Common Genetic Variants near the Brittle Cornea Syndrome Locus ZNF469 Influence the Blinding Disease Risk Factor Central Corneal Thickness

被引:116
作者
Lu, Yi [1 ]
Dimasi, David P. [2 ]
Hysi, Pirro G. [3 ]
Hewitt, Alex W. [4 ]
Burdon, Kathryn P. [2 ]
Toh, Tze'Yo [4 ,5 ]
Ruddle, Jonathan B. [4 ]
Li, Yi Ju [6 ,7 ]
Mitchell, Paul [8 ]
Healey, Paul R. [8 ]
Montgomery, Grant W. [1 ]
Hansell, Narelle [1 ]
Spector, Timothy D. [3 ]
Martin, Nicholas G. [1 ]
Young, Terri L. [6 ]
Hammond, Christopher J. [3 ]
Macgregor, Stuart [1 ]
Craig, Jamie E. [2 ]
Mackey, David A. [4 ,9 ]
机构
[1] Queensland Inst Med Res, Brisbane, Qld 4006, Australia
[2] Flinders Univ S Australia, Dept Ophthalmol, Adelaide, SA 5001, Australia
[3] Kings Coll London, Sch Med, St Thomas Hosp, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England
[4] Univ Melbourne, Ctr Eye Res Australia, Royal Victorian Eye & Ear Hosp, Melbourne, Vic, Australia
[5] Univ Tasmania, Hosp Eye, Launceston, Tas 7250, Australia
[6] Duke Univ, Med Ctr, Ctr Human Genet, Durham, NC USA
[7] Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Durham, NC USA
[8] Univ Sydney, Ctr Vis Res, Westmead Millennium Inst, Sydney, NSW 2006, Australia
[9] Univ Western Australia, Lions Eye Inst, Ctr Ophthalmol & Visual Sci, Perth, WA 6009, Australia
基金
英国惠康基金; 英国医学研究理事会; 英国生物技术与生命科学研究理事会; 澳大利亚国家健康与医学研究理事会; 美国国家卫生研究院;
关键词
OSTEOGENESIS IMPERFECTA; GLAUCOMA; MUTATIONS; ASSOCIATION; SELECTION; FOXC1; TWINS; EYE;
D O I
10.1371/journal.pgen.1000947
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Central corneal thickness (CCT), one of the most highly heritable human traits (h(2) typically>0.9), is important for the diagnosis of glaucoma and a potential risk factor for glaucoma susceptibility. We conducted genome-wide association studies in five cohorts from Australia and the United Kingdom (total N = 5058). Three cohorts were based on individually genotyped twin collections, with the remaining two cohorts genotyped on pooled samples from singletons with extreme trait values. The pooled sample findings were validated by individual genotyping the pooled samples together with additional samples also within extreme quantiles. We describe methods for efficient combined analysis of the results from these different study designs. We have identified and replicated quantitative trait loci on chromosomes 13 and 16 for association with CCT. The locus on chromosome 13 (nearest gene FOXO1) had an overall meta-analysis p-value for all the individually genotyped samples of 4.6 x 10(-10). The locus on chromosome 16 was associated with CCT with p = 8.95 x 10(-11). The nearest gene to the associated chromosome 16 SNPs was ZNF469, a locus recently implicated in Brittle Cornea Syndrome (BCS), a very rare disorder characterized by abnormal thin corneas. Our findings suggest that in addition to rare variants in ZNF469 underlying CCT variation in BCS patients, more common variants near this gene may contribute to CCT variation in the general population.
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页数:10
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