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. 2011 Jan;129(1):91-100.
doi: 10.1007/s00439-010-0904-6. Epub 2010 Oct 28.

Genome-wide Analysis of Copy Number Variants in Age-Related Macular Degeneration

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Genome-wide Analysis of Copy Number Variants in Age-Related Macular Degeneration

Kacie J Meyer et al. Hum Genet. .
Free PMC article

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.

Figures

Fig. 1
Fig. 1
Study design flow chart. DNA samples from a total of 400 AMD patients and 500 AMD-free controls of similar age and gender distribution were processed on either the Affymetrix 500K SNP Array Set or the Affymetrix 5.0 SNP Array. Two programs were used to analyze signal intensity data from each platform, and the NspI and StyI arrays of the 500K SNP Array Set were analyzed separately. After implementing measures of quality control, the complete data set contained 11,671 copy number variant (CNV) calls. A stringent criteria set derived from the complete data set is composed of 2,008 CNVs that were called by two or more independent tests. CNVs were classified as high interest by identifying those that were most prevalent in the AMD patient cohort and absent from controls
Fig. 2
Fig. 2
Chromosome 2q13 and 2p16.1 copy number variant (CNV) coordinates and validation. The coordinates used for the purpose of parts A and B yield the largest possible CNV size for each patient. a A deletion of chromosome 2q13 was identified in four patients diagnosed with AMD, but not in controls, and the coordinates of the deletion for each patient is displayed on a UCSC custom track. Deletions for all four patients overlap the genes MALL and NPHP1 and occur in a region of common copy number variation as seen in the Database of Genomic Variants track. b A non-genic duplication of 2p16.1 was identified in three individuals diagnosed with AMD, but not in controls, and the coordinates of the duplication for each patient are displayed on a UCSC custom track. The duplications are located less than 1.5 Mb upstream of EFEMP1, a gene involved in the pathogenesis of Doyne Honeycomb Retinal Dystrophy. c, d Gray shading indicates that the CNV was called by multiple independent tests within the same patient. c CNV coordinates, CNV size, CNV state, and array type for each patient identified with overlapping CNVs on chromosome 2q13. d CNV coordinates, CNV size, CNV state, and array type for each patient identified with overlapping CNVs on chromosome 2p16.1. e, f qPCR results were analyzed using the DDCt method, and the data were normalized to a pooled genomic DNA reference. e qPCR validation of NPHP1 copy number loss. The qPCR assay was designed within the NPHP1 gene. f qPCR validation of 2p16.1 non-genic copy number gain

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