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) is a complex multifactorial disease that affects the central region of the retina. AMD is clinically heterogeneous, leading to geographic atrophy (GA) and/or choroidal neovascularization (CNV) at advanced stages. Considerable data exists in support of a genetic predisposition for AMD. Recent linkage studies have provided evidence in favor of several AMD susceptibility loci. We have 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. Our results demonstrate evidence of linkage in regions that were suggested in at least one previous study at chromosomes 1q (236-240 cM in the Marshfield genetic map), 5p (40-50 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 Gln5345Arg change in HEMICENTIN-1 on chromosome 1q25 was not detected in 274 affected members in the restricted group with AMD, 346 additional patients with AMD, and 237 unaffected controls. Our results consolidate the chromosomal locations of several AMD susceptibility loci and, together with previous reports, should facilitate the search for disease-associated sequence variants.

Figure 1

Nonparametric linkage analysis at each marker by use of the NPL_ALL statistics (Whittemore and Halpern 1994). LOD scores (Kong and Cox 1997) for six disease subtypes were plotted for every marker location. The solid symbols denote the strict trait definition, and the empty ones denote the broad trait definition. The blue symbols indicate AMD, the red symbols indicate GA, and the green symbols indicate CNV.

Figure 2

Multipoint nonparametric linkage analysis at equally spaced locations throughout the genome by use of the NPL_ALL statistics (Whittemore and Halpern 1994). LOD scores (Kong and Cox 1997) for six disease subtypes are plotted at 1-cM intervals. The solid lines denote the strict trait definition, and the dotted lines denote the broad trait definition. The blue line indicates AMD, the red line indicates GA, and the green line indicates CNV.

Figure 3

Multipoint nonparametric linkage analysis at equally spaced locations throughout the genome by use of the NPL-ALL statistics (Whittemore and Halpern 1994). LOD scores (Kong and Cox 1997) for six disease subtypes are plotted at 1-cM intervals. The solid lines denote the strict trait definition, and the dotted lines denote the broad trait definition. The blue lines indicate AMD, the red lines indicate GA, and the green lines indicate CNV. The multipoint LOD score plots for four chromosomes of interest (1, 5, 9, and 22) are shown.