Discovering age- and sex-specific genetic risk factors in sensorineural hearing loss: genome-wide evidence from large-scale biobank studies

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

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 7,762 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).

In the meta-analysis focusing on the general population, 22 SNHL-associated loci (±1 Mb window) were observed, seven 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, three 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, 14 loci 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.

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 research into innovative therapies and preventative measures. Competing Interest Statement The authors have declared no competing interest. Funding Statement This study did not receive any funding Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability Available after publication GWAs catalog (not yet) and upon request