Modelling the genetic risk in age-related macular degeneration

Abstract

Late-stage age-related macular degeneration (AMD) is a common sight-threatening disease of the central retina affecting approximately 1 in 30 Caucasians. Besides age and smoking, genetic variants from several gene loci have reproducibly been associated with this condition and likely explain a large proportion of disease. Here, we developed a genetic risk score (GRS) for AMD based on 13 risk variants from eight gene loci. The model exhibited good discriminative accuracy, area-under-curve (AUC) of the receiver-operating characteristic of 0.820, which was confirmed in a cross-validation approach. Noteworthy, younger AMD patients aged below 75 had a significantly higher mean GRS (1.87, 95% CI: 1.69-2.05) than patients aged 75 and above (1.45, 95% CI: 1.36-1.54). Based on five equally sized GRS intervals, we present a risk classification with a relative AMD risk of 64.0 (95% CI: 14.11-1131.96) for individuals in the highest category (GRS 3.44-5.18, 0.5% of the general population) compared to subjects with the most common genetic background (GRS -0.05-1.70, 40.2% of general population). The highest GRS category identifies AMD patients with a sensitivity of 7.9% and a specificity of 99.9% when compared to the four lower categories. Modeling a general population around 85 years of age, 87.4% of individuals in the highest GRS category would be expected to develop AMD by that age. In contrast, only 2.2% of individuals in the two lowest GRS categories which represent almost 50% of the general population are expected to manifest AMD. Our findings underscore the large proportion of AMD cases explained by genetics particularly for younger AMD patients. The five-category risk classification could be useful for therapeutic stratification or for diagnostic testing purposes once preventive treatment is available.

Figure 1. Risk estimates for each of thirteen AMD risk variants from eight gene loci.

Odds ratios (OR) per risk allele were derived from multiple logistic regression models. Horizontal lines indicate 95% confidence intervals.

Figure 2. Area-under-the-curve of the receiver operating characteristic for the 13-SNP genetic risk score and by gene locus.

Observed AUC was 0.820 and the locus-specific AUCs were 0.513, 0.524, 0.536, 0.547, 0.555, 0.571, 0.686 and 0.710 from bottom to top.

Figure 3. Genetic risk score distribution in the study population and in a modeled population.

AMD cases are shown in red, controls in blue, while overlapping bars are shaded blue/red. (A) Genetic risk score distribution for cases (N = 986) and controls (N = 796) in the present study. (B) Counts of cases in (A) were scaled to represent 15% of the total population (assumed as AMD prevalence of the 85–90 year old general population). The density curve represents the risk score distribution in 381 European ancestry samples available through the 1000 Genomes Project (Release 20110521).