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

Stuart MacGregor; Jue-Sheng Ong; Jiyuan An; Xikun Han; Tiger Zhou; Owen M. Siggs; Matthew H. Law; Emmanuelle Souzeau; Shiwani Sharma; David J. Lynn; Jonathan Beesley; Bronwyn Sheldrick; Richard A. Mills; John Landers; Jonathan B. Ruddle; Stuart L. Graham; Paul R. Healey; Andrew J. R. White; Robert J. Casson; Stephen Best; John R. Grigg; Ivan Goldberg; Joseph E. Powell; David C. Whiteman; Graham L. Radford-Smith; Nicholas G. Martin; Grant W. Montgomery; Kathryn P. Burdon; David A. Mackey; Puya Gharahkhani; Jamie E. Craig; Alex W. Hewitt

doi:10.1038/s41588-018-0176-y

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

Stuart MacGregor, Jue-Sheng Ong, Jiyuan An, Xikun Han, Tiger Zhou, Owen M. Siggs, Matthew H. Law, Emmanuelle Souzeau, Shiwani Sharma, David J. Lynn, Jonathan Beesley, Bronwyn Sheldrick, Richard A. Mills, John Landers, Jonathan B. Ruddle, Stuart L. Graham, Paul R. Healey, Andrew J. R. White, Robert J. Casson, Stephen BestJohn R. Grigg, Ivan Goldberg, Joseph E. Powell, David C. Whiteman, Graham L. Radford-Smith, Nicholas G. Martin, Grant W. Montgomery, Kathryn P. Burdon, David A. Mackey, Puya Gharahkhani, Jamie E. Craig, Alex W. Hewitt

Centre for Ophthalmology and Visual Science (affiliated with the Lions Eye Institute)

Research output: Contribution to journal › Article › peer-review

140 Citations (Scopus)

Abstract

Intraocular pressure (IOP) is currently the sole modifiable risk factor for primary open-angle glaucoma (POAG), one of the leading causes of blindness worldwide(1). Both IOP and POAG are highly heritable(2). 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 reported(4-12). 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.

Original language	English
Pages (from-to)	1067-1071
Number of pages	5
Journal	Nature Genetics
Volume	50
Issue number	8
DOIs	https://doi.org/10.1038/s41588-018-0176-y
Publication status	Published - 1 Aug 2018

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10.1038/s41588-018-0176-y

https://dspace.flinders.edu.au/xmlui/bitstream/2328/38216/1/MacGregor_Genome-wide_AM2018.pdf

Translation of Genetic Eye Research Integrating Education, Counselling & Testing with Gene Discovery & Gene Based Therapies for Eye Disease
Mackey, D. (Investigator 01), Hewitt, A. (Investigator 02), Burdon, K. (Investigator 03) & Craig, J. (Investigator 04)
NHMRC National Health and Medical Research Council
1/01/12 → 31/12/16
Project: Research

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MacGregor, S., Ong, J.-S., An, J., Han, X., Zhou, T., Siggs, O. M., Law, M. H., Souzeau, E., Sharma, S., Lynn, D. J., Beesley, J., Sheldrick, B., Mills, R. A., Landers, J., Ruddle, J. B., Graham, S. L., Healey, P. R., White, A. J. R., Casson, R. J., ... Hewitt, A. W. (2018). Genome-wide association study of intraocular pressure uncovers new pathways to glaucoma. Nature Genetics, 50(8), 1067-1071. https://doi.org/10.1038/s41588-018-0176-y

@article{de2c8e08d906441ab3d643149c3ccc05,

title = "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 worldwide(1). Both IOP and POAG are highly heritable(2). 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 reported(4-12). 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.",

keywords = "OPEN-ANGLE GLAUCOMA, CENTRAL CORNEAL THICKNESS, NAIL-PATELLA SYNDROME, SUSCEPTIBILITY LOCI, COMMON VARIANTS, GENOTYPE IMPUTATION, CLOSURE GLAUCOMA, MUTATIONS, TRAITS, RISK",

