title: Comprehensive analysis of Copy Number Variation of genes at chromosome 1 and 10 loci associated with late age related macular degeneration.
abstract: Copy Number Variants (CNVs) are now recognized as playing a significant role in complex disease etiology. Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss in the western world. While a number of genes and environmental factors have been associated with both risk and protection in AMD, the role of CNVs has remained largely unexplored. We analyzed the two major AMD risk-associated regions on chromosome 1q32 and 10q26 for CNVs using Multiplex Ligation-dependant Probe Amplification. The analysis targeted nine genes in these two key regions, including the Complement Factor H (CFH) gene, the 5 CFH-related (CFHR) genes representing a known copy number "hotspot", the F13B gene as well as the ARMS2 and HTRA1 genes in 387 cases of late AMD and 327 controls. No copy number variation was detected at the ARMS2 and HTRA1 genes in the chromosome 10 region, nor for the CFH and F13B genes at the chromosome 1 region. However, significant association was identified for the CFHR3-1 deletion in AMD cases (p = 2.38 × 10(-12)) OR = 0.31, CI-0.95 (0.23-0.44), for both neovascular disease (nAMD) (p = 8.3 × 10(-9)) OR = 0.36 CI-0.95 (0.25-0.52) and geographic atrophy (GA) (p = 1.5 × 10(-6)) OR = 0.36 CI-0.95 (0.25-0.52) compared to controls. In addition, a significant association with deletion of CFHR1-4 was identified only in patients who presented with bilateral GA (p = 0.02) (OR = 7.6 CI-0.95 1.38-41.8). This is the first report of a phenotype specific association of a CNV for a major subtype of AMD and potentially allows for pre-diagnostic identification of individuals most likely to proceed to this end stage of disease.
authors.affiliation: Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia.
authors.forename: Stuart
authors.initials: S
authors.lastname: Cantsilieris
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: White
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Richardson
authors.forename: Robyn H
authors.initials: RH
authors.lastname: Guymer
authors.forename: Paul N
authors.initials: PN
authors.lastname: Baird
mesh_terms: D000368:Aged; D001798:Blood Proteins / Q000235:genetics; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D003180:Complement C3b Inactivator Proteins / Q000235:genetics; D017242:Complement Factor H / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D057092:Geographic Atrophy / Q000235:genetics*; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D016015:Logistic Models; D008268:Macular Degeneration / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D021141:Nucleic Acid Amplification Techniques / Q000379:methods; D011446:Prospective Studies; D011506:Proteins / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics
chemical_list: C514392:ARMS2 protein, human; D001798:Blood Proteins; C493495:CFH protein, human; C517621:CFHR1 protein, human; C105970:CFHR3 protein, human; D003180:Complement C3b Inactivator Proteins; D011506:Proteins; D017242:Complement Factor H; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases