July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Genome-wide association study of intraocular pressure identifies 83 novel loci
Author Affiliations & Notes
  • Anthony P Khawaja
    NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, United Kingdom
  • Jessica Cooke Bailey
    Department of Population and Quantitative Health Sciences, Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States
  • Mark James Simcoe
    Department of Ophthalmology, King's College London, St. Thomas' Hospital, London, United Kingdom
  • Robert P Igo
    Department of Population and Quantitative Health Sciences, Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States
  • Louis R. Pasquale
    Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States
  • Paul J Foster
    NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, United Kingdom
  • Janey L Wiggs
    Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States
  • Christopher J Hammond
    Department of Ophthalmology, King's College London, St. Thomas' Hospital, London, United Kingdom
  • Pirro G Hysi
    Department of Ophthalmology, King's College London, St. Thomas' Hospital, London, United Kingdom
  • Footnotes
    Commercial Relationships   Anthony Khawaja, None; Jessica Cooke Bailey, None; Mark Simcoe, None; Robert Igo, None; Louis Pasquale, None; Paul Foster, None; Janey Wiggs, None; Christopher Hammond, None; Pirro Hysi, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 1178. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Anthony P Khawaja, Jessica Cooke Bailey, Mark James Simcoe, Robert P Igo, Louis R. Pasquale, Paul J Foster, Janey L Wiggs, Christopher J Hammond, Pirro G Hysi; Genome-wide association study of intraocular pressure identifies 83 novel loci. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1178.

      Download citation file:


      © ARVO (1962-2015); The Authors (2016-present)

      ×
  • Supplements
Abstract

Purpose : Raised intraocular pressure (IOP) is the cardinal modifiable risk factor for glaucoma. Previous genome-wide association studies (GWAS) have identified 8 loci associated with IOP. However, together these explain only a small fraction of IOP heritability. We aimed to discover additional loci in the largest GWAS of IOP to date, and to examine the relevance of these loci to disease by testing for association with primary open-angle glaucoma (POAG) in an independent cohort.

Methods : In total, 139,555 participants of European descent were included from three cohorts: UK Biobank, EPIC-Norfolk and the previously reported combined results from 14 studies in the International Glaucoma Genetics Consortium (IGGC). Corneal compensated IOP was measured using the Ocular Response Analyzer in UK Biobank and EPIC-Norfolk, and the majority of IGGC studies used Goldmann applanation tonometry. A linear mixed model GWAS for IOP was carried out in UK Biobank and EPIC-Norfolk, and results then meta-analyzed with IGGC. Gene-set enrichment analyses were conducted using MAGENTA. Significant loci from the IOP GWAS were then tested for association with POAG in the NEIGHBORHOOD study (3,853 cases and 33,480 controls) using logistic regression.

Results : There were 112 unique autosomal genomic regions associated with IOP at genome-wide significance (P<5x10-8), 83 of which were novel (not previously associated with IOP, glaucoma or related traits). The strongest novel locus was in DGKG (P= 8.9x10-52). Gene-set enrichment analysis revealed a strong role for angiogenesis (P=7.3x10-5), driven in part by loci in ANGPT1 (P=2.7x10-18) and ANGPT2 (P=1.7x10-13). Other hits included all previously reported IOP-associated loci (including TMCO1 P=2.4x10-87, GAS7 P=4.0x10-68, ABCA1 P=6.2x10-59 and CAV1/CAV2 P=2.5x10-56), known POAG loci (including FOXC1 P=1.8x10-28, TXNRD2 P=5.2x10-12 and ATXN2 P=3.4x10-10) and known primary angle-closure glaucoma loci (PLEKHA7 P=7.2x10-21, FERMT2 P= 7.1x10-13 and GLIS3 P= 1.2x10-10). The majority of the top significant IOP loci were at least nominally associated with POAG in NEIGHBORHOOD.

Conclusions : This analysis has identified a large number of novel genetic loci that underlie IOP regulation. Our results support an important role for angiogenic factors which presumably target Schlemm’s canal, a lymphatic vessel. Additionally, these loci appear to mediate risk for POAG.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×