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Rare-variant association analysis reveals known and new age-related hearing loss genes


Age-related (AR) hearing loss (HL) is a prevalent sensory deficit in the elderly population. Several studies showed that common variants increase ARHL susceptibility. Here, we demonstrate that rare-variants play a crucial role in ARHL etiology. We analyzed exome and imputed data from white-European UK Biobank volunteers, performing both single-variant and rare-variant aggregate association analyses using self-reported ARHL phenotypes. We identified and replicated associations between ARHL and rare-variants in KLHDC7B, PDCD6, MYO6, SYNJ2, and TECTA. PUS7L and EYA4 also revealed rare-variant associations with ARHL. EYA4, MYO6, and TECTA are all known to underline Mendelian nonsyndromic HL. PDCD6, a new HL gene, plays an important role in apoptosis and has widespread inner ear expression, particularly in the inner hair cells. An unreplicated common variant association was previously observed for KHLDC7B, here we demonstrate that rare-variants in this gene also play a role in ARHL etiology. Additionally, the first replicated association between SYNJ2 and ARHL was detected. Analysis of common variants revealed several previously reported, i.e., ARHGEF28, and new, i.e., PIK3R3, ARHL associations, as well as ones we replicate here for the first time, i.e., BAIAP2L2, CRIP3, KLHDC7B, MAST2, and SLC22A7. It was also observed that the odds ratios for rare-variant ARHL associations, were higher than those for common variants. In conclusion, we demonstrate the vital role rare-variants, including those in Mendelian nonsyndromic HL genes, play in the etiology of ARHL.

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Fig. 1: An illustration of samples used in the analysis.
Fig. 2: Manhattan plots for the discovery and mega-sample rare-variant aggregate association analysis.
Fig. 3: Expression of PDCD6/Pdcd6 in the human and mouse inner ear.

Data availability

Individual-level sequence and phenotype data, from which we derived the traits studied here, are available to approved researchers in the UK Biobank repository. Instructions for access to UK Biobank data are available at Summary statistics for the rare-variants tested in this study are also available in the GWAS Catalog (accession ID is GCP000519).

Code availability

The code used to run the analyses and create the figures presented here is available at


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The research conducted using the UK Biobank Resource was performed under application numbers 32285 ATD and 36827 SML.


This work was supported by a grant from the National Institute of Deafness and other Communication Disorders (NIDCD) DC017712 to SML and ATD.

Author information

Authors and Affiliations



DMCS: analyzed UK Biobank data and drafted the manuscript; GL analyzed UK Biobank data; TB, RW, and YH: extracted and prepared data for analysis; AA: analyzed expression data and aided in drafting the manuscript; MKK and JLE: analyzed expression data, performed data extraction and preparation; IS and GW: performed data interpretation and reviewed the manuscript; ATD: designed experiments; revised the manuscript; and obtained funding; SML designed experiments, drafted and finalized manuscript and obtained funding. All the authors agreed to the final version of the manuscript.

Corresponding author

Correspondence to Suzanne M. Leal.

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Competing interests

The authors declare no competing interests.

Ethical approval

The UK Biobank study was conducted under generic approval from the National Health Services’ National Research Ethics Service. The present analyses were approved by the Human Investigations Committee at Columbia University (institutional review board protocol number IRB-AAAS3494) and Yale University (2000026836).

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Supplementary information

Table S1 .UK Biobank - Quality control of UK Biobank Study Participants

Table S2 Inclusion/Exclusion criteria for cases and controls

Table S3


Table S4. Analytical and empirical permutation p-values for single variant analysis of the variants brought to replication from the discovery (A) and the mega sample (B)

Table S5. Rare-variants included in the aggregate analysis


Table S6. Analytical and empirical permutation p-values for rare-variant aggegrate analysis of the genes brought to replication from the discovery sample

Supplementary figures description

Supplementary figures

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Cornejo-Sanchez, D.M., Li, G., Fabiha, T. et al. Rare-variant association analysis reveals known and new age-related hearing loss genes. Eur J Hum Genet 31, 638–647 (2023).

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