Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration

Abstract

We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH (P < 10(-75)), ARMS2 (P < 10(-59)), C2/CFB (P < 10(-20)), C3 (P < 10(-9)), and CFI (P < 10(-6)). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 x 10(-11)), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci (LIPC, P = 1.3 x 10(-7); CETP, P = 7.4 x 10(-7)) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c-associated alleles near LPL (P = 3.0 x 10(-3)) and ABCA1 (P = 5.6 x 10(-4)). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies.

Fig. 1.

Summary of genome-wide association scan results. (Upper) Summary of the significance of the association signal at each examined SNP in the discovery samples. The five known loci are highlighted in green. The three strongest loci after follow (TIMP3, LIPC, and CETP) are highlighted in blue. (Lower) Quantile—quantile plot for test statistics. Shaded region corresponds to a 90% confidence interval for the test statistics.

Fig. 2.

Regional plots for association signals in five previously reported loci. Detailed plots of association in the discovery samples in five confirmed regions (CFH, ARMS, C2/CFB, C3, and CFI) are shown. The most significant SNP in each region is highlighted in a red square, and other SNPs are drawn as colored circles reflecting linkage disequilibrium with the top selected SNP. Exons and transcript direction for genes in each region are indicated at bottom of each panel.

Fig. 3.

Regional plot for association signals in the three previously uncharacterized loci. Detail plots for the regions surrounding the SYN3/TIMP3, LIPC, and CETP regions. Original, follow-up, and combined P values for the SNP selected for replication are indicated on the left. Discovery sample P values for the index SNP and other nearby SNPs are plotted.