Genome-Wide Association Study Identifies Two Common Loci Associated with Pigment Dispersion Syndrome/Pigmentary Glaucoma and Implicates Myopia in its Development

Mark J. Simcoe; Ameet Shah; Baojian Fan; Hélène Choquet; Nicole Weisschuh; Naushin H. Waseem; Chen Jiang; Ronald B. Melles; Robert Ritch; Omar A. Mahroo; Bernd Wissinger; Eric Jorgenson; Janey L. Wiggs; David F. Garway-Heath; Pirro G. Hysi; Christopher J. Hammond

doi:10.1016/j.ophtha.2022.01.005

Original language	English
Pages (from-to)	626-636
Number of pages	11
Journal	Ophthalmology
Volume	129
Issue number	6
Early online date	11 Jan 2022
DOIs	https://doi.org/10.1016/j.ophtha.2022.01.005
Accepted/In press	5 Jan 2022
E-pub ahead of print	11 Jan 2022
Published	Jun 2022
Additional links	Link to publication in Scopus

Bibliographical note

Funding Information: Collection of cases and controls for the Harvard cohort was supported in part by National Institutes ofHealth/ National Eye Institute (grant no. P30 EY014104 ); the Wellcome Trust (grant no. 206619/Z/17/Z [to M.J.S. and O.A.M.]); Fight for Sight UK (to M.J.S. and P.G.H.); Genotyping of the GERA cohort was funded by the National Institute on Aging , National Institute of Mental Health , and National Institute of Health Common Fund (grant no. RC2 AG036607 ); National Eye Institute (grant no. R01 EY027004 [to H.C. and E.J.]); National Institute of Diabetes and Digestive and Kidney Diseases (grant no. R01 DK116738 ), and the National Cancer Institute (grant no. R01CA2416323 ). Funding Information: R.R.: Royalties ? Guardion, Ocular Instruments, C-MER; Consultant ? Sensimed; Lecture and Travel Payments ? Santen; Leadership or Fiduciary Role ? New York Glaucoma Research Institute; Stock ? C-MER; Other Financial support ? Intelon Optics, Glauconix Inc, Sanoculis, Emerald Bioscience Inc.Collection of cases and controls for the Harvard cohort was supported in part by National Institutes ofHealth/National Eye Institute (grant no. P30 EY014104); the Wellcome Trust (grant no. 206619/Z/17/Z [to M.J.S. and O.A.M.]); Fight for Sight UK (to M.J.S. and P.G.H.); Genotyping of the GERA cohort was funded by the National Institute on Aging, National Institute of Mental Health, and National Institute of Health Common Fund (grant no. RC2 AG036607); National Eye Institute (grant no. R01 EY027004 [to H.C. and E.J.]); National Institute of Diabetes and Digestive and Kidney Diseases (grant no. R01 DK116738), and the National Cancer Institute (grant no. R01CA2416323). J.L.W.: Consultant ? Allergan, Editas, Maze, Regenxbio, Avellino; Grants ? Aerpio. B.W.: Grants ? European Commission and American Health Assistance Foundation. Obtained funding: N/A; Study was performed as part of the authors' regular employment duties. No additional funding was provided. Publisher Copyright: © 2022 American Academy of Ophthalmology

Abstract

Purpose: To identify genetic variants associated with pigment dispersion syndrome (PDS) and pigmentary glaucoma (PG) in unrelated patients and to further understand the genetic and potentially causal relationships between PDS and associated risk factors. Design: A 2-stage genome-wide association meta-analysis with replication and subsequent in silico analyses including Mendelian randomization. Participants: A total of 574 cases with PG or PDS and 52 627 controls of European descent. Methods: Genome-wide association analyses were performed in 4 cohorts and meta-analyzed in 3 stages: (1) a discovery meta-analysis was performed in 3 cohorts, (2) replication was performed in the fourth cohort, and (3) all 4 cohorts were meta-analyzed to increase statistical power. Two-sample Mendelian randomization was used to determine whether refractive error and intraocular pressure exert causal effects over PDS. Main Outcome Measures: The association of genetic variants with PDS and whether myopia exerts causal effects over PDS. Results: Significant association was present at 2 novel loci for PDS/PG. These loci and follow-up analyses implicate the genes gamma secretase activator protein (GSAP) (lead single nucleotide polymorphism [SNP]: rs9641220, P = 6.0×10 ^-10) and glutamate metabotropic receptor 5 (GRM5)/TYR (lead SNP: rs661177, P = 3.9×10 ^-9) as important factors in disease risk. Mendelian randomization showed significant evidence that negative refractive error (myopia) exerts a direct causal effect over PDS (P = 8.86×10 ^-7). Conclusions: Common SNPs relating to the GSAP and GRM5/TYR genes are associated risk factors for the development of PDS and PG. Although myopia is a known risk factor, this study uses genetic data to demonstrate that myopia is, in part, a cause of PDS and PG.

King's College London

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