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

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.

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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.

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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, J., 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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