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Modelling the Genetic Risk in Age-Related Macular Degeneration

By Felix Grassmann, Lars G. Fritsche, Claudia N. Keilhauer, Iris M. Heid and Bernhard H. F. Weber


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

Topics: 610 Medizin, ddc:610
Publisher: 'Public Library of Science (PLoS)'
Year: 2012
DOI identifier: 10.1371/journal.pone.0037979
OAI identifier:

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  7. (2010). An imbalance of human complement regulatory proteins CFHR1, CFHR3 and factor H influences risk for age-related macular degeneration (AMD). Human molecular genetics 19: 4694–4704. Available: pubmed/20843825.
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  12. (2007). Complement C3 variant and the risk of age-related macular degeneration. The New England journal of medicine 357:
  13. (2005). Complement factor H polymorphism in age-related macular degeneration.
  14. (1974). Conditional Logit Analysis of Qualitative Choice Behavior. FRONTIERS IN ECONOMETRICS.
  15. (2009). Contribution of Copy Number Variation in the Regulation of Complement Activation Locus to Development of Age-Related Macular Degeneration. Investigative Ophthalmology.
  16. (2010). Core Team
  17. (2010). Determination of a gene and environment risk model for age-related macular degeneration. The British journal of ophthalmology 94:
  18. (2010). epicalc: Epidemiological calculator.
  19. (2009). Feature selection and classification of MAQC-II breast cancer and multiple myeloma microarray gene expression data.
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  21. (2010). Genomewide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC).
  22. (2008). Genotype score in addition to common risk factors for prediction of type 2 diabetes. The New England journal of medicine 359: 2208–2219. Available:http:// &rendertype=abstract.
  23. (2005). Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Human molecular genetics 14: 3227–3236.
  24. (2001). Internal validation of predictive models: efficiency of some procedures for logistic regression analysis.
  25. (2005). Meta-analysis of genome scans of age-related macular degeneration. Human molecular genetics 14: 2257–2264. Available: pubmed/15987700. Accessed
  26. (2003). Meta-Analysis of Prostate-Specific Antigen and Digital Rectal Examination as Screening Tests for Prostate Carcinoma.
  27. (2007). PLINK: a tool set for whole-genome association and population-based linkage analyses. American journal of human genetics 81: 559–575. Available:http:// &rendertype=abstract.
  28. (2009). Prediction model for prevalence and incidence of advanced age-related macular degeneration based on genetic, demographic, and environmental variables.
  29. (2006). Predictive testing for complex diseases using multiple genes: Fact or fiction?
  30. (2004). Prevalence of age-related macular degeneration in the United States. Archives of ophthalmology 122:
  31. (2006). Prevalence of age-related maculopathy
  32. (2006). Ranibizumab for neovascular age-related macular degeneration. The New England journal of medicine 355:
  33. (2006). Ranibizumab versus verteporfin for neovascular age-related macular degeneration. The New England journal of medicine 355: 1432–1444. Available:http:// Accessed
  34. (2011). Risk and non risk associated variants at the 10q26 AMD locus influence ARMS2 mRNA expression but exclude pathogenic effects due to protein deficiency.
  35. (2011). Risk models for progression to advanced age-related macular degeneration using demographic, environmental, genetic, and ocular factors.
  36. (2009). rmeta: Meta-analysis. R package version 2.16.
  37. (2008). SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics
  38. (2007). The relationship of dietary carotenoid and vitamin A, E, and C intake with agerelated macular degeneration in a case-control study:
  39. (2007). The relationship of dietary lipid intake and age-related macular degeneration in a case-control study:
  40. (2005). The US twin study of age-related macular degeneration: relative roles of genetic and environmental influences.
  41. (1991). The Wisconsin age-related maculopathy grading system.
  42. (2010). Treatment of age-related macular degeneration: beyond VEGF.
  43. (2007). Variation in complement factor 3 is associated with risk of age-related macular degeneration.
  44. (2006). Variation in factor B (BF) and complement component 2 (C2) genes is associated with agerelated macular degeneration.
  45. (2009). Variation near complement factor I is associated with risk of advanced AMD. European journal of human genetics:

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