July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
A multi-ethnic genome-wide association study of primary-open angle glaucoma identifies novel risk loci
Author Affiliations & Notes
  • Helene Choquet
    Division of Research, Kaiser Permanente Northern California, Oakland, California, United States
  • Khanh K Thai
    Division of Research, Kaiser Permanente Northern California, Oakland, California, United States
  • Jie Yin
    Division of Research, Kaiser Permanente Northern California, Oakland, California, United States
  • Thomas J Hoffmann
    Institute for Human Genetics, University of California, San Francisco, San Francisco, California, United States
    Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, United States
  • Mark N Kvale
    Institute for Human Genetics, University of California, San Francisco, San Francisco, California, United States
  • Yambazi Banda
    Institute for Human Genetics, University of California, San Francisco, San Francisco, California, United States
  • Catherine Schaefer
    Division of Research, Kaiser Permanente Northern California, Oakland, California, United States
  • Neil Risch
    Division of Research, Kaiser Permanente Northern California, Oakland, California, United States
    Institute for Human Genetics, University of California, San Francisco, San Francisco, California, United States
  • Ronald Melles
    Department of Ophthalmology, Kaiser Permanente Northern California , Redwood City, California, United States
  • Saidas K Nair
    Departments of Ophthalmology and Anatomy, School of Medicine, University of California San Francisco, San Francisco, California, United States
  • Eric Jorgenson
    Division of Research, Kaiser Permanente Northern California, Oakland, California, United States
  • Footnotes
    Commercial Relationships   Helene Choquet, None; Khanh Thai, None; Jie Yin, None; Thomas Hoffmann, None; Mark Kvale, None; Yambazi Banda, None; Catherine Schaefer, None; Neil Risch, None; Ronald Melles, None; Saidas Nair, None; Eric Jorgenson, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 1179. doi:
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    • Get Citation

      Helene Choquet, Khanh K Thai, Jie Yin, Thomas J Hoffmann, Mark N Kvale, Yambazi Banda, Catherine Schaefer, Neil Risch, Ronald Melles, Saidas K Nair, Eric Jorgenson; A multi-ethnic genome-wide association study of primary-open angle glaucoma identifies novel risk loci. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1179.

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

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Abstract

Purpose : Glaucoma is a progressive optic neuropathy and a leading cause of irreversible blindness. Genome-wide association studies (GWAS) have reported a number of loci associated with primary-open angle glaucoma (POAG), the most common type of glaucoma, often associated with elevated intraocular pressure (IOP). However, these loci explain little heritability, suggesting many remain undiscovered.

Methods : We conducted a GWAS of POAG in the Kaiser Permanente Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort, consisting of 4,986 POAG cases and 58,426 controls from four race/ethnicity groups (non-Hispanic whites, Hispanic/Latinos, East Asians, and African-Americans). We tested novel loci discovered in GERA in an external replication cohort: the multi-ethnic UK Biobank (UKB), which includes 7,329 glaucoma cases and 169,561 controls. We then conversely investigated novel glaucoma-associated loci from the UKB in GERA, and conducted a multi-ethnic meta-analysis combining GERA and UKB. Finally, expression of the genes at the identified loci was assessed in silico in human ocular tissues using publicly available databases.

Results : We identified 12 loci associated with POAG at genome-wide significance (P<5.0x10-8) in the GERA discovery cohort, of which 5 were novel. Three novel loci (FMNL2, PDE7B, and TMTC2) replicated at Bonferroni significance in UKB with the same direction of effect. The GWAS of glaucoma in the UKB identified 9 additional novel loci, 6 of which replicated in GERA (IKZF2, CADM2, DGKG, ANKH, EXOC2, and LMX1B). A meta-analysis combining GERA and UKB identified 24 additional novel loci that would still require external replication. Most of the genes at the identified loci were expressed in ocular tissues with relevance in glaucoma pathogenesis. Interestingly, variants at FMNL2 and DGKG have also been shown to be associated with higher IOP levels in our recent GWAS of IOP.

Conclusions : Our findings provide evidence that some, but not all genes, likely contribute to glaucoma risk through their effect on elevated IOP. Identification of novel loci underlying POAG/glaucoma represents an important step toward understanding glaucoma genetic etiology.

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

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