Schrauwen Isabelle, Ealy Megan, Huentelman Matthew J, Thys Melissa, Homer Nils, Vanderstraeten Kathleen, Fransen Erik, Corneveaux Jason J, Craig David W, Claustres Mireille, Cremers Cor W R J, Dhooge Ingeborg, Van de Heyning Paul, Vincent Robert, Offeciers Erwin, Smith Richard J H, Van Camp Guy
Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
Am J Hum Genet. 2009 Mar;84(3):328-38. doi: 10.1016/j.ajhg.2009.01.023. Epub 2009 Feb 19.
Otosclerosis is a common form of progressive hearing loss, characterized by abnormal bone remodeling in the otic capsule. The etiology of the disease is largely unknown, and both environmental and genetic factors have been implicated. To identify genetic factors involved in otosclerosis, we used a case-control discovery group to complete a genome-wide association (GWA) study with 555,000 single-nucleotide polymorphisms (SNPs), utilizing pooled DNA samples. By individual genotyping of the top 250 SNPs in a stepwise strategy, we were able to identify two highly associated SNPs that replicated in two additional independent populations. We then genotyped 79 tagSNPs to fine map the two genomic regions defined by the associated SNPs. The region with the strongest association signal, p(combined) = 6.23 x 10(-10), is on chromosome 7q22.1 and spans intron 1 to intron 4 of reelin (RELN), a gene known for its role in neuronal migration. Evidence for allelic heterogeneity was found in this region. Consistent with the GWA data, expression of RELN was confirmed in the inner ear and in stapes footplate specimens. In conclusion, we provide evidence that implicates RELN in the pathogenesis of otosclerosis.
耳硬化症是一种常见的进行性听力损失形式，其特征是耳囊内出现异常的骨重塑。该病的病因在很大程度上尚不清楚，环境和遗传因素都被认为与之有关。为了确定与耳硬化症相关的遗传因素，我们使用一个病例对照发现组，利用混合DNA样本，对555,000个单核苷酸多态性（SNP）进行全基因组关联（GWA）研究。通过逐步策略对前250个SNP进行个体基因分型，我们能够识别出两个高度相关的SNP，它们在另外两个独立人群中得到了重复验证。然后我们对79个标签SNP进行基因分型，以精细定位由相关SNP定义的两个基因组区域。关联信号最强的区域，p（合并） = 6.23 x 10（-10），位于7号染色体的7q22.1，跨越reelin（RELN）基因的内含子1至内含子4，该基因因其在神经元迁移中的作用而闻名。在该区域发现了等位基因异质性的证据。与GWA数据一致，RELN的表达在内耳和镫骨足板标本中得到了证实。总之，我们提供的证据表明RELN与耳硬化症的发病机制有关。