author = "Stuart MacGregor and Jue-Sheng Ong and Jiyuan An and Xikun Han and Tiger Zhou and Siggs, {Owen M.} and Law, {Matthew H.} and Emmanuelle Souzeau and Shiwani Sharma and Lynn, {David J.} and Jonathan Beesley and Bronwyn Sheldrick and Mills, {Richard A.} and John Landers and Ruddle, {Jonathan B.} and Graham, {Stuart L.} and Healey, {Paul R.} and White, {Andrew J. R.} and Casson, {Robert J.} and Stephen Best and Grigg, {John R.} and Ivan Goldberg and Powell, {Joseph E.} and Whiteman, {David C.} and Radford-Smith, {Graham L.} and Martin, {Nicholas G.} and Montgomery, {Grant W.} and Burdon, {Kathryn P.} and Mackey, {David A.} and Puya Gharahkhani and Craig, {Jamie E.} and Hewitt, {Alex W.}",

year = "2018",

month = aug,

day = "1",

doi = "10.1038/s41588-018-0176-y",

language = "English",

volume = "50",

pages = "1067--1071",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group - Macmillan Publishers",

number = "8",

}

MacGregor, S, Ong, J-S, An, J, Han, X, Zhou, T, Siggs, OM, Law, MH, Souzeau, E, Sharma, S, Lynn, DJ, Beesley, J, Sheldrick, B, Mills, RA, Landers, J, Ruddle, JB, Graham, SL, Healey, PR, White, AJR, Casson, RJ, Best, S, Grigg, JR, Goldberg, I, Powell, JE, Whiteman, DC, Radford-Smith, GL, Martin, NG, Montgomery, GW, Burdon, KP, Mackey, DA, Gharahkhani, P, Craig, JE & Hewitt, AW 2018, 'Genome-wide association study of intraocular pressure uncovers new pathways to glaucoma', Nature Genetics, vol. 50, no. 8, pp. 1067-1071. https://doi.org/10.1038/s41588-018-0176-y

TY - JOUR

T1 - Genome-wide association study of intraocular pressure uncovers new pathways to glaucoma

AU - MacGregor, Stuart

AU - Ong, Jue-Sheng

AU - An, Jiyuan

AU - Han, Xikun

AU - Zhou, Tiger

AU - Siggs, Owen M.

AU - Law, Matthew H.

AU - Souzeau, Emmanuelle

AU - Sharma, Shiwani

AU - Lynn, David J.

AU - Beesley, Jonathan

AU - Sheldrick, Bronwyn

AU - Mills, Richard A.

AU - Landers, John

AU - Ruddle, Jonathan B.

AU - Graham, Stuart L.

AU - Healey, Paul R.

AU - White, Andrew J. R.

AU - Casson, Robert J.

AU - Best, Stephen

AU - Grigg, John R.

AU - Goldberg, Ivan

AU - Powell, Joseph E.

AU - Whiteman, David C.

AU - Radford-Smith, Graham L.

AU - Martin, Nicholas G.

AU - Montgomery, Grant W.

AU - Burdon, Kathryn P.

AU - Mackey, David A.

AU - Gharahkhani, Puya

AU - Craig, Jamie E.

AU - Hewitt, Alex W.

PY - 2018/8/1

Y1 - 2018/8/1

N2 - Intraocular pressure (IOP) is currently the sole modifiable risk factor for primary open-angle glaucoma (POAG), one of the leading causes of blindness worldwide(1). Both IOP and POAG are highly heritable(2). 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 reported(4-12). 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.

AB - Intraocular pressure (IOP) is currently the sole modifiable risk factor for primary open-angle glaucoma (POAG), one of the leading causes of blindness worldwide(1). Both IOP and POAG are highly heritable(2). 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 reported(4-12). 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.

KW - OPEN-ANGLE GLAUCOMA

KW - CENTRAL CORNEAL THICKNESS

KW - NAIL-PATELLA SYNDROME

KW - SUSCEPTIBILITY LOCI

KW - COMMON VARIANTS

KW - GENOTYPE IMPUTATION

KW - CLOSURE GLAUCOMA

KW - MUTATIONS

KW - TRAITS

KW - RISK

U2 - 10.1038/s41588-018-0176-y

DO - 10.1038/s41588-018-0176-y

M3 - Article

C2 - 30054594

SN - 1061-4036

VL - 50

SP - 1067

EP - 1071

JO - Nature Genetics

JF - Nature Genetics

IS - 8

ER -

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

Abstract

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Translation of Genetic Eye Research Integrating Education, Counselling & Testing with Gene Discovery & Gene Based Therapies for Eye Disease

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