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Alexandra Pietraszkiewicz, Freekje Van Asten, Alan Kwong, Rinki Ratnapriya, Goncalo Abecasis, Anand Swaroop, Emily Chew; Rare Variant Pathway Analysis in the Age-Related Eye Disease Study 2. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1833.
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© ARVO (1962-2015); The Authors (2016-present)
AMD is a clinically heterogeneous disease, and GWAS studies have implicated a number of biological pathways that may underlie the variation in AMD pathogenesis and observed phenotypes. Identification of rare variants at risk loci helps to determine causative genes. Here, we collapsed rare variants into pathways and studied their association to clinical phenotypes in a subset of AREDS 2 participants who underwent whole-genome-sequencing (WGS) (n=1503).
Loss of function rare variants (stop-gain, frameshift, essential splice site, or start-loss; allele frequency <0.1% in the study population) at the 34 known AMD loci were identified from WGS data and annotated with VEP build 86 using GRCh37 coordinates and RefSeq genes. Genes were grouped into the following pathways by searching the NCBI Gene database for functional information and validating in Reactome: complement, ECM, lipids, cell survival, cell signaling, immune system, visual, and a final category including variants of unknown significance. Phenotypes analyzed include advanced AMD, geographic atropy (GA), central geographic atrophy (CGA), choroidal neovascularization (CNV), drusen area, reticular drusen, and calcified drusen.
This study identified rare variants in 15.7% of AREDS 2 participants, and there was an association between the presence of rare variants and late AMD, as measured by increased AREDS scale score (p=0.025). The following pathway-phenotype associations were observed: complement and CGA (p=0.014; OR=4.218), complement and calcified drusen (p=0.02; OR=3.92), cell survival and CNV (p=0.045; OR=1.612), ECM and GA (p=0.035; OR=2.459), lipids and drusen area (p=0.003), and rare variants in the unknown category and late AMD (p=0.023; OR 1.756).
This study supports the hypothesis that variation in biological pathways drives the development of heterogeneous clinical phenotypes in AMD, similar to results of previous studies of complement and GA. Our analysis revealed a novel association between the development of CNV and rare variants in the cell survival pathway. Surprisingly, we found a protective effect of rare variants in the lipids pathway on drusen area. Further studies are needed to elucidate the role of rare variants in other pathways.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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