期刊
PLOS GENETICS
卷 6, 期 5, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1000947
关键词
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资金
- Australian National Health and Medical Research Council (NHMRC) [2004-2009]
- NHMRC [974159, 211069, 457349, 262120, 529923, 2005-2007, 496675]
- Clifford Craig Medical Research Trust
- Ophthalmic Research Institute of Australia (ORIA)
- Glaucoma Australia
- American Health Assistance Foundation (AHAF)
- Peggy and Leslie Cranbourne Foundation
- Foundation for Children
- Jack Brockhoff Foundation
- National Eye Institute (NEI) [2007-2010]
- National Institutes of Health (NIH)
- CIDR
- NIH/NEI [1RO1EY018246]
- Netherlands Scientific Organization (NWO) [480-05-003]
- Pfizer
- Wellcome Trust
- EU [HEALTH-F2-2008-201865-GEFOS, HEALTH-F4-2007-201413, QLG2-CT-2002-01254]
- Dept of Health via the National Institute for Health Research (NIHR)
- NIHR
- CJH
- Biotechnology and Biological Sciences Research Council (BBSRC) [G20234]
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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