Chipping Away At The Common Variant Genetics of Age Related Macular Degeneration. L. G. Fritsche on behalf of The International AMD Genomics Consortium (https://amdgenetics.org/) Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI.
Age-related macular degeneration (AMD) is a major cause of blindness in the elderly. Disease predisposition is complex and influenced by multiple environmental and genetic 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 predominantly late-stage AMD cases (N25,000) and appropriately age-matched controls (N25,000) obtained via international collaboration.
We examined the genome using a custom array, that included 250,000 rare/common variants, derived from prior large-scale sequencing efforts, including targeted sequencing of known AMD loci. Also included were 250,000 common variants distributed evenly across the genome. Comprehensive genotyping of 50,000 individuals is underway at CIDR (http://www.cidr.jhmi.edu/).
Here, we report an initial analysis of common variants (minor allele frequency 1%) using currently available genotype data for 12,030 late-stage AMD patients and 11,332 controls of European ancestry. After adjusting for population structure, age and sex, our genome-wide association study confirmed 18 of the 19 AMD loci previously reported by The AMD Gene Consortium (Fritsche et al., NatGenet 2013; P10-5), and identified several independent signals in known loci (near CFH, CFB/C2, C3, APOE, LIPC, and COL8A1). Among the more interesting signals is an independently associated coding variant in TNXB near CFB/C2. Our analysis also suggests several novel loci with P5x10-8, including loci specifically associated with the neovascular form of late-stage AMD, but not the atrophic form. In addition to loci near genes that indicate an overall enrichment of several pathways (e.g. complement cascade, arteriogenesis), we identify loci near genes without known function, such as a locus that maps near a microRNA gene (MIR4532).
Pooling resources and effort, our consortium is carrying out the largest ever genetic study of AMD. We identified novel loci and revealed additional signals hidden near some known loci. Careful follow-up will uncover the genetic architecture and biological significance of these findings. Not only will this experiment accelerate the acquisition of knowledge on the underlying disease causes, but also facilitate numerous subanalyses (e.g. genotype-phenotype correlations, risk model evaluation).
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