title: Rare Genetic Variants Associated With Development of Age-Related Macular Degeneration.
abstract: OBJECTIVE
  Rare variants in the complement genes CFH, CFI, C9, and C3 have been found to be highly associated with age-related macular degeneration (AMD); however, the effect on clinical characteristics and familial segregation by these variants is lacking.
  
  
  OBJECTIVE
  To determine the contribution of rare CFH Arg1210Cys, CFI Gly119Arg, C9 Pro167Ser, and C3 Lys155Gln variants in the development of AMD in 22 multiplex families and to describe clinical differences in carriers vs noncarriers in these families and a large case-control cohort.
  
  
  METHODS
  This retrospective case-control study included 114 affected and 60 unaffected members of 22 multiplex families with AMD as well as 1589 unrelated patients with AMD and 1386 unrelated control individuals enrolled in the European Genetic Database (EUGENDA). Patients were recruited from March 29, 2006, to April 26, 2013, and data were collected from April 20, 2012, to May 7, 2014. All participants underwent an extensive ophthalmic examination and completed a questionnaire. Venous blood samples were obtained from all participants for genetic analysis, including whole-exome sequencing and measurements of complement activation. Data were analyzed from September 23, 2014, to November 4, 2015.
  
  
  METHODS
  Differences between carriers and noncarriers of rare variants in age at onset of symptoms, the family history of AMD, complement activation levels (C3d:C3 ratio), the presence of reticular pseudodrusen, and AMD phenotype.
  
  
  RESULTS
  Among the 114 affected and 60 unaffected members of 22 multiplex families with AMD and the 1598 unrelated patients with AMD and 1386 controls in the EUGENDA cohort who underwent analysis, the presence of the CFI Gly119Arg, C9 Pro167Ser, or C3 Lys155Gln variant was confirmed in 18 individuals in 5 families but did not completely segregate with the disease. In the case-control cohort, the 91 affected carriers of these variants were younger at symptom onset (mean [SD] age, 67.4 [8.5] vs 71.3 [8.9] years; P = .01) and more often reported a positive family history (35 of 79 [44.3%] vs 367 of 1201 [30.6%]; P = .008) compared with the 1498 noncarriers. Patients with advanced atrophic AMD carried these rare variants more frequently than patients with neovascular AMD (11 of 93 [11.8%] vs 40 of 835 [4.8%]; P = .04).
  
  
  CONCLUSIONS
  Previously reported rare variants do not completely segregate within families with AMD. However, patients carrying these rare variants differ clinically from noncarriers by an earlier age at symptom onset, higher prevalence of a positive family history, and AMD phenotype. These results suggest that genetic tests for AMD might be designed to detect common and rare genetic variants, especially in families, because rare variants contribute to the age at onset and progression of the disease.
authors.affiliation: Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Nicole T M
authors.initials: NT
authors.lastname: Saksens
authors.affiliation: Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Maartje J
authors.initials: MJ
authors.lastname: Geerlings
authors.affiliation: Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Bjorn
authors.initials: B
authors.lastname: Bakker
authors.affiliation: Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Tina
authors.initials: T
authors.lastname: Schick
authors.affiliation: Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Mohamed R
authors.initials: MR
authors.lastname: Daha
authors.affiliation: Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Fauser
authors.affiliation: Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands4Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Camiel J F
authors.initials: CJ
authors.lastname: Boon
authors.affiliation: Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Eiko K
authors.initials: EK
authors.lastname: de Jong
authors.affiliation: Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Carel B
authors.initials: CB
authors.lastname: Hoyng
authors.affiliation: Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands5Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Anneke I
authors.initials: AI
authors.lastname: den Hollander
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D003176:Complement C3 / Q000235:genetics*; D003186:Complement C9 / Q000235:genetics*; D017242:Complement Factor H / Q000235:genetics; D017244:Complement Factor I / Q000235:genetics*; D005260:Female; D060005:Genotyping Techniques; D057092:Geographic Atrophy / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010375:Pedigree; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D014792:Visual Acuity / Q000502:physiology; D057135:Wet Macular Degeneration / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology
chemical_list: C493495:CFH protein, human; D003176:Complement C3; D003186:Complement C9; D017242:Complement Factor H; D017244:Complement Factor I