title: Multiallelic copy number variation in the complement component 4A (C4A) gene is associated with late-stage age-related macular degeneration (AMD).
abstract: BACKGROUND
  Age-related macular degeneration (AMD) is the leading cause of vision loss in Western societies with a strong genetic component. Candidate gene studies as well as genome-wide association studies strongly implicated genetic variations in complement genes to be involved in disease risk. So far, no association of AMD with complement component 4 (C4) was reported probably due to the complex nature of the C4 locus on chromosome 6.
  
  
  METHODS
  We used multiplex ligation-dependent probe amplification (MLPA) to determine the copy number of the C4 gene as well as of both relevant isoforms, C4A and C4B, and assessed their association with AMD using logistic regression models.
  
  
  RESULTS
  Here, we report on the analysis of 2645 individuals (1536 probands and 1109 unaffected controls), across three different centers, for multiallelic copy number variation (CNV) at the C4 locus. We find strong statistical significance for association of increased copy number of C4A (OR 0.81 (0.73; 0.89);P = 4.4 × 10(-5)), with the effect most pronounced in individuals over 78 years (OR 0.67 (0.55; 0.81)) and females (OR 0.77 (0.68; 0.87)). Furthermore, this association is independent of known AMD-associated risk variants in the nearby CFB/C2 locus, particularly in females and in individuals over 78 years.
  
  
  CONCLUSIONS
  Our data strengthen the notion that complement dysregulation plays a crucial role in AMD etiology, an important finding for early intervention strategies and future therapeutics. In addition, for the first time, we provide evidence that multiallelic CNVs are associated with AMD pathology.
authors.affiliation: Institute of Human Genetics, University of Regensburg, Regensburg, 93053, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Grassmann
authors.affiliation: Centre for Eye Research, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Australia.
authors.forename: Stuart
authors.initials: S
authors.lastname: Cantsilieris
authors.affiliation: Institute of Human Genetics, University of Regensburg, Regensburg, 93053, Germany.
authors.forename: Anja-Sabrina
authors.initials: AS
authors.lastname: Schulz-Kuhnt
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: White
authors.affiliation: Centre for Eye Research, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Australia.
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Richardson
authors.affiliation: Centre for Eye Research, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Australia.|School of Medicine, Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia.
authors.forename: Alex W
authors.initials: AW
authors.lastname: Hewitt
authors.affiliation: School of Medicine, Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Vote
authors.affiliation: Institute of Human Genetics, University of Regensburg, Regensburg, 93053, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Schmied
authors.affiliation: Centre for Eye Research, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Australia.
authors.forename: Robyn H
authors.initials: RH
authors.lastname: Guymer
authors.affiliation: Institute of Human Genetics, University of Regensburg, Regensburg, 93053, Germany. bweb@klinik.uni-regensburg.de.
authors.forename: Bernhard H F
authors.initials: BH
authors.lastname: Weber
authors.affiliation: Centre for Eye Research, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Australia. pnb@unimelb.edu.au.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Baird
mesh_terms: D000483:Alleles; D015331:Cohort Studies; D015934:Complement C4a / Q000235:genetics*; D005260:Female; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics*; D008297:Male; D060885:Multiplex Polymerase Chain Reaction
chemical_list: D015934:Complement C4a
keywords: AMD; Age-related macular degeneration; C4; Complement; Copy number variation (CNV); Genetic association; Multiallelic