Abstract

Hearing loss is one of the top contributors to years lived with disability and is a risk factor for dementia. Molecular evidence on the cellular origins of hearing loss in humans is growing. Here, we performed a genome-wide association meta-analysis of clinically diagnosed and self-reported hearing impairment on 723,266 individuals and identified 48 significant loci, 10 of which are novel. A large proportion of associations comprised missense variants, half of which lie within known familial hearing loss loci. We used single-cell RNA-sequencing data from mouse cochlea and brain and mapped common-variant genomic results to spindle, root, and basal cells from the stria vascularis, a structure in the cochlea necessary for normal hearing. Our findings indicate the importance of the stria vascularis in the mechanism of hearing impairment, providing future paths for developing targets for therapeutic intervention in hearing loss.

Original languageEnglish
Pages (from-to)1077-1091
Number of pages15
JournalAmerican Journal of Human Genetics
Volume109
Issue number6
DOIs
StatePublished - 2 Jun 2022

Funding

FundersFunder number
Data Tecnica International
Dutch Hearing Health Foundation
Forschung Für Leben
StratRegen
Tysta Skolan
Zoe Global Ltd
National Institutes of Health
U.S. Department of DefenseW81XWH-21-1-0578
National Institute on AgingR01 AG049607, R01 AG054076, RF1 AG063507, R01 AG059421, U01 AG052409, U01 AG058589, RF1 AG066524
National Heart, Lung, and Blood Institute
National Institute on Deafness and Other Communication DisordersR01DC019370, R01DC013817
National Institute of Neurological Disorders and StrokeR01 NS017950, UH2 NS100605
Congressionally Directed Medical Research Programs
Eli Lilly and Company
Merck KGaA
Wellcome Trust
Chronic Disease Research Foundation
Manchester Biomedical Research Centre
Framingham Heart StudyN01-HC-25195, 75N92019D00031, HHSN268201500001I
Beneficentia StiftungD70-RESRICGIROTTO
Medical Research Council
National Institute for Health and Care Research
Department of Health and Social Care
European Commission
Robert Bosch Stiftung
Deutsche Forschungsgemeinschaft
Academy of FinlandR01 AG059727, UF1 NS125513, P30 AG066546, 312073
Hjärnfonden
Knut och Alice Wallenbergs Stiftelse
Vetenskapsrådet
Horizon 2020848261, 722046
Svenska Läkaresällskapet503, SLS-779681
share-holder of Oscellaria AB
shareholders of PersoMedix AB

    Keywords

    • ARHL
    • GWAS
    • basal cells
    • cochlea
    • genetics
    • hair cells
    • hearing loss
    • root cells
    • spindle cells
    • stria vascularis

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