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Xiaowei Zhan, Jennifer Bragg-Gresham, Lars G Fritsche, Kari E Branham, Dwight Stambolian, Emily Y Chew, Anand Swaroop, Goncalo Abecasis; Whole Genome Sequencing Scan of 2,099 Samples in Age-related Macular Degeneration Study. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4571.
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Age-related Macular Degeneration (AMD) is a leading cause of blindness among the elderly. Over the past several years, genetic studies of common variation have provided many clues about disease biology. Due to assay limitations, these studies have typically ignored rare variants or examined them only in a small set of candidate regions. Here, we set out to systematically study the contribution of rare variants to disease.
We assembled a collection of 2,099 cases and controls with advanced AMD (67% neovascularization, 33% geographic atrophy) from Kellogg Eye Center at University of Michigan, Age-Related Eye Disease Study and University of Pennsylvania. We matched case and control according to age, gender and ethnicity. We sequenced the genome of all individuals to characterize genetic variation systematically.
As of today, 2,099 samples have been sequenced, representing >39 Terabytes (3.9 x 1013 bytes) of sequence data. This corresponds to a total genomic coverage of 9,237x and an average coverage of 4.4x per sample. In an initial analysis, we discovered and genotyped ~31 million variants. The set includes many previously studied variants, such as the complement factor H variants Y402H (fcase = 0.44, fcontrol= 0.63, p-value = 3.2x10-34) and R1210C (fcase = 0.0048, fcontrol = 0, p-value = 1.5x10-3), but also many new functionally interesting variants, such as 20 missense and 1 nonsense mutations that are very rare (median minor allele frequency = 0.05 %) and missing from previous studies.
We provide a first detailed look at the genetic of AMD, through whole genome sequencing of more than 2,000 individuals. Our data will enable a systematic genomewide search for rare risk alleles and should allow us to evaluate the effect of nonsense variants in many previously associated genes.
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