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Goncalo Abecasis, Matthew Schu, Xiaowei Zhan, Sivakumaram Arumugam, Jennifer Bragg Gresham, Lars Fritsche, AMD Gene Exome Chip Consortium; Chipping Away At The Genetics of Age Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4977.
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© ARVO (1962-2015); The Authors (2016-present)
Age-related macular degeneration (AMD) is a common form of blindness in the elderly. Disease predisposition is complex and influenced by a variety of environmental and genetic risk factors. To extend understanding of AMD genetics and biology, we set out to examine the association between common and rare genetic variation in a large set of AMD cases and controls.
Through international collaboration, we set out to assemble a sample of large sample of AMD cases and matched controls. We designed a custom genotyping array including 250,000 common and rare coding variants discovered in large scale sequencing experiments (and enriched for variants discovered in sequencing experiments targeting individuals with AMD) and an additional set of 250,000 common variants distributed evenly across the genome. Working in collaboration with the National Institutes of Health Center for Inherited Disease Research, we then set out to genotype all available samples using this custom array.
We successfully assembled and organized an international research team focused on age-related macular degeneration genetics. We centrally curated and organized DNA samples for >48,000 individuals (48.25% macular degeneration cases and 51.75% controls). Among cases, 46.5% had neovascular disease, 14.7% had geographic atrophy, and 9.0% had geographic atrophy in one eye and neovascular disease in the fellow eye (resulting in 70.2% of cases with advanced disease). In remaining cases, 16.5% had large drusen and 13.3% had earlier signs of disease. We successfully designed and manufactured a low cost custom genotyping array, especially designed for studies of AMD - including ~250,000 coding variants (approximately 50% of these with frequency <0.1%) and a grid of additional variants allowing us to tag or impute common variants with frequency >5% across the genome. We are expecting the first set of samples to be genotyped by January 2013 and all 48,000 samples to be genotyped by Spring 2013.
Our experiment illustrates how collaborative teams with a shared research interest can organize. Pooling resources and effort, we were able to study a very large number of individuals, as will be needed for studies of rare coding variants. We expect 80% power to detect variants with a frequency of >0.1% that lead >2.45-fold increase in disease risk. At the ARVO meeting, we will review results from our initial rounds of analysis.
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