Age-related macular degeneration: a high-resolution genome scan for susceptibility loci in a population enriched for late stage disease

Abstract

Age-related macular degeneration (AMD) leads to geographic atrophy (GA) and/or choroidal neovascularization (CNV). Considerable data exists in support of a genetic predisposition for AMD. Recent linkage studies have provided evidence in favor of several AMD susceptibility loci. The authors performed a high-resolution (5-CM) genome scan of 412 affected relative pairs that were enriched for late-stage disease (GA and/or CNV). Nonparametric linkage analysis was performed using two different diagnostic criteria, and also by dividing the affected individuals according to GA or CNV phenotype. The results demonstrate evidence of linkage in regions that were suggested in at least one previous study at chromosomes 1q (236 to 240 cM in the Marshfield genetic map), 5p (40 to 50 cM), and 9q (111 cM). Multipoint analysis of affected relatives with CNV provided evidence of additional susceptibility loci on chromosomes 2p (10 cM) and 22q (25 cM). A recently identified Gln5345 Arg change in HEMICENTIN-1 on chromosome 1q 25 was not detected in 274 affected members in the restricted group with AMD, 346 additional patients with AMD, and 237 unaffected controls. These results consolidate the chromosomal locations of several AMD susceptibility loci and, together with previous reports, should facilitate the search for disease-associated sequence variants.—Hans E. Grossniklaus Age-related macular degeneration (AMD) leads to geographic atrophy (GA) and/or choroidal neovascularization (CNV). Considerable data exists in support of a genetic predisposition for AMD. Recent linkage studies have provided evidence in favor of several AMD susceptibility loci. The authors performed a high-resolution (5-CM) genome scan of 412 affected relative pairs that were enriched for late-stage disease (GA and/or CNV). Nonparametric linkage analysis was performed using two different diagnostic criteria, and also by dividing the affected individuals according to GA or CNV phenotype. The results demonstrate evidence of linkage in regions that were suggested in at least one previous study at chromosomes 1q (236 to 240 cM in the Marshfield genetic map), 5p (40 to 50 cM), and 9q (111 cM). Multipoint analysis of affected relatives with CNV provided evidence of additional susceptibility loci on chromosomes 2p (10 cM) and 22q (25 cM). A recently identified Gln5345 Arg change in HEMICENTIN-1 on chromosome 1q 25 was not detected in 274 affected members in the restricted group with AMD, 346 additional patients with AMD, and 237 unaffected controls. These results consolidate the chromosomal locations of several AMD susceptibility loci and, together with previous reports, should facilitate the search for disease-associated sequence variants.—Hans E. Grossniklaus