In this study, we investigated the association of ACAN variants with otosclerosis, a frequent cause of hearing loss among young adults. We sequenced the coding, 5′-UTR and 3′-UTR regions of ACAN in 1497 unrelated otosclerosis cases and 1437 matched controls from six different subpopulations. The association between variants in ACAN and the disease risk was tested through single variant and gene-based association tests. After correction for multiple testing, 14 variants were significantly associated with otosclerosis, ten of which represented independent association signals. Eight variants showed a consistent association across all subpopulations. Allelic odds ratios of the variants identified four predisposing and ten protective variants. Gene-based tests showed an association of very rare variants in the 3′-UTR with the phenotype. The associated exonic variants are all located in the CS domain of ACAN and include both protective and predisposing variants with a broad spectrum of effect sizes and population frequencies. This includes variants with strong effect size and low frequency, typical for monogenic diseases, to low effect size variants with high frequency, characteristic for common complex traits. This single-gene allelic spectrum with both protective and predisposing alleles is unique in the field of complex diseases. In conclusion, these findings are a significant advancement to the understanding of the etiology of otosclerosis.

在这项研究中，我们调查了ACAN变异与耳硬化症的关系，耳硬化症是年轻人听力损失的常见原因。我们对来自六个不同亚群的 1497 例无关耳硬化病例和 1437 例匹配对照中的ACAN的编码、5'-UTR 和 3'-UTR 区域进行了测序。ACAN中变体之间的关联并且通过单变体和基于基因的关联测试来测试疾病风险。经过多次测试校正后，14 个变体与耳硬化症显着相关，其中 10 个代表独立的关联信号。八个变体在所有亚群中显示出一致的关联。变体的等位基因优势比确定了四种易感变体和十种保护性变体。基于基因的测试显示 3'-UTR 中非常罕见的变体与表型相关。相关的外显子变体均位于ACAN的 CS 域并包括具有广泛影响大小和人群频率的保护性和易感性变体。这包括具有强效应大小和低频率的变体（典型的单基因疾病），以及具有高频率的低效应大小变体（常见复杂性状的特征）。这种具有保护性和易感性等位基因的单基因等位基因谱在复杂疾病领域是独一无二的。总之，这些发现对于理解耳硬化症的病因是一个重大进步。