Abstract
Age-related hearing loss is a prevalent and growing public health issue among the elderly. Here, we perform a multi-ancestry genome-wide association study comprising 456,613 cases and 1,053,834 controls, identifying 140 independent loci associated with age-related hearing loss, including 44 novel signals. We further fine-map 9 likely causal missense variants for age-related hearing loss and provide evidence of purifying selection for age-related hearing loss-associated variants. Notably, genetic risk for age-related hearing loss is strongly correlated with behavior traits such as neuroticism score and irritability. Integration of molecular phenotypes identifies 22 genes and 85 DNA methylation sites significantly associated with age-related hearing loss. Moreover, analyses incorporating spatial and single-cell transcriptomic identify the inner ear as a crucial site of age-related hearing loss, emphasizing the importance of hair cells, supporting cells, basal and root cells of the stria vascularis to its pathogenesis. Our study provides genetic and cellular insights into age-related hearing loss and advance our understanding of its genetics architecture.
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Data availability
All GWAS summary statistics used for ARHL meta-analysis are available as below: the ARHL GWAS of East Asian from BBJ is publicly available at https://pheweb.jp/pheno/Hearing_Loss; the ARHL GWASs of East Asian, European, African and Admixed American from MVP are available via the dbGap study accession number phs002453; the ARHL GWAS of European from Trpchevska et al. is available at https://zenodo.org/records/5769707#.Ybm6v33MKhx. The summary statistic of the cross ancestry meta-analysis from this study is available at https://zenodo.org/records/17141085. The summary-level xQTL data used for SMR are available as follow: eQTL data from eQTLGen project are available at https://www.eqtlgen.org/cis-eqtls.html and the meta-analysis data of mQTL from LBC and BSGS are available at https://cnsgenomics.com/software/smr/#Download. The Roadmap Epigenomics Mapping Consortium epigenomic annotations data are available for download at http://compbio.mit.edu/roadmap. The 1000 Genome project of European reference data (phase 3) are available at https://ftp.1000genomes.ebi.ac.uk/vol1/ftp/phase3/. The spatial transcriptomics data of mouse embryos at E16.5 used for gsMap is available at https://db.cngb.org/stomics/mosta/download. The single-cell RNA-seq data of mouse cochlea for Jean et al., Iyer et al., Eshel et al., and Sun et al. is available from the dataset access via the gEAR portal (https://umgear.org/p?s=7fd80bf5, https://umgear.org/p?s=728a05e2, https://umgear.org/p?s=bb49463b, and https://umgear.org/p?s=653896d7). Source data are provided in this paper.
Code availability
Code used in GWAS meta-analysis and results visualization are available at Github (https://github.com/Crazzy-Rabbit/project_hearing_loss/), which has been archived on Zenodo and assigned a DOI: (https://doi.org/10.5281/zenodo.17614049).
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Acknowledgements
This research was supported by the Fundamental Research Funds for the Central Universities (Y.W.), the 1·3·5 project for disciplines of excellence, West China Hospital, Sichuan University (ZYYC24006 to Y.W., ZYJC20002 to H.Y.), National Key Research and Development Program of China grant 82171836 (H.Y.). The research was supported by the National Supercomputing Center in Chengdu. The numerical calculations in this paper have been done on the Hefei Advanced Computing Center. This study makes use of data from the UK Biobank (project ID: 151441). We acknowledge the use of Grammarly for assistance with grammar correction.
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Y.W. conceived and designed the experiment. Y.W. supervised the study. L.S. conducted all analyses with the assistance or guidance from Y.W., H.Y., Y.Z., J.L., K.G., W.L., and H.H. L.S. and Y.W. wrote the manuscript with the participation of all authors. All the authors approved the final version of the manuscript.
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Nature Communications thanks Christopher Cederroth, Yuanhao Yang and the other anonymous reviewer(s) for their contribution to the peer review of this work. A peer review file is available.
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Shi, L., He, H., Li, J. et al. Multi-ancestry GWAS of age-related hearing loss identifies 140 loci and key cellular mechanisms. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69894-z
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DOI: https://doi.org/10.1038/s41467-026-69894-z
