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Abhishek Nag, Pirro G Hysi, Christopher J Hammond; Analysis of intra-ocular pressure using a combination of next generation sequencing data and imputation-based method in the TwinsUK cohort. Invest. Ophthalmol. Vis. Sci. 2014;55(13):6407.
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Glaucoma is a major cause of visual impairment and the second leading cause of blindness in the world. So far, linkage studies have identified very rare penetrant mutations while genome-wide association studies have identified common variants with modest effect associated with glaucoma. The role of rare sequence mutations (MAF<5%) with intermediate effect size, which may underlie some of the unexplained heritability of glaucoma, has not yet been fully explored. We aimed to investigate the role of these variations in intra-ocular pressure (IOP) variance.
A sample 1150 unrelated subjects from the TwinsUK cohort who had their whole genome sequenced as a part of the UK10K project was used at the initial discovery stage. Association testing for IOP was performed for ~25 million identified variants (MAF<5%) using a linear regression model, adjusted for age and sex. An independent replication was conducted in a sample of 512 subjects from the TwinsUK cohort, fully unrelated to the former, whose genotypes were imputed using the UK10K reference haplotypes. A fixed effect inverse-variance meta-analysis of both sets of results was performed.
Seven loci were found that were significant in the meta-analysis (at the conventional GWAS threshold of significance of p<5x10-8) and associated in each of the two datasets (p<0.05). None of these were missense or stop-codon variations. All the associated variants were rare (minor allele frequency, MAF <1%), except for one (locus 12q13.2, that had MAF=2.7%). This variant was associated in both datasets (p=1.19x10-6 in the discovery study; and p=0.012 in the replication study).
We have investigated the role of sequence variations on a genome-wide scale using a combination of sequenced and imputed datasets from the TwinsUK cohort. Though we have identified some potential loci that could be associated with IOP, replication of these loci in independent studies is essential to deal with the possibility of false positive results when testing for the association of rare variations with a quantitative outcome like IOP.
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