Allele Association Studies in the Chromosome 1q31–32 Locus for Age–Related Macular Degeneration

Abstract

Abstract: : Purpose: To narrow the location of the previously reported locus (ARMD1) on chromosome 1q31–32 linked to age–related macular degeneration (AMD). Methods: The ARMD1 locus was conceptually divided into 6 gene–rich clusters for subsequent analysis. Two hundred and twenty gene–based single nucleotide polymorphisms (SNPs) were designed and validated to achieve a 20 kb average spacing across 31 of the 47 genes in the ARMD1 locus covering 4,276 kb of genomic DNA in 4 of the 6 clusters. Genotyping across the Fibulin–6 locus was performed at an average density of 17 kb. Initial genotyping with these 220 SNPs was performed on a subset of a case–control population including 233 AMD subjects and 135 controls. SNP allele and genotype frequencies were compared between cases and controls by chi–square analysis. Analysis of haplotypes comprised of 2–5 adjacent SNPs was performed using a sliding window aproach with the Haplo.stats program. Results: Significant (0.00000001 < p < 0.004) allele association was found for 9 markers spanning a 400 kb region containing 7 genes. Haplotype analysis suggested two adjacent SNPs within a single gene could account for most of the association to the region. Homozygotes for one of the haplotypes derived from these two SNPs had a 3.7 fold increased risk of AMD compared to those lacking this haplotype (95% CI = 2.0–6.7). No association was found with any SNPs across the Fibulin–6 locus. Conclusions: A 400 kb region of the 14,000 kb ARMD1 locus was highly associated with AMD in this case–control study. The haplotype analysis suggests that a segment of DNA centered over 1 gene contains a biologically meaningful variant which confers increased risk for AMD.

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