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M. B. Gorin, J. Jakobsdottir, Y. P. Conley, R. E. Ferrell, W. Chen, G. R. Abecasis, A. Swaroop, A. O. Edwards, D. E. Stambolian, D. E. Weeks; Further Explorations in the Genetics of Age-Related Maculopathy (ARM). Invest. Ophthalmol. Vis. Sci. 2009;50(13):3449.
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Identify new and replicate previously identified candidate genetic variants associated with ARM.
A combination of strategies have been used to successfully identify susceptibility genes for ARM including linkage studies, locus-specific, candidate gene, and genome-wide SNP association (GWA) studies. We integrated the findings from multiple linkage studies and the Age-related Eye Disease Study (AREDS) GWA public dataset with a set of 587 genes in biological pathways implicated in ARM based on a literature review. We created a prioritization strategy to select 1536 SNPs in 111 genes for association studies in 2,306 individuals. SNPs were tested for allelic associations using the MQLS statistic in ARM families and unrelated cases and controls and using the Fisher’s exact statistic in the Cardiovascular Health Study (CHS) cohort. 130 SNPs were genotyped in an extended cohort from the CHS and AREDS studies (1807 individuals).
We replicated associations for SNPs linked to CFH, C2, C3, and HTRA1/LOC387715 with P-values of 10-28, 10-6, 10-5, and 10-12 in our combined dataset. We identified several complement factor H related loci and a few novel genes that do not appear to be directly related to the complement activation pathway, including TBC1D16 and FAT4, with p-values < 10-3 and FAT3 with a marginal p-value of 0.05. These findings are being subjected to replication with 3,274 samples from an independent ARM GWA study that has been recently completed.
We have replicated association of four genes with ARM and identified several novel candidate genes.
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