Dataset Information

Genome-wide analysis of copy number variants in age-related macular degeneration.

ABSTRACT: Age-related macular degeneration (AMD) is a complex genetic disease, with many loci demonstrating appreciable attributable disease risk. Despite significant progress toward understanding the genetic and environmental etiology of AMD, identification of additional risk factors is necessary to fully appreciate and treat AMD pathology. In this study, we investigated copy number variants (CNVs) as potential AMD risk variants in a cohort of 400 AMD patients and 500 AMD-free controls ascertained at the University of Iowa. We used three publicly available copy number programs to analyze signal intensity data from Affymetrix GeneChip SNP Microarrays. CNVs were ranked based on prevalence in the disease cohort and absence from the control group; high interest CNVs were subsequently confirmed by qPCR. While we did not observe a single-locus "risk CNV" that could account for a major fraction of AMD, we identified several rare and overlapping CNVs containing or flanking compelling candidate genes such as NPHP1 and EFEMP1. These and other candidate genes highlighted by this study deserve further scrutiny as sources of genetic risk for AMD.

SUBMITTER: Meyer KJ

PROVIDER: S-EPMC3613489 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Genome-wide analysis of copy number variants in age-related macular degeneration.

Meyer Kacie J KJ Davis Lea K LK Schindler Emily I EI Beck John S JS Rudd Danielle S DS Grundstad A Jason AJ Scheetz Todd E TE Braun Terry A TA Fingert John H JH Alward Wallace L WL Kwon Young H YH Folk James C JC Russell Stephen R SR Wassink Thomas H TH Stone Edwin M EM Sheffield Val C VC

Human genetics 20101028 1

Age-related macular degeneration (AMD) is a complex genetic disease, with many loci demonstrating appreciable attributable disease risk. Despite significant progress toward understanding the genetic and environmental etiology of AMD, identification of additional risk factors is necessary to fully appreciate and treat AMD pathology. In this study, we investigated copy number variants (CNVs) as potential AMD risk variants in a cohort of 400 AMD patients and 500 AMD-free controls ascertained at the ...[more]

PMID: 20981449

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Project description:PurposeWe previously identified a genetic copy number polymorphism (CNP147) that was statistically associated with age-related macular degeneration (AMD) and that resides downstream of the complement factor H (CFH) gene. Factor H protein is polymorphic at amino acid 402, in which the resulting histidine containing moiety has been established to impart significant risk of AMD. We present a method to precisely determine the exact copy number of CNP147 and examine in more detail the association with AMD.DesignCase-control study.ParticipantsA total of 421 Age-Related Eye Disease Study (AREDS) subjects, of whom approximately 35% were diagnosed with neovascular disease, 19% were diagnosed with geographic atrophy, 16% were diagnosed with both, 30% were diagnosed with large drusen, and 215 were controls.MethodsBy using copy number assays available from Applied Biosystems Inc. (Carlsbad, CA), we examined 4 loci spanning CNP147 and neighboring CNP148 in an AREDS matched case-control sample set. We analyzed these data by copy number while controlling for 2 high-risk CFH variants, rs1061170 (Y402H) and rs1410996. We phased the high-risk CFH variants with CNP147 and analyzed haplotype frequencies in cases and controls. To further validate copy numbers, 6 Utah Centre D'etude du Polymorphism Humaine (CEPH) families were typed for CNP147, and the segregation was assessed.Main outcome measuresIncreased or decreased risk of AMD from genetic loci.ResultsHaving fewer than 2 copies of CNP147 was associated with an estimated 43% reduction in odds of having AMD in this sample set (adjusted odds ratio [OR] = 0.57, P=0.006). CNP148 variation is rare in Caucasians and was not statistically significant. Common haplotypes reveal that the risk alleles for rs1061170 and rs1410996 most frequently segregate with higher copy numbers for CNP147, but not exclusively, and that 1 haplotype that carried a deletion of CNP147 was highly protective (OR = 0.25 P=1.3×10(-13)) when compared with the reference.ConclusionsIn this matched subset of AREDS subjects, after adjusting for 2 known risk variants in CFH, CNP147 deletion statistically associates with diminished risk for AMD.Financial disclosure(s)The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Dataset Information

Genome-wide analysis of copy number variants in age-related macular degeneration.

Publications

Genome-wide analysis of copy number variants in age-related macular degeneration.

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