A susceptibility locus for myopia in the normal population is linked to the PAX6 gene region on chromosome 11:: A genomewide scan of dizygotic twins
A susceptibility locus for myopia in the normal population is linked to the PAX6 gene region on chromosome 11:: A genomewide scan of dizygotic twins
复制标题
DOI：
10.1086/423148
复制
发表时间：
2004-08-01
影响因子：
9.8
通讯作者：
Spector, TD
中科院分区：
文献类型：
--
作者：
Hammond, CJ;Andrew, T;Spector, TD
近视是一种常见的、复杂的性状，具有相当大的经济和社会影响，并且在高度受影响的个体中具有眼部发病率。我们对506对双胞胎进行了经典的双胞胎研究，并推断屈光不正的遗传度为0.89（95%置信区间为0.86 - 0.91）。通过使用广义线性模型实施的最佳Haseman-Elston回归方法分析了221对双卵双胞胎对的全基因组扫描，在4个位点显示与屈光不正的显著连锁（LOD >3.2），在染色体11 p13上40 cM处的最大LOD得分为6.1。在该位点的连锁证据，以及在染色体3q 26（LOD 3.7），8 p23（LOD 4.1）和4 q12（LOD 3.3）的其他连锁峰，保持不变或变得更强后，模型拟合检查和离群值被降低权重。潜在的候选基因的检查显示PAX 6基因直接低于11 p13位点的最高峰。PAX 6对眼睛的身份和生长至关重要，但报告的突变通常会导致灾难性的先天性表型，如无虹膜。单倍型标记的17个单核苷酸多态性（SNPs），其中包括PAX 6基因，并有共同的次要等位基因频率，确定了5个SNPs解释0.999的单倍型多样性。标记SNP的连锁和关联分析显示所有标记的连锁的强有力证据，最小chi（1）（2）为7.5（P = 0.006），但没有关联。这表明PAX 6可能在近视发展中起作用，可能是因为上游启动子或调节子的遗传变异，尽管本研究中没有证明PAX 6常见变体与近视之间存在明确的关联。
Myopia is a common, complex trait with considerable economic and social impact and, in highly affected individuals, ocular morbidity. We performed a classic twin study of 506 unselected twin pairs and inferred the heritability of refractive error to be 0.89 (95% confidence interval 0.86 - 0.91). A genomewide scan of 221 dizygotic twin pairs, analyzed by use of optimal Haseman-Elston regression methods implemented by use of generalized linear modeling, showed significant linkage (LOD >3.2) to refractive error at four loci, with a maximum LOD score of 6.1 at 40 cM on chromome 11p13. Evidence of linkage at this locus, as well as at the other linkage peaks at chromosomes 3q26 (LOD 3.7), 8p23 (LOD 4.1), and 4q12 (LOD 3.3), remained the same or became stronger after model fit was checked and outliers were downweighted. Examination of potential candidate genes showed the PAX6 gene directly below the highest peak at the 11p13 locus. PAX6 is fundamental to identity and growth of the eye, but reported mutations usually result in catastrophic congenital phenotypes such as aniridia. Haplotype tagging of 17 single-nucleotide polymorphisms (SNPs), which covered the PAX6 gene and had common minor allele frequencies, identified 5 SNPs that explained 0.999 of the haplotype diversity. Linkage and association analysis of the tagging SNPs showed strong evidence of linkage for all markers with a minimum chi(1)(2) of 7.5 (P = .006) but no association. This suggests that PAX6 may play a role in myopia development, possibly because of genetic variation in an upstream promoter or regulator, although no definite association between PAX6 common variants and myopia was demonstrated in this study.