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Genome-wide association study of intraocular pressure uncovers new pathways to glaucoma

Nature Genetics volume 50, pages 1067–1071 (2018)Cite this article

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Abstract

Intraocular pressure (IOP) is currently the sole modifiable risk factor for primary open-angle glaucoma (POAG), one of the leading causes of blindness worldwide1. Both IOP and POAG are highly heritable2. We report a combined analysis of participants from the UK Biobank (n = 103,914) and previously published data from the International Glaucoma Genetic Consortium (n = 29,578)3,4 that identified 101 statistically independent genome-wide-significant SNPs for IOP, 85 of which have not been previously reported4,5,6,7,8,9,10,11,12. We examined these SNPs in 11,018 glaucoma cases and 126,069 controls, and 53 SNPs showed evidence of association. Gene-based tests implicated an additional 22 independent genes associated with IOP. We derived an allele score based on the IOP loci and loci influencing optic nerve head morphology. In 1,734 people with advanced glaucoma and 2,938 controls, participants in the top decile of the allele score were at increased risk (odds ratio (OR) = 5.6; 95% confidence interval (CI): 4.1–7.6) of glaucoma relative to the bottom decile.

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Fig. 1: Manhattan plot displaying associations with intraocular pressure in people of Northern European descent.
Fig. 2: Regression coefficients or effect size for the top associated SNPs at each locus associated with intraocular pressure at the genome-wide-significant level.

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Acknowledgements

This work was conducted by using the UK Biobank Resource (application number 25331) and publicly available data from the International Glaucoma Genetics Consortium. This work was supported by grants from the National Health and Medical Research Council (NHMRC) of Australia (1107098 (J.E.C.), 1116360 (D.A.M.), 1116495 (J.E.C.) and 1023911 (D.A.M.)), the Ophthalmic Research Institute of Australia and the BrightFocus Foundation. S.M. is supported by an Australian Research Council Future Fellowship. K.P.B., J.E.C. and A.W.H. are supported by NHMRC Fellowships. D.J.L. is supported by an EMBL Australia group leader award. We thank S. Wood and J. Pearson from QIMR Berghofer for IT support.

Author information

Author notes

  1. These authors jointly supervised this work: David A. Mackey, Puya Gharahkhani, Jamie E. Craig, Alex W. Hewitt.

Authors and Affiliations

  1. QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

    Stuart MacGregor, Jue-Sheng Ong, Jiyuan An, Xikun Han, Matthew H. Law, Jonathan Beesley, David C. Whiteman, Graham L. Radford-Smith, Nicholas G. Martin & Puya Gharahkhani

  2. Department of Ophthalmology, Flinders University, Flinders Medical Centre, Bedford Park, South Australia, Australia

    Tiger Zhou, Owen M. Siggs, Emmanuelle Souzeau, Shiwani Sharma, Bronwyn Sheldrick, Richard A. Mills, John Landers, Kathryn P. Burdon & Jamie E. Craig

  3. South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia

    David J. Lynn

  4. EMBL Australia Group, Infection & Immunity Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia

    David J. Lynn

  5. College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia

    David J. Lynn

  6. Centre for Eye Research Australia, University of Melbourne, Melbourne, Victoria, Australia

    Jonathan B. Ruddle & Alex W. Hewitt

  7. Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia

    Stuart L. Graham

  8. Centre for Vision Research, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia

    Paul R. Healey & Andrew J. R. White

  9. Discipline of Ophthalmology, Faculty of Medicine & Health Sciences, University of Sydney, Sydney Eye Hospital, Sydney, New South Wales, Australia

    Paul R. Healey, John R Grigg & Ivan Goldberg

  10. South Australian Institute of Ophthalmology, University of Adelaide, Adelaide, South Australia, Australia

    Robert J. Casson

  11. Eye Department, Greenlane Clinical Centre, Auckland District Health Board, Auckland, New Zealand

    Stephen Best

  12. Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, Sydney, New South Wales, Australia

    Joseph E. Powell

  13. St Vincent’s Clinical School, University of New South Wales, Sydney, New South Wales, Australia

    Joseph E. Powell

  14. University of Queensland School of Medicine, Brisbane, Queensland, Australia

    Graham L. Radford-Smith

  15. Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia

    Grant W. Montgomery

  16. Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia

    Kathryn P. Burdon, David A. Mackey & Alex W. Hewitt

  17. Centre for Ophthalmology and Visual Science, University of Western Australia, Crawley, Western Australia, Australia

    David A. Mackey

Authors
  1. Stuart MacGregor
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  2. Jue-Sheng Ong
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  5. Tiger Zhou
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Contributions

S.M., A.W.H., J.E.C., P.G. and D.A.M. designed the study and obtained funding. S.M., J.S.O., J.A., X.H., T.Z., M.H.L., S.S., J.E.P., D.L. and J.B. analyzed the data. S.M., T.Z., O.S., E.S., S.S., B.S., R.A.M., J.L., J.B.R., S.L.G., P.R.H., A.J.R.W., R.J.C., S.B., J.R.G., I.G., D.C.W., G.R.S., N.G.M., G.W.M., K.P.B., D.A.M., J.E.C. and A.W.H. contributed to data collection and contributed to genotyping. S.M., J.S.O., D.A.M., P.G. and A.W.H. wrote the first draft of the paper. All authors contributed to the final version of the paper.

Corresponding author

Correspondence to Stuart MacGregor.

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Supplementary Information

Supplementary Text and Figures

Supplementary Figures 1–8

Reporting Summary

Supplementary Table 1

Statistically independent hits that are associated with IOP at the genome-wide significant level, that show at least P < 0.05 with glaucoma. SNPs which are significant after correction for multiple testing (101 SNPs) are shown in bold. This Table presents the results for IOP and glaucoma meta-analysis as well as for each substudy separately

Supplementary Table 2

Statistically independent hits that are associated with IOP at the genome-wide significant level, but are not associated (P > 0.05) with glaucoma, or were more strongly associated with corneal parameters. rs66724425 in ADAMTS6 is known to be associated with central corneal thickness, and SNPs rs1570204, rs78658973, rs12492846 and rs2797560, were more strongly associated with corneal hysteresis than they were with IOP

Supplementary Table 3

GCTA-fastBAT gene-based tests for IOP and the corresponding gene-based results for glaucoma. Of these 22 genes, 4 were significant at P< 0.05 with glaucoma

Supplementary Table 4

Enriched pathways for genes associated with IOP identified using MAGMA and 5,917 pre-specified Gene Ontology gene sets. The corresponding effect size and P value for each pathway in glaucoma is also displayed

Supplementary Table 5

Enriched pathways for genes associated with IOP identified using DEPICT, which uses 14,462 preconstituted gene sets are significantly enriched for genes in the trait-associated loci. The corresponding P value for each pathway in glaucoma is also displayed

Supplementary Table 6

Cell type implicated by analysis of the FANTOM5 Cap Analysis of Gene Expression dataset

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MacGregor, S., Ong, JS., An, J. et al. Genome-wide association study of intraocular pressure uncovers new pathways to glaucoma. Nat Genet 50, 1067–1071 (2018). https://doi.org/10.1038/s41588-018-0176-y

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