Seven new loci associated with age-related macular degeneration

Abstract

Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 loci associated at P < 5 × 10(-8). These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis. Our results include seven loci with associations reaching P < 5 × 10(-8) for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL. A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined. Our findings provide new directions for biological, genetic and therapeutic studies of AMD.

FIGURE 1. Summary of genomewide association scan results

Summary of genomewide association scan results in the discovery GWAS sample. Previously described loci reaching p < 5×10⁻⁸ are labeled in blue; new loci reaching p < 5×10⁻⁸ for the first time after follow-up are labeled in green.

FIGURE 2. Sensitivity analysis

The top left panel compares estimated effect sizes for the original analysis and for an age-adjusted analysis (where age was included as a covariate and samples of unknown age were excluded). The top right panel compares analyses stratified by sex. The bottom left panel evaluates stratification by disease subtype. The bottom right panel evaluates stratification by ethnicity. The size of each marker reflects confidence intervals (with height reflecting confidence interval along the Y axis and width reflecting confidence interval along the X axis). Comparisons reaching p < 0.05 are labeled and colored in red.

FIGURE 3. Risk score analysis

We calculated a risk score for each individual, defined as the product of the number of risk alleles at each locus and the associated effect size for each allele (measured on the log-odds scale). The plot summarizes the ability of these overall genetic risk scores to distinguish cases and controls.