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Purpose <p>Investigate the genetic components of sensorineural hearing loss (SNHL) by performing genome-wide meta-analyses using the data from FinnGen and Estonian Biobank.</p> Methods <p>We studied genome-wide associations of SNHL in FinnGen and the Estonian Biobank in the general population and in sex- and age-of-onset stratified subgroups. The study-specific GWASs were combined through inverse variance-weighted genome-wide meta-analyses, encompassing a total of 531,059 individuals (Ncases = 35,960). Age-stratified meta-analyses included 28,198 individuals diagnosed at the age of 55&#xa0;years or after and 7762 individuals diagnosed before the age of 55&#xa0;years, with 495,099 controls. Sex-stratified meta-analyses included 313,501 females (Ncases = 17,761) and 217,558 males (Ncases = 18,199).</p> Results <p>In the meta-analysis focusing on the general population, 22 SNHL-associated loci (±1&#xa0;Mb window) were observed, three of which were previously unreported. In the sex-stratified analysis, two previously unreported SNHL loci were observed in the female subgroup and one locus in the male subgroup. Additionally, in the age-stratified analysis, two previously unreported SNHL loci were observed in the subgroup of those that were diagnosed at the age of 55&#xa0;years or after. In those diagnosed before the age of 55&#xa0;years, one previously unreported locus was observed. Overall, 32 loci were associated with SNHL at <i>p</i> &lt; 5 × 10<sup>–8</sup> in at least one of the study groups. Of these, nine have not been previously reported in association with SNHL. We also estimated if there were significant differences in the effect sizes of the lead variants at each locus between the analytical subgroups and observed differences for 14 variants.</p> Conclusions <p>Previously unreported SNHL risk loci and differences in effect sizes found in this study provide additional insight into the genetic underpinnings of SNHL. Our results validate the role of mechano-transduction and genetic components affecting the structure of the inner ear in the background of SNHL. Our study contributes to our understanding of the genetic causes of SNHL and may open the door for further translational research.</p>

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Discovering Age- and Sex-Specific Genetic Risk Factors in Sensorineural Hearing Loss: Genome-Wide Evidence from Large-Scale Biobanks

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月26日

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  • Argyro Bizaki-Vallaskangas,
  • Eeva Sliz,
  • Tuuli Lankinen,
  • Elmo Saarentaus,
  • Ville Salo,
  • Kristi Krebs,
  • Tytti Willberg,
  • Ilkka Kivekäs,
  • Joel Rämö,
  • Sanna Toppila-Salmi,
  • Aarno Dietz,
  • Vesa Hytönen,
  • Aarno Palotie,
  • Lili Milani,
  • Antti Mäkitie,
  • Johannes Kettunen

摘要

Purpose

Investigate the genetic components of sensorineural hearing loss (SNHL) by performing genome-wide meta-analyses using the data from FinnGen and Estonian Biobank.

Methods

We studied genome-wide associations of SNHL in FinnGen and the Estonian Biobank in the general population and in sex- and age-of-onset stratified subgroups. The study-specific GWASs were combined through inverse variance-weighted genome-wide meta-analyses, encompassing a total of 531,059 individuals (Ncases = 35,960). Age-stratified meta-analyses included 28,198 individuals diagnosed at the age of 55 years or after and 7762 individuals diagnosed before the age of 55 years, with 495,099 controls. Sex-stratified meta-analyses included 313,501 females (Ncases = 17,761) and 217,558 males (Ncases = 18,199).

Results

In the meta-analysis focusing on the general population, 22 SNHL-associated loci (±1 Mb window) were observed, three of which were previously unreported. In the sex-stratified analysis, two previously unreported SNHL loci were observed in the female subgroup and one locus in the male subgroup. Additionally, in the age-stratified analysis, two previously unreported SNHL loci were observed in the subgroup of those that were diagnosed at the age of 55 years or after. In those diagnosed before the age of 55 years, one previously unreported locus was observed. Overall, 32 loci were associated with SNHL at p < 5 × 10–8 in at least one of the study groups. Of these, nine have not been previously reported in association with SNHL. We also estimated if there were significant differences in the effect sizes of the lead variants at each locus between the analytical subgroups and observed differences for 14 variants.

Conclusions

Previously unreported SNHL risk loci and differences in effect sizes found in this study provide additional insight into the genetic underpinnings of SNHL. Our results validate the role of mechano-transduction and genetic components affecting the structure of the inner ear in the background of SNHL. Our study contributes to our understanding of the genetic causes of SNHL and may open the door for further translational research.