Genetics and Population Health, Queensland Institute of Medical Research, Brisbane, Australia.
Hum Mol Genet. 2010 Jul 1;19(13):2716-24. doi: 10.1093/hmg/ddq144. Epub 2010 Apr 15.
Optic nerve assessment is important for many blinding diseases, with cup-to-disc ratio (CDR) assessments commonly used in both diagnosis and progression monitoring of glaucoma patients. Optic disc, cup, rim area and CDR measurements all show substantial variation between human populations and high heritability estimates within populations. To identify loci underlying these quantitative traits, we performed a genome-wide association study in two Australian twin cohorts and identified rs3858145, P=6.2x10(-10), near the ATOH7 gene as associated with the mean disc area. ATOH7 is known from studies in model organisms to play a key role in retinal ganglion cell formation. The association with rs3858145 was replicated in a cohort of UK twins, with a meta-analysis of the combined data yielding P=3.4x10(-10). Imputation further increased the evidence for association for several SNPs in and around ATOH7 (P=1.3x10(-10) to 4.3x10(-11), top SNP rs1900004). The meta-analysis also provided suggestive evidence for association for the cup area at rs690037, P=1.5x10(-7), in the gene RFTN1. Direct sequencing of ATOH7 in 12 patients with optic nerve hypoplasia, one of the leading causes of blindness in children, revealed two novel non-synonymous mutations (Arg65Gly, Ala47Thr) which were not found in 90 unrelated controls (combined Fisher's exact P=0.0136). Furthermore, the Arg65Gly variant was found to have very low frequency (0.00066) in an additional set of 672 controls.
视神经评估对于许多致盲性疾病都很重要，杯盘比（CDR）评估常用于青光眼患者的诊断和病情进展监测。视盘、杯、边缘区和 CDR 测量值在不同人群之间存在显著差异，且人群内的遗传度估计值较高。为了确定这些数量性状的潜在基因座，我们在两个澳大利亚双胞胎队列中进行了全基因组关联研究，发现位于 ATOH7 基因附近的 rs3858145 与平均盘面积相关（P=6.2x10(-10)）。研究模式生物的结果表明，ATOH7 在视网膜神经节细胞形成中起着关键作用。rs3858145 的关联在英国双胞胎队列中得到了复制，对合并数据的meta 分析得出 P=3.4x10(-10)。进一步的推测增加了 ATOH7 内和周围的几个 SNPs 的关联证据（P=1.3x10(-10) 到 4.3x10(-11)，最高 SNP rs1900004）。meta 分析还为基因 RFTN1 中 rs690037 的杯面积提供了关联的提示性证据（P=1.5x10(-7)）。对 12 名视神经发育不良患者（儿童失明的主要原因之一）的 ATOH7 直接测序发现了两个新的非同义突变（Arg65Gly、Ala47Thr），在 90 名无关对照中未发现（合并 Fisher 精确检验 P=0.0136）。此外，在另外 672 名对照中，Arg65Gly 变体的发现频率非常低（0.00066）。
