Sex differences in the polygenic architecture of hearing problems in adults

Abstract

Background Hearing problems (HP) in adults are common and are associated with several comorbid conditions. Its prevalence increases with age, reflecting the cumulative effect of environmental factors and genetic predisposition. Although several risk loci have been already identified, HP biology and epidemiology are still insufficiently investigated by large-scale genetic studies. Methods Leveraging the UK Biobank, the Nurses’ Health Studies (I and II), the Health Professionals Follow-up Study, and the Million Veteran Program, we conducted a comprehensive genome-wide investigation of HP in 748,668 adult participants (discovery N = 501,825; replication N = 226,043; cross-ancestry replication N = 20,800). We leveraged the GWAS findings to characterize HP polygenic architecture, exploring sex differences, polygenic risk across ancestries, tissue-specific transcriptomic regulation, cause-effect relationships with genetically correlated traits, and gene interactions with HP environmental risk factors. Results We identified 54 risk loci and demonstrated that HP polygenic risk is shared across ancestry groups. Our transcriptomic regulation analysis highlighted the potential role of the central nervous system in HP pathogenesis. The sex-stratified analyses showed several additional associations related to peripheral hormonally regulated tissues reflecting a potential role of estrogen in hearing function. This evidence was supported by the multivariate interaction analysis that showed how genes involved in brain development interact with sex, noise pollution, and tobacco smoking in relation to their HP associations. Additionally, the genetically informed causal inference analysis showed that HP is linked to many physical and mental health outcomes. Conclusions The results provide many novel insights into the biology and epidemiology of HP in adults. Our sex-specific analyses and transcriptomic associations highlighted molecular pathways that may be targeted for drug development or repurposing. Additionally, the potential causal relationships identified may support novel preventive screening programs to identify individuals at risk.

Sex differences in the pleiotropy of hearing difficulty with imaging-derived phenotypes: a brain-wide investigation

“…Our previous study highlighted the association between the genetic basis of HD and brain transcriptomic regulation 10 . Based on this, we hypothesized that the brain structure and function have a role in the development of HD.…”

“…We leveraged a genome-wide association study (GWAS) meta-analysis of HD and GWAS of 3,935 IDPs to explore both sex-combined and sex-stratified pleiotropy between HD and IDPs. In brief, the meta-analysis for HD pooled data from the UKB 20 , Nurses' Health Study (NHS) I 21 , NHS II 21 , and Health Professionals Follow-Up Study (HPFS) 22 , which included 501,825 unrelated adults -56% of them were females 10 . The UKB is a large population-based prospective cohort including deep genetic information and health conditions data from over 500,000 UK participants (40-69 years old, 54% were females).…”

“…The most recent assessment was used in the GWAS when multiple assessments were available and those who were completely deaf were excluded 10 . The other three cohorts enrolled 121,700 (NHS I: 30-55 years old) and 116,430 (NHS II: 25-42 years old) female registered nurses and 51,529 male health professionals (HPFS: 40-74 years old).…”

“…In each study, a questionnaire was used to collect the hearing status of participants. Cases were defined when mild, moderate, severe (non-hearing aid user), or severe (hearing aid user) HD were reported 10 .…”

“…Detailed information about the meta-analyzed data of HD can be found elsewhere 10 . In this study, genome-wide association statistics related to 3,935 IDPs were assessed in up to 33,224 individuals (52% females) by the UKB team.…”