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Lars G Fritsche, ; Unravelling the Impact of Common and Rare Variants on Age-related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4570.
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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 (N≈25,000) and appropriately age-matched controls (N≈25,000) obtained via international collaboration.
We examined the genome using a custom array, that included >250,000 tagging SNP as well as >250,000 exomic variants, derived from prior large-scale sequencing efforts, including targeted sequencing of known AMD loci. Comprehensive genotyping of ≈50,000 individuals was done at CIDR (http://www.cidr.jhmi.edu), while quality control and 1000 Genomes Project imputation of the full data set are under way. Single variants test and gene-based burden test were performed and adjusted for population structure, age and sex.
The single variants analysis on > 18 million genotyped and well-imputed variants (Rsq>0.3) of an interim data set of 13,423 late AMD cases and 14,397 controls of European ancestry confirmed 19 of the 20 previously reported AMD loci with genome-wide significance (P<5x10-8), including independent association signals for the known rare risk variants in CFH, CFI, C3, and C9. Current analyses suggest nine novel AMD risk loci with P<5x10-8, including loci specifically associated with the neovascular form of late-stage AMD, but not the atrophic form. Sequential forward selection analyses culminated in a total set of 39 independently associated risk variants (32 common and 7 rare variants) that together might explain up to 30 % of the total variance of the disease.
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. While the underlying disease genes of the detected association signals remain widely unknown, pathway and expression analyses already indicate promising leads that will guide subsequent functional studies and might uncover the biological significance of these findings.
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