Analysis combining correlated glaucoma traits identifies five new risk loci for open-angle glaucoma

The NEIGHBORHOOD consortium; R. Rand Allingham; Murray Brilliant; Donald L. Budenz; John H. Fingert; Douglas Gaasterland; Teresa Gaasterland; Lisa Hark; Michael Hauser; Robert P. Igo, Jr.; Peter Kraft; Richard K. Lee; Paul R. Lichter; Yutao Liu; Syoko Moroi; Margaret Pericak-Vance; Anthony  Realini; Douglas Rhee; Julie E.  Richards; Robert Ritch; Joel S. Schuman; William K. Scott; Kuldev Singh; Arthur J. Sit; Douglas Vollrath; Gadi Wollstein; Donald J. Zack

doi:10.1038/s41598-018-20435-9

Analysis combining correlated glaucoma traits identifies five new risk loci for open-angle glaucoma

The NEIGHBORHOOD consortium, R. Rand Allingham, Murray Brilliant, Donald L. Budenz, John H. Fingert, Douglas Gaasterland, Teresa Gaasterland, Lisa Hark, Michael Hauser, Robert P. Igo, Jr., Peter Kraft, Richard K. Lee, Paul R. Lichter, Yutao Liu, Syoko Moroi, Margaret Pericak-Vance, Anthony Realini, Douglas Rhee, Julie E. Richards, Robert RitchJoel S. Schuman, William K. Scott, Kuldev Singh, Arthur J. Sit, Douglas Vollrath, Gadi Wollstein, Donald J. Zack

College of Medicine and Public Health

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Abstract

Open-angle glaucoma (OAG) is a major cause of blindness worldwide. To identify new risk loci for OAG, we performed a genome-wide association study in 3,071 OAG cases and 6,750 unscreened controls, and meta-analysed the results with GWAS data for intraocular pressure (IOP) and optic disc parameters (the overall meta-analysis sample size varying between 32,000 to 48,000 participants), which are glaucoma-related traits. We identified and independently validated four novel genome-wide significant associations within or near MYOF and CYP26A1, LINC02052 and CRYGS, LMX1B, and LMO7 using single variant tests, one additional locus (C9) using gene-based tests, and two genetic pathways-"response to fluid shear stress" and "abnormal retina morphology"-in pathway-based tests. Interestingly, some of the new risk loci contribute to risk of other genetically-correlated eye diseases including myopia and age-related macular degeneration. To our knowledge, this study is the first integrative study to combine genetic data from OAG and its correlated traits to identify new risk variants and genetic pathways, highlighting the future potential of combining genetic data from genetically-correlated eye traits for the purpose of gene discovery and mapping.

Original language	English
Article number	3124
Number of pages	12
Journal	Scientific Reports
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41598-018-20435-9
Publication status	Published - 15 Feb 2018

Bibliographical note

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Keywords

Open-angle glaucoma (OAG)
blindness
meta-analysis
glaucoma-related traits

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Gharahkhani_Analysis_P2018Final published version, 1.95 MBLicence: CC BY

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The NEIGHBORHOOD consortium, Allingham, R. R., Brilliant, M., Budenz, D. L., Fingert, J. H., Gaasterland, D., Gaasterland, T., Hark, L., Hauser, M., Igo, Jr., R. P., Kraft, P., Lee, R. K., Lichter, P. R., Liu, Y., Moroi, S., Pericak-Vance, M., Realini, A., Rhee, D., Richards, J. E., ... Zack, D. J. (2018). Analysis combining correlated glaucoma traits identifies five new risk loci for open-angle glaucoma. Scientific Reports, 8(1), Article 3124. https://doi.org/10.1038/s41598-018-20435-9

