A genome-wide association study of optic disc parameters.
A genome-wide association study of optic disc parameters.
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DOI：
10.1371/journal.pgen.1000978
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发表时间：
2010-06-10
期刊：
影响因子：
4.5
通讯作者：
van Duijn CM
中科院分区：
文献类型：
--
作者：
Ramdas WD;van Koolwijk LM;Ikram MK;Jansonius NM;de Jong PT;Bergen AA;Isaacs A;Amin N;Aulchenko YS;Wolfs RC;Hofman A;Rivadeneira F;Oostra BA;Uitterlinden AG;Hysi P;Hammond CJ;Lemij HG;Vingerling JR;Klaver CC;van Duijn CM
视神经头与许多眼科疾病有关，包括近视和开角型青光眼等常见疾病。两个最重要的参数是视盘面积的大小和垂直杯盘比（VCDR）。两者都是高度可遗传的，但在基因上很大程度上是不确定的。我们对全基因组关联（GWA）数据进行了荟萃分析，以确定与视盘面积和VCDR相关的遗传变异。该基因发现包括来自基于人群的鹿特丹研究I和鹿特丹研究II队列的7360名不相关个体。这些队列揭示了视盘区域的两个全基因组显著位点，位于CDC7基因117 kb内的1p22染色体上的rs1192415 （p = 6.72×10−19）和位于ATOH7基因10 kb内的10q21.3-q22.1染色体上的rs1900004 （p = 2.67×10−33）。他们发现了两个VCDR的全基因组显著位点，CDKN2B基因9p21染色体上的rs1063192 （p = 6.15×10−11）和14q22.3-q23染色体上的rs10483727 (p = 2.93×10−10)，位于SIX1基因40 kbp内。研究结果在两个独立的荷兰队列（鹿特丹研究III和伊拉斯谟·鲁芬家族研究；N = 3,612）和TwinsUK队列（N = 843）中得到了重复。与复制队列的荟萃分析证实了这4个位点，并揭示了位于16q12.1的第三个位点与视盘区域相关，以及位于11q13、13q13、17q23（临界显著）和22q12.1的其他4个位点与VCDR相关。ATOH7也与视盘面积无关的VCDR相关。其中3个位点与开角型青光眼轻度相关。视盘区域基因座所涉及的蛋白质途径与VCDR所确定的蛋白质途径重叠，表明它们具有共同的遗传起源。视神经头的形态学特征与许多眼科疾病有关。视盘面积是衡量近视和开角型青光眼（OAG）的重要指标。视盘的另一个重要临床参数是垂直杯盘比（VCDR）。虽然研究表明视盘面积和VCDR具有较高的遗传性，但其遗传决定因素仍未确定。因此，我们对这些数量性状进行了全基因组关联（GWA）研究，使用了超过11,000名高加索参与者的数据，并将研究结果与近视和OAG联系起来。我们发现了与视盘面积相关的三个基因座的证据：CDC7/TGFBR3区域、ATOH7和SALL1；6个VCDR: CDKN2B、SIX1、SCYL1、CHEK2、ATOH7和DCLK1；另外还有一个临界显著位点：BCAS3。这些基因座都与近视无关。ATOH7、CDKN2B和SIX1与OAG存在关联的边缘证据，有待进一步证实。本研究揭示了视神经生理发育的新见解，并可能揭示导致（神经）眼疾病（如OAG）的病理生理蛋白途径。
The optic nerve head is involved in many ophthalmic disorders, including common diseases such as myopia and open-angle glaucoma. Two of the most important parameters are the size of the optic disc area and the vertical cup-disc ratio (VCDR). Both are highly heritable but genetically largely undetermined. We performed a meta-analysis of genome-wide association (GWA) data to identify genetic variants associated with optic disc area and VCDR. The gene discovery included 7,360 unrelated individuals from the population-based Rotterdam Study I and Rotterdam Study II cohorts. These cohorts revealed two genome-wide significant loci for optic disc area, rs1192415 on chromosome 1p22 (p = 6.72×10−19) within 117 kb of the CDC7 gene and rs1900004 on chromosome 10q21.3-q22.1 (p = 2.67×10−33) within 10 kb of the ATOH7 gene. They revealed two genome-wide significant loci for VCDR, rs1063192 on chromosome 9p21 (p = 6.15×10−11) in the CDKN2B gene and rs10483727 on chromosome 14q22.3-q23 (p = 2.93×10−10) within 40 kbp of the SIX1 gene. Findings were replicated in two independent Dutch cohorts (Rotterdam Study III and Erasmus Rucphen Family study; N = 3,612), and the TwinsUK cohort (N = 843). Meta-analysis with the replication cohorts confirmed the four loci and revealed a third locus at 16q12.1 associated with optic disc area, and four other loci at 11q13, 13q13, 17q23 (borderline significant), and 22q12.1 for VCDR. ATOH7 was also associated with VCDR independent of optic disc area. Three of the loci were marginally associated with open-angle glaucoma. The protein pathways in which the loci of optic disc area are involved overlap with those identified for VCDR, suggesting a common genetic origin. Morphologic characteristics of the optic nerve head are involved in many ophthalmic diseases. Its size, called the optic disc area, is an important measure and has been associated with e.g. myopia and open-angle glaucoma (OAG). Another important and clinical parameter of the optic disc is the vertical cup-disc ratio (VCDR). Although studies have shown a high heritability of optic disc area and VCDR, its genetic determinants are still undetermined. We therefore conducted a genome-wide association (GWA) study on these quantitative traits, using data of over 11,000 Caucasian participants, and related the findings to myopia and OAG. We found evidence for association of three loci with optic disc area: CDC7/TGFBR3 region, ATOH7, and SALL1; and six with VCDR: CDKN2B, SIX1, SCYL1, CHEK2, ATOH7, and DCLK1; and additionally one borderline significant locus: BCAS3. None of the loci could be related to myopia. There was marginal evidence for association of ATOH7, CDKN2B, and SIX1 with OAG, which remains to be confirmed. The present study reveals new insights into the physiological development of the optic nerve and may shed light on the pathophysiological protein pathways leading to (neuro-) ophthalmologic diseases such as OAG.
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