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<p>Age-related (AR) hearing loss (HL) is the most prevalent sensorineural disorder in older adults. Here we demonstrate that rare-variants in well-established Mendelian HL genes play an important role in ARHL etiology. In all we identified 32 Mendelian HL genes which are associated with ARHL. We performed single and rare-variant aggregate association analyses using exome data obtained from white-Europeans with self-reported hearing phenotypes from the UK Biobank. Our analysis revealed previously unreported associations between ARHL and rare-variants in Mendelian non-syndromic and syndromic HL genes, including <i>MYO15A</i>, and <i>WFS1</i>. Additionally, rare-variant aggregate association analyses identified associations with Mendelian HL genes i.e., <i>ACTG1</i>, <i>GRHL2</i>, <i>KCNQ4</i>, <i>MYO7A</i>, <i>PLS1</i>, <i>TMPRSS3</i>, and <i>TNRC6B</i>. Four novel ARHL genes were also detected: <i>FBXO2</i> and <i>PALM3</i>, implicated in HL in mice, <i>TWF1</i>, associated with HL in Dalmatian dogs, and <i>TXNDC17</i>. In-silico analyses provided further evidence of inner ear expression of these genes in both murine and human models, supporting their relevance to ARHL. Analysis of variants with minor allele frequency &gt;0.005 revealed additional ARHL associations with known e.g., <i>ILDR1</i> and novel i.e., <i>ABHD12, COA8</i>, <i>KANSL1</i>, <i>SERAC1</i>, and <i>UBE3B</i> Mendelian non-syndromic and syndromic HL genes as well as ARHL associations with genes that have not been previously reported to be involved in HL e.g., <i>VCL</i>. Rare-variants in Mendelian HL genes typically exhibited higher effect sizes for ARHL compared to those in other associated genes. In conclusion, this study highlights the critical role Mendelian non-syndromic and syndromic HL genes play in the etiology of ARHL.</p>

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Mendelian non-syndromic and syndromic hearing loss genes contribute to presbycusis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月7日

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  • Diana M. Cornejo-Sanchez,
  • Thashi Bharadwaj,
  • Rui Dong,
  • Gao T. Wang,
  • Isabelle Schrauwen,
  • Andrew T. DeWan,
  • Suzanne M. Leal

摘要

Age-related (AR) hearing loss (HL) is the most prevalent sensorineural disorder in older adults. Here we demonstrate that rare-variants in well-established Mendelian HL genes play an important role in ARHL etiology. In all we identified 32 Mendelian HL genes which are associated with ARHL. We performed single and rare-variant aggregate association analyses using exome data obtained from white-Europeans with self-reported hearing phenotypes from the UK Biobank. Our analysis revealed previously unreported associations between ARHL and rare-variants in Mendelian non-syndromic and syndromic HL genes, including MYO15A, and WFS1. Additionally, rare-variant aggregate association analyses identified associations with Mendelian HL genes i.e., ACTG1, GRHL2, KCNQ4, MYO7A, PLS1, TMPRSS3, and TNRC6B. Four novel ARHL genes were also detected: FBXO2 and PALM3, implicated in HL in mice, TWF1, associated with HL in Dalmatian dogs, and TXNDC17. In-silico analyses provided further evidence of inner ear expression of these genes in both murine and human models, supporting their relevance to ARHL. Analysis of variants with minor allele frequency >0.005 revealed additional ARHL associations with known e.g., ILDR1 and novel i.e., ABHD12, COA8, KANSL1, SERAC1, and UBE3B Mendelian non-syndromic and syndromic HL genes as well as ARHL associations with genes that have not been previously reported to be involved in HL e.g., VCL. Rare-variants in Mendelian HL genes typically exhibited higher effect sizes for ARHL compared to those in other associated genes. In conclusion, this study highlights the critical role Mendelian non-syndromic and syndromic HL genes play in the etiology of ARHL.