Shiley Eye Institute, University of California, La Jolla, California 92093, USA.
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Nat Commun. 2017 Mar 30;8:14898. doi: 10.1038/ncomms14898.
The structure of the cornea is vital to its transparency, and dystrophies that disrupt corneal organization are highly heritable. To understand the genetic aetiology of Fuchs endothelial corneal dystrophy (FECD), the most prevalent corneal disorder requiring transplantation, we conducted a genome-wide association study (GWAS) on 1,404 FECD cases and 2,564 controls of European ancestry, followed by replication and meta-analysis, for a total of 2,075 cases and 3,342 controls. We identify three novel loci meeting genome-wide significance (P<5 × 10): KANK4 rs79742895, LAMC1 rs3768617 and LINC00970/ATP1B1 rs1200114. We also observe an overwhelming effect of the established TCF4 locus. Interestingly, we detect differential sex-specific association at LAMC1, with greater risk in women, and TCF4, with greater risk in men. Combining GWAS results with biological evidence we expand the knowledge of common FECD loci from one to four, and provide a deeper understanding of the underlying pathogenic basis of FECD.
角膜的结构对于其透明度至关重要，而破坏角膜组织的营养不良是高度遗传性的。为了了解最常见的需要移植的角膜疾病——Fuchs 内皮角膜营养不良（FECD）的遗传病因，我们对 1404 例 FECD 病例和 2564 例欧洲血统对照进行了全基因组关联研究（GWAS），随后进行了复制和荟萃分析，共涉及 2075 例病例和 3342 例对照。我们发现了三个新的达到全基因组显著水平的位点（P<5×10）：KANK4 rs79742895、LAMC1 rs3768617 和 LINC00970/ATP1B1 rs1200114。我们还观察到已建立的 TCF4 基因座的压倒性影响。有趣的是，我们在 LAMC1 中检测到性别特异性关联的差异，女性的风险更大，而在 TCF4 中，男性的风险更大。将 GWAS 结果与生物学证据相结合，我们将常见的 FECD 基因座从一个扩展到四个，更深入地了解了 FECD 的潜在发病基础。
