title: Risk Prediction for Progression of Macular Degeneration: 10 Common and Rare Genetic Variants, Demographic, Environmental, and Macular Covariates.
abstract: OBJECTIVE
  To determine the association between genetic variants and transition to advanced age-related macular degeneration (AMD), and to develop a predictive model and online application to assist in clinical decision making.
  
  
  METHODS
  Among 2951 subjects in the Age-Related Eye Disease Study, 834 progressed from no AMD, early AMD, or intermediate AMD to advanced disease. Survival analysis was used to assess which genetic, demographic, environmental, and macular covariates were independently associated with progression. Attributable risk, area under the curve statistics (AUCs), and reclassification odds ratios (ORs) were calculated. Split-sample validation was performed. An online risk calculator was developed and is available in the public domain at www.seddonamdriskscore.org.
  
  
  RESULTS
  Ten genetic loci were independently associated with progression, including newly identified rare variant C3 K155Q (hazard ratio: 1.7, 95% confidence interval: 1.2-2.5, P = 0.002), three variants in CFH, and six variants in ARMS2/HTRA1, CFB, C3, C2, COL8A1, and RAD51B. Attributable risk calculations revealed that 80% of incident AMD is attributable to genetic factors, adjusting for demographic covariates and baseline macular phenotypes. In a model including 10 genetic loci, age, sex, education, body mass index, smoking, and baseline AMD status, the AUC for progression to advanced AMD over 10 years was 0.911. Split-sample validation showed a similar AUC (0.907). Reclassification analyses indicated that subjects were categorized into a more accurate risk category if genetic information was included (OR 3.2, P < 0.0001).
  
  
  CONCLUSIONS
  Rare variant C3 K155Q was independently associated with AMD progression. The comprehensive model may be useful for identifying and monitoring high-risk patients, selecting appropriate therapies, and designing clinical trials.
authors: Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Boston, Massachusetts, United States 2Department of Ophthalmology, Tufts University School of Medicine, Boston, Massachusetts, United States 3Sackler School of Gra.
authors: Johanna M
authors: JM
authors: Seddon
authors: Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Boston, Massachusetts, United States.
authors: Rachel E
authors: RE
authors: Silver
authors: Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, Massachusetts, United States.
authors: Manlik
authors: M
authors: Kwong
authors: Channing Division of Network Medicine, Harvard Medical School, Harvard University, Boston, Massachusetts, United States.
authors: Bernard
authors: B
authors: Rosner
mesh_terms: D000368:Aged; D003176:Complement C3 / Q000235:genetics; D018450:Disease Progression; D004777:Environment; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D015994:Incidence; D008266:Macula Lutea / Q000473:pathology*; D008268:Macular Degeneration / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D018570:Risk Assessment / Q000379:methods*; D012307:Risk Factors; D013997:Time Factors; D014481:United States / Q000453:epidemiology
chemical_list: D003176:Complement C3
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