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 language | English |
|---|---|
| Pages (from-to) | 1077-1091 |
| Number of pages | 15 |
| Journal | American Journal of Human Genetics |
| Volume | 109 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 2 Jun 2022 |
| Publication type | A1 Journal article-refereed |
Funding
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. C.R.C. is supported by the UK National Institute for Health Research (NIHR) Biomedical Research Center but the views expressed herein are his own and do not represent those of NIHR nor the UK Department of Health and Social Care. Y.Z. and V.M.L. are co-founders and shareholders of PersoMedix AB. In addition, V.M.L. is CEO and shareholder of HepaPredict AB and discloses support by the Robert Bosch Foundation, Merck KGaA, and Eli Lilly and Company. J.H.L. is co-founder and share-holder of Oscellaria AB. H.L. receives support from a consulting contract between Data Tecnica International and the National Institute on Aging (NIA), National Institutes of Health (NIH). M.A.N. received a competitive contract awarded to Data Tecnica International LLC by the National Institutes of Health to support open science research, and he also currently serves on the scientific advisory board for Clover Therapeutics and is an advisor to Neuron23 Inc as a data science fellow. P.F.S. is consultant and shareholder of Neumora. This study was supported by the GENDER-Net Co-Plus Fund (GNP-182), the European Union's Horizon 2020 Research and Innovation Programme, Grant Agreement No 848261 and No 722046 to C.R.C. C.R.C. received additional funding from Forschung Für Leben, Svenska Läkaresällskapet (SLS-779681), Hörselforskningsfonden (503), and Tysta Skolan. J.H.L. received funding from Swedish Brain Foundation (Hjärnfonden) and Swedish Research Council. F.L. received funding from Knut and Alice Wallenberg Foundation, Tysta Skolan, Swedish Research Council, StratRegen, and Swedish Brain Foundation. R.H. received funding from NIDCD/NIH R01DC013817, NIDCD/NIH R01DC019370, the Hearing Restoration Project, and CDMRP/DOD W81XWH-21-1-0578. S.S. received funding from the National Heart, Lung, and Blood Institute contract for the Framingham Heart Study (contract No. N01-HC-25195, No. HHSN268201500001I, and No. 75N92019D00031), the National Institute on Aging (R01 AG054076, R01 AG049607, U01 AG052409, R01 AG059421, RF1 AG063507, RF1 AG066524, U01 AG058589), and the National Institute of Neurological Disorders and Stroke (R01 NS017950 and UH2 NS100605). Additional funding was obtained from the German Research Foundation through the Collaborative Research Center 889 (BV), Academy of Finland (grant #312073, J.K.); R01 AG059727, P30 AG066546, and UF1 NS125513 (S.L.S.B.); and Beneficentia Stiftung and D70-RESRICGIROTTO (G.G.). TwinsUK is funded by the Wellcome Trust, Medical Research Council, European Union, Chronic Disease Research Foundation (CDRF), Zoe Global Ltd and the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Center based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. Hearing research within The Rotterdam Study has been founded by the Dutch Hearing Health Foundation. Cohort-specific data collection, I.M.L. L.M. P.K.E.M. E.S. T.P. S.P. C.C.M. A.B.S.G. H.L. A.T. C.L.S. D.I.C.; analysis, N.T. M.B.F. L.B. S.Y. E.B.R.T. K.K. Y.Z. M.N. D.I.C. F.M.K.W. A.G. J.K. E.S. R.E. M.P.C. S.C. G.G.N. H.L. N.L.H.C. F.C.; critical revisions of the manuscript, V.G. L.J.L. J.H.L. R.H. T.P. E.S. J.R. A.M. J.K. A.B.V. H.L. A.T. A.G.; writing editing, Y.G. H.J.H. L.B. M.B.F. A.P.N. C.R.C. B.C.O. N.T. C.B. A.K.K. B.C. S.Y. E.S. J.R. A.M. J.K. A.B.V. C.C.M. A.B.S.G. D.I.C. F.M.K.W.; overseeing project, L.B. A.P.N. C.R.C. B.C.O. P.F.S. S.S. L.M. P.K.E.M. J.v.B.H. J.M.F. E.S. T.P. E.S. M.A.N.; study concept and design, Y.G. H.J.H. C.M.L. V.G. A.G. J.M.S. J.v.M. A.C. K.C. V.M.L. C.S. L.J.L. F.L. J.H.L. R.H. L.B. M.B.F. R.S. G.G. N.Q. A.P.N. C.R.C. B.C.O. N.T. P.F.S. S.S. E.S. J.R. A.M. J.K. A.B.V. