, UK. Electronic address: frances.williams@kcl.ac.uk.

Abstract

Age-related hearing impairment (ARHI) is the most common sensory impairment in the aging population; a third of individuals are affected by disabling hearing loss by the age of 65. It causes social isolation and depression and has recently been identified as a risk factor for dementia. The genetic risk factors and underlying pathology of ARHI are largely unknown, meaning that targets for new therapies remain elusive, yet heritability estimates range between 35% and 55%. We performed genome-wide association studies (GWASs) for two self-reported hearing phenotypes, using more than 250,000 UK Biobank (UKBB) volunteers aged between 40 and 69 years. Forty-four independent genome-wide significant loci (p < 5E-08) were identified, considerably increasing the number of established trait loci. Thirty-four loci are novel associations with hearing loss of any form, and only one of the ten known hearing loci has a previously reported association with an ARHI-related trait. Gene sets from these loci are enriched in auditory processes such as synaptic activities, nervous system processes, inner ear morphology, and cognition, while genetic correlation analysis revealed strong positive correlations with multiple personality and psychological traits for the first time. Immunohistochemistry for protein localization in adult mouse cochlea implicate metabolic, sensory, and neuronal functions for NID2, CLRN2, and ARHGEF28. These results provide insight into the genetic landscape underlying ARHI, opening up novel therapeutic targets for further investigation. In a wider context, our study also highlights the viability of using self-report phenotypes for genetic discovery in very large samples when deep phenotyping is unavailable.

PMID:
31564434
PMCID:
PMC6817556
[Available on 2020-04-03]
DOI:
10.1016/j.ajhg.2019.09.008

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