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Pirro G. Hysi, Abhishek Nag, Diana Kozareva, Terri L. Young, David A. Mackey, Tim D. Spector, Christopher J. Hammond; A Combined Use of Gene Expression Profiling and Genome-Wide Association Studies for the Identification of Nuclear Cataract Genetic Risk Factors. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1546.
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© ARVO (1962-2015); The Authors (2016-present)
Cataract is a major cause of visual impairment worldwide. Despite its high prevalence, little is known about its causes and mechanisms operating at a molecular level. Family studies have demonstrated that age-related cataract (both nuclear and cortical) is heritable, but presumably because of its polygenic nature and environmental influences, susceptibility genes have been elusive so far. The aim of this work was to enhance the capability to identify genetic risk factors for nuclear cataract by combining results from whole genome association and expression studies.
We have carried out a large scale genome wide association study (GWAS) of 2895 subjects over the age of 50 years from the TwinsUK cohort with quantitative nuclear cataract scores derived from digital Scheimpflug lens images for whom whole genome SNP information was available. We compared the results obtained from the GWAS with a peripheral blood mRNA expression analysis in a subset of 195 subjects. Both analyses were regression based and corrected for age.
No genome-wide significant results were obtained after multiple testing correction in both GWAS and expression datasets. However, comparison of the two sets of results revealed that for some genes there was strongly suggestive concordance between GWAS and expression results. Notably DDAH1, the fifth-highest-ranked gene in the GWAS showed some of the strongest associations between its expression and degree of nuclear opacity. DDAH1 participate in a number of molecular processes and is better known for its NOS inhibitory properties.
Despite modest power and tissue-specificity limitations, these results demonstrate the benefits of integrated analysis of different "omics" approaches and their potential to further knowledge about disease. They also identify a strong nuclear cataract candidate gene in DDAH1.
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