Follow–Up SNP Association Analysis of Linkage Peaks on Chromosomes 16p for Age–Related Macular Degeneration (AMD)

Abstract

Abstract: : Purpose: Age–related macular degeneration (AMD) is one of the most significant causes of vision loss in older adults. There is substantial evidence that genes play a critical role in its etiology. To identify susceptibility genes for AMD, several genome–wide linkage screens have recently been completed. One of the consistent regions of interest across studies is chromosomes16p, which we have explored in more detail. The goal of this study was to further localize the AMD gene on 16p. Methods: We genotyped 114 SNPs in the 20–32 Mb interval on 16p (density ∼100 kb). All SNPs were chosen to have minor allele frequency of at least 10%. Both family–based analysis, using the pedigree disequilibrium test (PDT), and case–control analysis, using logistic regression with adjustment for age at exam and sex, were used to test for single–marker allelic association between these SNPs and AMD. The PDT was applied to a data set of 65 AMD discordant sibpairs, and the case–control analysis was performed on an independent data set of 380 cases and 175 rigorously examined controls. Results: On chr 16p, the PDT gave strong evidence for association (p<0.01) for 11 SNPs in two clusters separated by 6 Mb . Most of the evidence for association came from patients with neovascular AMD. The linkage signals remain strong for the proximal region, with a peak score of 1.66 in 110 families, particularly in families where at least two relatives are affected with neovascular AMD. The case–control analysis also identified multiple SNPs in those same two clusters with significant increased odds ratios (P<0.05), driven mostly by those with neovascular AMD. Conclusions: The clustering of results in two regions suggests that more than one gene in this region may be involved in AMD. Additional genotyping for further localization of these signals is necessary to identify the underlying AMD risk gene(s).

Keywords: gene mapping • age-related macular degeneration • genetics