背景:成人听力问题(HP)很常见,并且与多种合并症相关。它的患病率随着年龄的增长而增加,反映环境因素和遗传倾向的累积效应。尽管已经确定了几个风险位点,大规模的遗传研究仍未充分研究HP生物学和流行病学。
方法:利用英国生物银行,护士健康研究(I和II),卫生专业人员后续研究,和百万退伍军人计划,我们在748,668名成年参与者中对HP进行了全面的全基因组调查(发现N=501,825;复制N=226,043;跨祖先复制N=20,800).我们利用GWAS的发现来描述HP多基因结构,探索性别差异,跨祖先的多基因风险,组织特异性转录组调控,与遗传相关性状的因果关系,以及基因与HP环境危险因素的相互作用。
结果:我们确定了54个风险位点,并证明HP多基因风险在祖先群体中是共有的。我们的转录组调控分析强调了中枢神经系统在HP发病机制中的潜在作用。性别分层分析显示,与外周激素调节组织有关的其他几个关联反映了雌激素在听力功能中的潜在作用。这一证据得到了多变量相互作用分析的支持,该分析显示了参与大脑发育的基因如何与性别相互作用,噪音污染,和吸烟与他们的HP关联。此外,遗传信息因果推断分析显示,HP与许多身心健康结局相关.
结论:这些结果为成人HP的生物学和流行病学提供了许多新的见解。我们的性别特异性分析和转录组关联强调了可能针对药物开发或再利用的分子途径。此外,所发现的潜在因果关系可能支持新的预防性筛查计划,以确定有风险的个体.
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.
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.
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.
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.