Chen Peng, Miyake Masahiro, Fan Qiao, Liao Jiemin, Yamashiro Kenji, Ikram Mohammad K, Chew Merywn, Vithana Eranga N, Khor Chiea-Chuen, Aung Tin, Tai E-Shyong, Wong Tien-Yin, Teo Yik-Ying, Yoshimura Nagahisa, Saw Seang-Mei, Cheng Ching-Yu
Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore 117597, Singapore.
Department of Ophthalmology, Kyoto University Graduate School of Medicine, Kyoto 6068507, Japan.
Hum Mol Genet. 2014 Nov 15;23(22):6129-36. doi: 10.1093/hmg/ddu322. Epub 2014 Jun 24.
Corneal curvature (CC) measures the steepness of the cornea and is an important parameter for clinically diseases such as astigmatism and myopia. Despite the high heritability of CC, only two associated genes have been discovered to date. We performed a three-stage genome-wide association study meta-analysis in 12 660 Asian individuals. Our Stage 1 was done in multiethnic cohorts comprising 7440 individuals, followed by a Stage 2 replication in 2473 Chinese and Stage 3 in 2747 Japanese. The SNP array genotype data were imputed up to the 1000 Genomes Project Phase 1 cosmopolitan panel. The SNP association with the radii of CC was investigated in the linear regression model with the adjustment of age, gender and principal components. In addition to the known genes, MTOR (also known as FRAP1) and PDGFRA, we discovered two novel genes associated with CC: CMPK1 (rs17103186, P = 3.3 × 10(-12)) and RBP3 (rs11204213 [Val884Met], P = 1.1 × 10(-13)). The missense RBP3 SNP, rs11204213, was also associated with axial length (AL) (P = 4.2 × 10(-6)) and had larger effects on both CC and AL compared with other SNPs. The index SNPs at the four indicated loci explained 1.9% of CC variance across the Stages 1 and 2 cohorts, while 33.8% of CC variance was explained by the genome-wide imputation data. We identified two novel genes influencing CC, which are related to either corneal shape or eye size. This study provides additional insights into genetic architecture of corneal shape.
角膜曲率（CC）用于测量角膜的陡峭程度，是诸如散光和近视等临床疾病的一个重要参数。尽管CC具有较高的遗传度，但迄今为止仅发现了两个相关基因。我们对12660名亚洲个体进行了一项三阶段全基因组关联研究荟萃分析。我们的第一阶段研究在包含7440名个体的多民族队列中进行，随后在2473名中国人中进行了第二阶段重复验证，并在2747名日本人中进行了第三阶段研究。单核苷酸多态性（SNP）阵列基因型数据被推算至千人基因组计划第一阶段的世界范围样本。在调整年龄、性别和主成分的线性回归模型中研究了SNP与CC半径的关联。除了已知基因MTOR（也称为FRAP1）和PDGFRA外，我们还发现了两个与CC相关的新基因：CMPK1（rs17103186，P = 3.3×10⁻¹²）和RBP3（rs11204213 [Val884Met]，P = 1.1×10⁻¹³）。错义RBP3 SNP rs11204213也与眼轴长度（AL）相关（P = 4.2×10⁻⁶），并且与其他SNP相比，对CC和AL的影响更大。四个指定位点的索引SNP解释了第一阶段和第二阶段队列中CC变异的1.9%，而全基因组推算数据解释了33.8%的CC变异。我们鉴定出两个影响CC的新基因，它们与角膜形状或眼睛大小有关。这项研究为角膜形状的遗传结构提供了更多见解。
