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JL Haines, JM Lamb, S Schmidt, A Agarwal, E Postel, M De La Paz-Schmidlekofer, JR Gilbert, WK Scott, MA Pericak-Vance; Follow-up of Genomic Screen Regions in Age-Related Macular Degeneration . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1846.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: We have initiated collection of a large dataset of multiplex families in the Southeast United States with age-related macular degeneration (AMD) with the overall goal of identifying the genes that underlie risk and expression of AMD. A recently completed genomic screen (Weeks et al., Am J. Opthal. 132: 682-692, 2001) identified four chromosomal regions (1q31, 9p13, 10q26, 17q25) of potential interest, defined as lod scores greater than 2. Multiple markers in these four regions were tested to determine if we could replicate any of these regions. Methods: AMD was defined according to a slightly modified version of an international classification system (Bird et al., Ophthal. 39: 367-74, 1995) and included individuals with grades 3, 4, and 5 as affected. The dataset consisted of 70 multiplex families (163 affected, 43 unaffected individuals; 125 total affected relative pairs) collected from North Carolina and Tennessee. Both parametric (heterogeneity lod scores for both autosomal dominant and autosomal recessive models) and non-parametric (sibpair MLS) analyses were performed for each marker and region. Conditional lod score analysis was performed using Genehunter-plus. Three markers were genotyped for each region, including at least one marker demonstrating high lod scores in the Weeks et al. dataset. Results: The scores for chromosomes 1, 9, and 17 were unimpressive. The highest lod scores under any model were 0.18 at D1S1647, 0.14 at D9S1121, and 0.45 at D17S1822. The results for chromosome 10 were more interesting. The highest score was a 1.12 at D10S1230 using the sibpair MLS approach (the parametric heterogeneity score was 0.55). Analyzing the data using just grades 4 and 5 or just grade 5 did not substantially change the results. Conditional lod score analysis weighting the linkage results by the known negative association with the APOE-4 allele slightly increased the scores for chromosomes 1 and 17 (peak scores 0.43 and 0.48 respectively) but did not substantially change the scores on chromosome 9 and 10. Conclusion: A set of 70 multiplex AMD families has been collected and analyzed for linkage to 4 proposed AMD chromosomal regions. Significant lod scores were not identified for any of these regions, but a modestly suggestive score was observed on chromosome 10. Further analysis of this region is underway.
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