June 2020
Volume 61, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2020
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.
Author Affiliations & Notes
  • Janey Wiggs
    Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States
  • Puya Gharahkhani
    Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  • Eric Jorgenson
    Division of Research, Kaiser Permanente Northern California (KPNC), Oakland, California, United States
  • Pirro G Hysi
    Department of Twin Research and Genetic Epidemiology, King's College London, United Kingdom
  • Anthony Khawaja
    NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, United Kingdom
  • Sarah Pendergrass
    Geisinger Research, Biomedical and Translational Informatics Institute, Pennsylvania, United States
  • Xikun Han
    Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  • David Mackey
    Lions Eye Institute, Centre for Ophthalmology and Visual Science, University of Western Australia,, Perth, Western Australia, Australia
  • Christopher Hammond
    Ophthalmology, King's College London, St. Thomas' Hospital, London, United Kingdom
  • Michael A Hauser
    Ophthalmology, Duke University School of Medicine, Durham, North Carolina, United States
  • Louis R Pasquale
    Ophthalmology, 10. Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Caroline Klaver
    Ophthalmology, Radboud University Medical Center, Nijmegen, Netherlands
  • Michiaki Kubo
    Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Japan
  • Tin Aung
    Singapore Eye Research Institute, Singapore National Eye Centre, Singapore
    Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore
  • Jamie E Craig
    Ophthalmology, Flinders University, Flinders Medical Centre, South Australia, Australia
  • Stuart MacGregor
    Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  • Footnotes
    Commercial Relationships   Janey Wiggs, Aerpio (F), Allergan (C), Editas (C), Maze (C), Regenxbio (C); Puya Gharahkhani, None; Eric Jorgenson, None; Pirro Hysi, None; Anthony Khawaja, Aerie (C), Allergan (C), Novartis (C), Santen (C), Thea (F); Sarah Pendergrass, None; Xikun Han, None; David Mackey, None; Christopher Hammond, None; Michael Hauser, None; Louis Pasquale, Bausch + Lomb (C), Emerald Bioscience (C), Eyenovia (C), Nicox (C), Verily (C); Caroline Klaver, None; Michiaki Kubo, None; Tin Aung, None; Jamie Craig, None; Stuart MacGregor, None
  • Footnotes
    Support  NIH/NEI R01 EY022305, EY027004, EY015473, NEIGHBORHOOD consortium, ANZRAG study, FinnGen Study, 23andMe Research Team, International Glaucoma Genetics Consortium.
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 1890. doi:
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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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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : 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.

Methods : 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.

Results : 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.

Conclusions : 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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