Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland.
Department of Otolaryngology - Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA, USA.
Nat Commun. 2023 Jan 18;14(1):157. doi: 10.1038/s41467-022-32936-3.
Otosclerosis is one of the most common causes of conductive hearing loss, affecting 0.3% of the population. It typically presents in adulthood and half of the patients have a positive family history. The pathophysiology of otosclerosis is poorly understood. A previous genome-wide association study (GWAS) identified a single association locus in an intronic region of RELN. Here, we report a meta-analysis of GWAS studies of otosclerosis in three population-based biobanks comprising 3504 cases and 861,198 controls. We identify 23 novel risk loci (p < 5 × 10) and report an association in RELN and three previously reported candidate gene or linkage regions (TGFB1, MEPE, and OTSC7). We demonstrate developmental stage-dependent immunostaining patterns of MEPE and RUNX2 in mouse otic capsules. In most association loci, the nearest protein-coding genes are implicated in bone remodelling, mineralization or severe skeletal disorders. We highlight multiple genes involved in transforming growth factor beta signalling for follow-up studies.
耳硬化症是最常见的传导性听力损失原因之一，影响 0.3%的人群。它通常在成年期出现，一半的患者有阳性家族史。耳硬化症的病理生理学尚不清楚。先前的全基因组关联研究（GWAS）在 RELN 的内含子区域确定了一个单一的关联位点。在这里，我们报告了三个基于人群的生物库中进行的耳硬化症 GWAS 研究的荟萃分析，该研究包括 3504 例病例和 861198 例对照。我们确定了 23 个新的风险位点（p<5×10），并报告了 RELN 以及三个先前报道的候选基因或连锁区域（TGFB1、MEPE 和 OTSC7）的关联。我们在小鼠耳囊中证明了 MEPE 和 RUNX2 的发育阶段依赖性免疫染色模式。在大多数关联位点中，最近的编码蛋白基因与骨重塑、矿化或严重骨骼疾病有关。我们强调了多个涉及转化生长因子β信号的基因，以供进一步研究。
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