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.
Highlights
Age-related macular degeneration (AMD) is a common degenerative disease of the central retina and a leading cause of severe vision impairment in Western societies [1]
SNP selection based on published data and linkage disequilibrium structure Eight loci (CFH, age-related maculopathy susceptibility 2 (ARMS2)/HtrA serine peptidase 1 (HTRA1), complement factor I (CFI), complement factor B (CFB), component 3 (C3), apolipoprotein E (APOE), LIPC and tissue inhibitor of metalloproteinases-3 gene (TIMP3)) with 13 SNPs and established association with AMD were included into our genetic risk score modeling (Table S1)
There were three further SNPs with reportedly established association, which we did not select for the model: (i) at the complement factor H (CFH) locus, an association of four variants with AMD is known; rs1410996 is present on two distinct haplotypes, each of which is tagged by rs800292 or rs6677604 (r2 = 0.283 to rs1410996 [27]), respectively [13], while rs800292 and rs667604 are uncorrelated (r2 = 0.008 [27]), (ii) among the three highly correlated ARMS/HTRA variants, rs10490924 was reported to fully capture the disease risk at this locus [28]
Summary
Age-related macular degeneration (AMD) is a common degenerative disease of the central retina and a leading cause of severe vision impairment in Western societies [1]. AMD is a complex disease influenced by genetic and environmental factors with estimates of heritability varying from 45% to 71% [6]. Several AMD susceptibility loci have been identified. Two loci are accounting for an estimated 50% of AMD cases: complement factor H (CFH) on 1q32 and age-related maculopathy susceptibility 2 (ARMS2)/HtrA serine peptidase 1 (HTRA1) on 10q26 [7,8]. Fine-mapping studies and functional analyses at the CFH locus indicate at least three independent risk variants [8,9,10,11,12,13]. At the ARMS2/HTRA1 region, a single risk haplotype was found to fully explain the observed association [14]
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