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title = "Analysis combining correlated glaucoma traits identifies five new risk loci for open-angle glaucoma",

abstract = "Open-angle glaucoma (OAG) is a major cause of blindness worldwide. To identify new risk loci for OAG, we performed a genome-wide association study in 3,071 OAG cases and 6,750 unscreened controls, and meta-analysed the results with GWAS data for intraocular pressure (IOP) and optic disc parameters (the overall meta-analysis sample size varying between 32,000 to 48,000 participants), which are glaucoma-related traits. We identified and independently validated four novel genome-wide significant associations within or near MYOF and CYP26A1, LINC02052 and CRYGS, LMX1B, and LMO7 using single variant tests, one additional locus (C9) using gene-based tests, and two genetic pathways-{"}response to fluid shear stress{"} and {"}abnormal retina morphology{"}-in pathway-based tests. Interestingly, some of the new risk loci contribute to risk of other genetically-correlated eye diseases including myopia and age-related macular degeneration. To our knowledge, this study is the first integrative study to combine genetic data from OAG and its correlated traits to identify new risk variants and genetic pathways, highlighting the future potential of combining genetic data from genetically-correlated eye traits for the purpose of gene discovery and mapping.",

keywords = "Open-angle glaucoma (OAG), blindness, meta-analysis, glaucoma-related traits",

author = "Puya Gharahkhani and Burdon, {Kathryn P.} and {Cooke Bailey}, {Jessica N.} and Alex Hewitt and Matthew Law and Pasquale, {Louis R.} and Jae Kang and Haines, {Jonathan L.} and Emmanuelle Souzeau and Tiger Zhou and Siggs, {Owen M.} and John Landers and Mona Awadalla and Shiwani Sharma and Mills, {Richard A.} and Bronwyn Ridge and David Lynn and Robert Casson and Graham, {Stuart L.} and Ivan Goldberg and Andrew White and Healey, {Paul R.} and John Grigg and Mitchell Lawlor and Paul Mitchell and Jonathan Ruddle and Michael Coote and Mark Walland and Stephen Best and Andrea Vincent and Jesse Gale and {Radford Smith}, Graham and Whiteman, {David C.} and Montgomery, {Grant W.} and Nicholas Martin and Mackey, {David A.} and Wiggs, {Janey L.} and Stuart MacGregor and Craig, {Jamie E.} and {The NEIGHBORHOOD consortium} and Allingham, {R. Rand} and Murray Brilliant and Budenz, {Donald L.} and Fingert, {John H.} and Douglas Gaasterland and Teresa Gaasterland and Lisa Hark and Michael Hauser and {Igo, Jr.}, {Robert P.} and Peter Kraft and Lee, {Richard K.} and Lichter, {Paul R.} and Yutao Liu and Syoko Moroi and Margaret Pericak-Vance and Anthony Realini and Douglas Rhee and Richards, {Julie E.} and Robert Ritch and Schuman, {Joel S.} and Scott, {William K.} and Kuldev Singh and Sit, {Arthur J.} and Douglas Vollrath and Gadi Wollstein and Zack, {Donald J.}",

note = "Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article{\textquoteright}s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article{\textquoteright}s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.",

year = "2018",

month = feb,

day = "15",

doi = "10.1038/s41598-018-20435-9",

language = "English",

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The NEIGHBORHOOD consortium, Allingham, RR, Brilliant, M, Budenz, DL, Fingert, JH, Gaasterland, D, Gaasterland, T, Hark, L, Hauser, M, Igo, Jr., RP, Kraft, P, Lee, RK, Lichter, PR, Liu, Y, Moroi, S, Pericak-Vance, M, Realini, A, Rhee, D, Richards, JE, Ritch, R, Schuman, JS, Scott, WK, Singh, K, Sit, AJ, Vollrath, D, Wollstein, G & Zack, DJ 2018, 'Analysis combining correlated glaucoma traits identifies five new risk loci for open-angle glaucoma', Scientific Reports, vol. 8, no. 1, 3124. https://doi.org/10.1038/s41598-018-20435-9

TY - JOUR

T1 - Analysis combining correlated glaucoma traits identifies five new risk loci for open-angle glaucoma

AU - Gharahkhani, Puya

AU - Burdon, Kathryn P.

AU - Cooke Bailey, Jessica N.

AU - Hewitt, Alex

AU - Law, Matthew

AU - Pasquale, Louis R.

AU - Kang, Jae

AU - Haines, Jonathan L.

AU - Souzeau, Emmanuelle

AU - Zhou, Tiger

AU - Siggs, Owen M.

AU - Landers, John

AU - Awadalla, Mona

AU - Sharma, Shiwani

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AU - Casson, Robert

AU - Graham, Stuart L.

