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Johanna M Seddon, Erin Wagner, Yi Yu, Eric H Souied, Ilkka J Immonen, Soumya Raychaudhuri, Mark Daly; Novel associations with age-related macular degeneration: a common variant near CTRB1 and a protective rare variant in PELI3. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2646.
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© 2017 Association for Research in Vision and Ophthalmology.
Although more than 20 common frequency or age-related macular degeneration (AMD) variants have been discovered with genome-wide association studies and rare variants have been identified in other genetic studies, substantial disease heritability remains unexplained. In this study we sought to identify additional variants, both common and rare, that are associated with advanced AMD.
We genotyped 4,332 advanced AMD cases and 4,642 unrelated controls of European ancestry from three different populations using the Illumina Infinium HumanExome BeadChip. We performed meta-association analyses to identify associations between AMD and common variants. We also conducted single variant and gene-based burden tests to identify associations with rare variants.
We identified a novel rare (minor allele frequency < 1%) non-synonymous single nucleotide polymorphism (SNP), A307V, in the novel AMD gene PELI3 (odds ratio [OR] = 0.27, P = 5.6×10−7). Mutations in PELI3 could possibly influence AMD risk by modulating signals between Toll-like receptors and innate immune pathway. The new rare variant has a large effect size that is similar to the rare mutations we reported previously in a targeted sequencing study, which remain significant in this analysis: CFH R1210C (OR = 18.82, P = 3.5×10−7), CFH N1050Y (OR = 0.40, P = 8.0x10-13), C3 K155Q (OR = 3.27, P = 1.5×10−10), and C9 P167S (OR = 2.04, P = 2.8×10−7). We also identified a novel common variant (rs8056814) in the promoter region of CTRB1 with a significantly decreased risk of AMD associated with the ‘A’ allele (OR = 0.71, P = 7.7×10−7). This SNP is in high linkage disequilibrium with one that has been shown to regulate expression levels of CTRB1, which is a known risk factor for type 1 diabetes and is associated with variation in high-density lipoprotein cholesterol levels.
This large exome wide analysis of AMD genetic variation supports the involvement of both common and rare variants in AMD pathogenesis. It also expands the role of the high-density lipoprotein pathway and implicates parts of the innate immune pathway outside that of the complement system in the etiology of AMD.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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