Wolfson Centre for Age-Related Diseases, King's College London, London, SE1 1UL, UK.
The Medical University of South Carolina, Charleston, SC, USA.
BMC Biol. 2022 Jun 27;20(1):150. doi: 10.1186/s12915-022-01349-5.
Age-related hearing loss is a common, heterogeneous disease with a strong genetic component. More than 100 loci have been reported to be involved in human hearing impairment to date, but most of the genes underlying human adult-onset hearing loss remain unknown. Most genetic studies have focussed on very rare variants (such as family studies and patient cohort screens) or very common variants (genome-wide association studies). However, the contribution of variants present in the human population at intermediate frequencies is hard to quantify using these methods, and as a result, the landscape of variation associated with adult-onset hearing loss remains largely unknown.
Here we present a study based on exome sequencing and self-reported hearing difficulty in the UK Biobank, a large-scale biomedical database. We have carried out variant load analyses using different minor allele frequency and impact filters, and compared the resulting gene lists to a manually curated list of nearly 700 genes known to be involved in hearing in humans and/or mice. An allele frequency cutoff of 0.1, combined with a high predicted variant impact, was found to be the most effective filter setting for our analysis. We also found that separating the participants by sex produced markedly different gene lists. The gene lists obtained were investigated using gene ontology annotation, functional prioritisation and expression analysis, and this identified good candidates for further study.
Our results suggest that relatively common as well as rare variants with a high predicted impact contribute to age-related hearing impairment and that the genetic contributions to adult hearing difficulty may differ between the sexes. Our manually curated list of deafness genes is a useful resource for candidate gene prioritisation in hearing loss.
年龄相关性听力损失是一种常见的、具有很强遗传成分的异质性疾病。迄今为止，已有 100 多个位点被报道与人类听力障碍有关，但大多数导致人类成年后听力损失的基因仍不清楚。大多数遗传研究都集中在非常罕见的变异上（如家族研究和患者队列筛查）或非常常见的变异上（全基因组关联研究）。然而，使用这些方法很难量化人群中中等频率变异的贡献，因此，与成年听力损失相关的变异景观在很大程度上仍然未知。
在这里，我们展示了一项基于英国生物库（一个大型生物医学数据库）外显子组测序和自我报告听力困难的研究。我们使用不同的次要等位基因频率和影响过滤器进行了变异负荷分析，并将得到的基因列表与一个手工整理的近 700 个已知与人类和/或小鼠听力有关的基因列表进行了比较。发现等位基因频率截止值为 0.1，同时预测变异影响较高，这是我们分析的最有效过滤器设置。我们还发现，按性别将参与者分开会产生明显不同的基因列表。使用基因本体注释、功能优先级和表达分析对获得的基因列表进行了研究，这确定了进一步研究的良好候选者。
我们的结果表明，具有高预测影响的相对常见和罕见变异也会导致与年龄相关的听力损伤，而成年听力障碍的遗传贡献可能因性别而异。我们手动整理的耳聋基因列表是听力损失候选基因优先级的有用资源。
