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A.J. Lotery, S. Ennis, S.V. Goverdhan, J. Hoh, A. Cree, A. Collins; Linkage Association Mapping of the CFH Gene Region in a UK Cohort of Age–Related Macular Degeneration Patients . Invest. Ophthalmol. Vis. Sci. 2006;47(13):3270.
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The complement genes in the ch. 1 region found to be associated with age related macular degeneration (AMD) exhibit a high degree of linkage disequilibrium (LD). Independent association mapping studies using high resolution SNP data may further refine the causal locus. We have applied a novel LD mapping technique in order to independently study the association of AMD with the CFH gene region in a cohort of UK individuals of Caucasian ethnicity.
Using a subset of SNP data from a genome–wide scan for age related macular degeneration (Hoh et al), a novel LD mapping approach based on the rho (ρ) metric for association was applied to fine map the AMD disease locus on chromosome 1. The method uses composite likelihood and exploits the power gained by applying genomic distances measured in linkage disequilibrium units (LDUs). Stage 1 of this study applied this LD mapping technique to SNP data for a 2 megabase region surrounding the CFH locus in order to estimate the 95% confidence interval (CI) of association with AMD. Stage 2 involved selection of an enriched cohort of 100 caucasian subjects with AMD and 100 controls recruited from ophthalmic clinics at the Southampton Eye Unit. AMD phenotypes were characterised by clinical examination, stereoscopic fundus photography, fluorescein angiography and optical coherence tomography. Given the estimated 95% CI, a panel of 50 SNP's (non–synonomous coding variants, splice site variants and non–coding variants with a minor allele frequency > 5%) were identified to map the entire interval at a high density. Efforts were made to exclude SNP's which mapped to multiple locations in this highly duplicated region. The selected SNP’s were genotyped in the independent case/control cohort. High resolution association mapping within this confidence interval was used to identify the point location(s) of genomic variants implicated in AMD.
Using our LD mapping technique on available SNP data, we identified a 95% CI region (200 Kb) around the CFH gene using the composite likelihood approach. This 95% CI region exhibits three blocks of complete LD, interrupted by regions with minimal evidence of historical recombination and includes 3 CFH genes; CFH, CFHL3 and CFHL1. Association mapping results of the 50 high density SNP's across these 3 CFH genes will be presented.
LD mapping is a useful analytical tool for association studies. This study is of value in refining the CFH genotype association with AMD.
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