AU - Goldberg, Ivan

AU - White, Andrew

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AU - Grigg, John

AU - Lawlor, Mitchell

AU - Mitchell, Paul

AU - Ruddle, Jonathan

AU - Coote, Michael

AU - Walland, Mark

AU - Best, Stephen

AU - Vincent, Andrea

AU - Gale, Jesse

AU - Radford Smith, Graham

AU - Whiteman, David C.

AU - Montgomery, Grant W.

AU - Martin, Nicholas

AU - Mackey, David A.

AU - Wiggs, Janey L.

AU - MacGregor, Stuart

AU - Craig, Jamie E.

AU - The NEIGHBORHOOD consortium

AU - Allingham, R. Rand

AU - Brilliant, Murray

AU - Budenz, Donald L.

AU - Fingert, John H.

AU - Gaasterland, Douglas

AU - Gaasterland, Teresa

AU - Hark, Lisa

AU - Hauser, Michael

AU - Igo, Jr., Robert P.

AU - Kraft, Peter

AU - Lee, Richard K.

AU - Lichter, Paul R.

AU - Liu, Yutao

AU - Moroi, Syoko

AU - Pericak-Vance, Margaret

AU - Realini, Anthony

AU - Rhee, Douglas

AU - Richards, Julie E.

AU - Ritch, Robert

AU - Schuman, Joel S.

AU - Scott, William K.

AU - Singh, Kuldev

AU - Sit, Arthur J.

AU - Vollrath, Douglas

AU - Wollstein, Gadi

AU - Zack, Donald J.

N1 - Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

PY - 2018/2/15

Y1 - 2018/2/15

N2 - Open-angle glaucoma (OAG) is a major cause of blindness worldwide. To identify new risk loci for OAG, we performed a genome-wide association study in 3,071 OAG cases and 6,750 unscreened controls, and meta-analysed the results with GWAS data for intraocular pressure (IOP) and optic disc parameters (the overall meta-analysis sample size varying between 32,000 to 48,000 participants), which are glaucoma-related traits. We identified and independently validated four novel genome-wide significant associations within or near MYOF and CYP26A1, LINC02052 and CRYGS, LMX1B, and LMO7 using single variant tests, one additional locus (C9) using gene-based tests, and two genetic pathways-"response to fluid shear stress" and "abnormal retina morphology"-in pathway-based tests. Interestingly, some of the new risk loci contribute to risk of other genetically-correlated eye diseases including myopia and age-related macular degeneration. To our knowledge, this study is the first integrative study to combine genetic data from OAG and its correlated traits to identify new risk variants and genetic pathways, highlighting the future potential of combining genetic data from genetically-correlated eye traits for the purpose of gene discovery and mapping.

AB - Open-angle glaucoma (OAG) is a major cause of blindness worldwide. To identify new risk loci for OAG, we performed a genome-wide association study in 3,071 OAG cases and 6,750 unscreened controls, and meta-analysed the results with GWAS data for intraocular pressure (IOP) and optic disc parameters (the overall meta-analysis sample size varying between 32,000 to 48,000 participants), which are glaucoma-related traits. We identified and independently validated four novel genome-wide significant associations within or near MYOF and CYP26A1, LINC02052 and CRYGS, LMX1B, and LMO7 using single variant tests, one additional locus (C9) using gene-based tests, and two genetic pathways-"response to fluid shear stress" and "abnormal retina morphology"-in pathway-based tests. Interestingly, some of the new risk loci contribute to risk of other genetically-correlated eye diseases including myopia and age-related macular degeneration. To our knowledge, this study is the first integrative study to combine genetic data from OAG and its correlated traits to identify new risk variants and genetic pathways, highlighting the future potential of combining genetic data from genetically-correlated eye traits for the purpose of gene discovery and mapping.

KW - Open-angle glaucoma (OAG)

KW - blindness

KW - meta-analysis

KW - glaucoma-related traits

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U2 - 10.1038/s41598-018-20435-9

DO - 10.1038/s41598-018-20435-9

M3 - Article

SN - 2045-2322

VL - 8

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 3124

ER -

Analysis combining correlated glaucoma traits identifies five new risk loci for open-angle glaucoma

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Keywords

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