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Janey Wiggs, Puya Gharahkhani, Eric Jorgenson, Pirro G Hysi, Anthony Khawaja, Sarah Pendergrass, Xikun Han, David Mackey, Christopher Hammond, Michael A Hauser, Louis R Pasquale, Caroline Klaver, Michiaki Kubo, Tin Aung, Jamie E Craig, Stuart MacGregor; A large cross-ancestry meta-analysis of genome-wide association studies identifies 69 novel risk loci for primary open-angle glaucoma, and shows a genetic link to Alzheimer’s disease.. Invest. Ophthalmol. Vis. Sci. 2020;61(7):1890.
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Primary open angle glaucoma (POAG) is a leading cause of irreversible blindness worldwide. Recent POAG genome-wide association studies (GWAS) have identified important risk loci, however despite this success the POAG genetic architecture remains incomplete. To identify novel POAG risk loci we conducted the largest GWAS for POAG to date, using 34,039 cases and 347,699 controls across European, Asian, and African ancestries.
We performed a four-stage meta-analysis. In the first stage, we conducted a fixed-effect meta-analysis of 16,537 POAG cases vs 197,958 controls of European descent. In the second stage, we replicated the stage 1 findings in 3 independent datasets comprising 7,286 self-report cases and 107,362 controls of European descent from the United Kingdom Biobank study (UKBB), 6,935 POAG cases and 39,588 controls of Asian descent, and 3,281 POAG cases and 2,791 controls of African ancestry. In the third stage, we meta-analyzed the GWAS results from stage 1 and 2 (34,039 cases vs 347,699 controls), and in the fourth stage, we validated the association of the genome-wide significant SNPs from Stage 3 in a dataset comprising 43,254 participants with self-reported POAG and 1,471,118 controls from 23andMe.
After discovery and replication, we identified 127 independent genome-wide significant loci for POAG, of which 69 were not previously reported. These novel loci include key genes known to be involved in dementia/cognitive function, e.g. MAPT (rs242559[C], OR=1.08, P=8.8e-10), TRIOBP (rs5750494[T], OR=1.08, P=2.4e-16), and APP (rs13049669[T], OR=1.1 , P=2.2e-09). A genome-wide genetic correlation of 15% (P<0.05) between glaucoma and Alzheimer’s disease (based on 72K Alzheimer’s cases, 383K controls) was also identified. The correlation of the effect estimates for the genome-wide significant loci was 0.78 (95% confidence interval 0.66-0.86) between Europeans and Asians and 0.68 (95% confidence interval 0.52-0.79) between Europeans and Africans. The new risk loci have functional relevance supported by eQTL and chromatin interaction data.
Using a large multiethnic meta-analysis we identified important new risk loci for POAG, supporting a biological link between POAG and Alzheimer’s disease, and suggesting novel therapeutic targets.
This is a 2020 ARVO Annual Meeting abstract.
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