Genome-wide association identifies ATOH7 as a major gene determining human optic disc size.
Genome-wide association identifies ATOH7 as a major gene determining human optic disc size.
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DOI：
10.1093/hmg/ddq144
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发表时间：
2010-07-01
影响因子：
3.5
通讯作者：
Mackey DA
中科院分区：
文献类型：
--
作者：
Macgregor S;Hewitt AW;Hysi PG;Ruddle JB;Medland SE;Henders AK;Gordon SD;Andrew T;McEvoy B;Sanfilippo PG;Carbonaro F;Tah V;Li YJ;Bennett SL;Craig JE;Montgomery GW;Tran-Viet KN;Brown NL;Spector TD;Martin NG;Young TL;Hammond CJ;Mackey DA
视神经评估对于许多致盲疾病是重要的，杯盘比（CDR）评估通常用于青光眼患者的诊断和进展监测。视盘、视杯、边缘面积和CDR测量结果均显示人群间存在显著差异，人群内遗传力估计值较高。为了确定这些数量性状的基因座，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，并确定了ATOH 7基因附近的rs3858145，P = 6.2 × 10−10，与平均椎间盘面积相关。从模式生物的研究中已知ATOH 7在视网膜神经节细胞形成中起关键作用。与rs3858145的关联在英国双胞胎队列中得到了重复，对合并数据的荟萃分析得出P = 3.4 × 10−10。插补进一步增加了ATOH7及其周围的几个SNP相关的证据（P = 1.3 × 10−10至4.3 × 10−11，最高SNP rs1900004）。荟萃分析还提供了提示性证据，表明在基因RFTN1中，rs690037（P = 1.5 × 10−7）处的髋臼杯面积存在相关性。在12例视神经发育不良（儿童失明的主要原因之一）患者中对ATOH 7进行直接测序，发现两种新的非同义突变（Arg65Gly，Ala47Thr），在90名无关对照中未发现（结合Fisher精确P = 0.0136）。此外，发现Arg65Gly变体在另外一组672个对照中具有非常低的频率（0.00066）。
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 = 6.2 × 10−10, 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 = 3.4 × 10−10. Imputation further increased the evidence for association for several SNPs in and around ATOH7 (P = 1.3 × 10−10 to 4.3 × 10−11, top SNP rs1900004). The meta-analysis also provided suggestive evidence for association for the cup area at rs690037, P = 1.5 × 10−7, 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.
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影响因子：
64.8
作者：
Frazer, Kelly A.;Ballinger, Dennis G.;Cox, David R.;Hinds, David A.;Stuve, Laura L.;Gibbs, Richard A.;Belmont, John W.;Boudreau, Andrew;Hardenbol, Paul;Leal, Suzanne M.;Pasternak, Shiran;Wheeler, David A.;Willis, Thomas D.;Yu, Fuli;Yang, Huanming;Zeng, Changqing;Gao, Yang;Hu, Haoran;Hu, Weitao;Li, Chaohua;Lin, Wei;Liu, Siqi;Pan, Hao;Tang, Xiaoli;Wang, Jian;Wang, Wei;Yu, Jun;Zhang, Bo;Zhang, Qingrun;Zhao, Hongbin;Zhao, Hui;Zhou, Jun;Gabriel, Stacey B.;Barry, Rachel;Blumenstiel, Brendan;Camargo, Amy;Defelice, Matthew;Faggart, Maura;Goyette, Mary;Gupta, Supriya;Moore, Jamie;Nguyen, Huy;Onofrio, Robert C.;Parkin, Melissa;Roy, Jessica;Stahl, Erich;Winchester, Ellen;Ziaugra, Liuda;Altshuler, David;Shen, Yan;Yao, Zhijian;Huang, Wei;Chu, Xun;He, Yungang;Jin, Li;Liu, Yangfan;Shen, Yayun;Sun, Weiwei;Wang, Haifeng;Wang, Yi;Wang, Ying;Xiong, Xiaoyan;Xu, Liang;Waye, Mary M. Y.;Tsui, Stephen K. W.;Wong, J. Tze-Fei;Galver, Luana M.;Fan, Jian-Bing;Gunderson, Kevin;Murray, Sarah S.;Oliphant, Arnold R.;Chee, Mark S.;Montpetit, Alexandre;Chagnon, Fanny;Ferretti, Vincent;Leboeuf, Martin;Olivier, Jean-Franccois;Phillips, Michael S.;Roumy, Stephanie;Sallee, Clementine;Verner, Andrei;Hudson, Thomas J.;Kwok, Pui-Yan;Cai, Dongmei;Koboldt, Daniel C.;Miller, Raymond D.;Pawlikowska, Ludmila;Taillon-Miller, Patricia;Xiao, Ming;Tsui, Lap-Chee;Mak, William;Song, You Qiang;Tam, Paul K. H.;Nakamura, Yusuke;Kawaguchi, Takahisa;Kitamoto, Takuya;Morizono, Takashi;Nagashima, Atsushi;Ohnishi, Yozo;Sekine, Akihiro;Tanaka, Toshihiro;Tsunoda, Tatsuhiko;Deloukas, Panos;Bird, Christine P.;Delgado, Marcos;Dermitzakis, Emmanouil T.;Gwilliam, Rhian;Hunt, Sarah;Morrison, Jonathan;Powell, Don;Stranger, Barbara E.;Whittaker, Pamela;Bentley, David R.;Daly, Mark J.;de Bakker, Paul I. W.;Barrett, Jeff;Chretien, Yves R.;Maller, Julian;McCarroll, Steve;Patterson, Nick;Pe'er, Itsik;Price, Alkes;Purcell, Shaun;Richter, Daniel J.;Sabeti, Pardis;Saxena, Richa;Schaffner, Stephen F.;Sham, Pak C.;Varilly, Patrick;Altshuler, David;Stein, Lincoln D.;Krishnan, Lalitha;Smith, Albert Vernon;Tello-Ruiz, Marcela K.;Thorisson, Gudmundur A.;Chakravarti, Aravinda;Chen, Peter E.;Cutler, David J.;Kashuk, Carl S.;Lin, Shin;Abecasis, Goncalo R.;Guan, Weihua;Li, Yun;Munro, Heather M.;Qin, Zhaohui Steve;Thomas, Daryl J.;McVean, Gilean;Auton, Adam;Bottolo, Leonardo;Cardin, Niall;Eyheramendy, Susana;Freeman, Colin;Marchini, Jonathan;Myers, Simon;Spencer, Chris;Stephens, Matthew;Donnelly, Peter;Cardon, Lon R.;Clarke, Geraldine;Evans, David M.;Morris, Andrew P.;Weir, Bruce S.;Tsunoda, Tatsuhiko;Johnson, Todd A.;Mullikin, James C.;Sherry, Stephen T.;Feolo, Michael;Skol, Andrew
通讯作者：
Skol, Andrew
影响因子：
4.4
作者：
Hewitt, Alex W.;Poulsen, Johan P.;Mackey, David A.
通讯作者：
Mackey, David A.
影响因子：
30.8
作者：
Abecasis, GR;Cherny, SS;Cardon, LR
通讯作者：
Cardon, LR
影响因子：
2.5
作者：
Brown, NL;Dagenais, SL;Glaser, T
通讯作者：
Glaser, T
影响因子：
4.6
作者：
Hutcheson, DA;Hanson, MI;Vetter, ML
通讯作者：
Vetter, ML