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. C.R.C. is supported by the UK National Institute for Health Research (NIHR) Biomedical Research Center but the views expressed herein are his own and do not represent those of NIHR nor the UK Department of Health and Social Care. Y.Z. and V.M.L. are co-founders and shareholders of PersoMedix AB. In addition, V.M.L. is CEO and shareholder of HepaPredict AB and discloses support by the Robert Bosch Foundation, Merck KGaA, and Eli Lilly and Company. J.H.L. is co-founder and share-holder of Oscellaria AB. H.L. receives support from a consulting contract between Data Tecnica International and the National Institute on Aging (NIA), National Institutes of Health (NIH). M.A.N. received a competitive contract awarded to Data Tecnica International LLC by the National Institutes of Health to support open science research, and he also currently serves on the scientific advisory board for Clover Therapeutics and is an advisor to Neuron23 Inc as a data science fellow. P.F.S. is consultant and shareholder of Neumora. Additional funding was obtained from the German Research Foundation through the Collaborative Research Center 889 (BV), Academy of Finland (grant # 312073 , J.K.); R01 AG059727 , P30 AG066546 , and UF1 NS125513 (S.L.S.B.); and Beneficentia Stiftung and D70-RESRICGIROTTO (G.G.). TwinsUK is funded by the Wellcome Trust , Medical Research Council , European Union , Chronic Disease Research Foundation (CDRF), Zoe Global Ltd and the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Center based at Guy's and St Thomas' NHS Foundation Trust in partnership with King’s College London . Hearing research within The Rotterdam Study has been founded by the Dutch Hearing Health Foundation . This study was supported by the GENDER-Net Co-Plus Fund ( GNP-182 ), the European Union's Horizon 2020 Research and Innovation Programme , Grant Agreement No 848261 and No 722046 to C.R.C. C.R.C. received additional funding from Forschung Für Leben , Svenska Läkaresällskapet ( SLS-779681 ), Hörselforskningsfonden ( 503 ), and Tysta Skolan . J.H.L. received funding from Swedish Brain Foundation (Hjärnfonden) and Swedish Research Council . F.L. received funding from Knut and Alice Wallenberg Foundation , Tysta Skolan , Swedish Research Council , StratRegen , and Swedish Brain Foundation . R.H. received funding from NIDCD/NIH R01DC013817 , NIDCD/NIH R01DC019370 , the Hearing Restoration Project , and CDMRP/DOD W81XWH-21-1-0578 . S.S. received funding from the National Heart, Lung, and Blood Institute contract for the Framingham Heart Study (contract No. N01-HC-25195 , No. HHSN268201500001I , and No. 75N92019D00031 ), the National Institute on Aging ( R01 AG054076 , R01 AG049607 , U01 AG052409 , R01 AG059421 , RF1 AG063507 , RF1 AG066524 , U01 AG058589 ), and the National Institute of Neurological Disorders and Stroke ( R01 NS017950 and UH2 NS100605 ).
Keywords
- ARHL
- basal cells
- cochlea
- genetics
- GWAS
- hair cells
- hearing loss
- root cells
- spindle cells
- stria vascularis
Publication forum classification
- Publication forum level 3
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
