A Genome–Wide Linkage Analysis for Geographic Atrophy Suggests Linkage to Multiple Chromosomes

Abstract

Abstract: : Purpose: Genetic studies of age–related macular degeneration (AMD) often involve persons with both choroidal neovascularization (CNV), and geographic atrophy (GA) but little is known regarding which genes/genetic loci influence the biological pathways for these disease end points. Methods: In order to evaluate the genetic associations with retinal pigmentary abnormalities and GA in the absence of signs of CNV, a genome scan was performed on a sample of 34 extended families (including 297 individuals and 346 sibling pairs), ascertained through a proband showing signs of advanced AMD. Fundus photographs were taken for each subject and were graded on a six–step retinal pigmentary abnormality/GA scale ranging from the absence of increased retinal pigment, retinal pigment epithelial depigmentation, or GA to the presence of pure GA. A model–free linkage analysis for GA was performed on this sample using age as a covariate for 338 markers covering chromosomes 1–22. The Haseman–Elston regression using the w4 weighting method was used for all linkage analyses. Results: Multipoint analysis provided evidence for linkage with p–values < 0.01 in the 1q25, 5p13, 6q23–25, 8q24, 11q14 and 12p11 regions. The most significant peak was that found on chromosome 1, with an empirical p–value of 4.38x10^–3. The linkage peaks were compared with previously published genome scans looking at GA subsets of AMD, with concordance found on chromosome 5. The peaks found on chromosomes 1 and 6 have been observed in other genome scans for AMD and may represent more general susceptibility genes. The regions on chromosomes 8, 11 and 12 are novel to this study. A genome scan from the entire Beaver Dam Eye Study Cohort (including 601 families and 1042 sibling pairs) was also performed. Model–free linkage for GA indicated linkage peaks in the 1p32, 3q26, 8q22, 9q31, 11q23, 12q24 and 15q21 regions. The peak on chromosome 8 is near the peak found in the analysis of the larger families. The peaks on chromosomes 12 and 15 are close those found in an earlier genome scan for AMD. Conclusions: These findings suggest a multigenic model for pigmentary abnormalities/GA.

Keywords: age-related macular degeneration • genetics • clinical (human) or epidemiologic studies: risk factor assessment