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R.G. Weleber, J. Majewski, D.W. Schultz, M. Schain, T.C. Matise, J. Ott, T.S. Acott, M.L. Klein; Age-related Macular Degeneration: A Genome-wide Scan in Extended Families . Invest. Ophthalmol. Vis. Sci. 2003;44(13):1503.
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Purpose: We performed a genome-wide scan and genetic linkage analysis to identify loci associated with age-related macular degeneration (AMD). Methods: We collected 70 families consisting of at least 3 living affected members. The families ranged from small nuclear families to extended multigenerational pedigrees, consisting of a total of 344 affected and 217 unaffected members available for genotyping. We carried out linkage analysis under three genetic models: a parametric model with a dominant mode of inheritance and a set of age-dependent penetrances (Klein et al. 1998), a non age-dependent parametric model with a 5% phenocopy rate and 95% penetrances, and a non-parametric allele sharing model based on the exponential Zlr statistic. We performed the analyses on the entire pedigrees, but also subdivided the families into nuclear pedigrees in order to minimize the confounding effects of heterogeneity or multiple susceptibility alleles entering the pedigrees through spouses. Finally, in order to dissect potential genetic factors responsible for differences in disease manifestation, we stratified the sample by two major AMD phenotypes (predominantly neovascular AMD and predominantly geographic AMD), and by the age of affected family members. All analyses were performed using the ALLEGRO and LINKAGE programs. Results: We have previously demonstrated linkage between AMD and 1q25-31 in a single large family. Here, we identify another large family that links to 1q25-31 with a LOD score of 2.59 (dominant inheritance model). In the entire sample, we detect the following loci with scores exceeding a LOD = 2 cutoff under at least one of the models considered: 1q31 (HLOD = 2.07 at D1S518), 3p13 (HLOD = 2.19 at D3S1304/D3S4545), 4q32 (HLOD = 2.66 at D4S2368), 9q33 (LODZlr = 2.01 at D9S930/D9S934), 10q26 (HLOD = 3.06 at D10S1230). Conclusion: Our study found new loci (4q32 and 9q33) that should be considered in future mapping and mutational analyses of AMD and strengthened the evidence supporting loci suggested by other studies (1q31, 10q26 and 3p13).
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