New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics

Henriët Springelkamp, Adriana I Iglesias, Aniket Mishra, René Höhn, Robert Wojciechowski, Anthony P Khawaja, Abhishek Nag, Ya Xing Wang, Jie Jin Wang, Gabriel Cuellar-Partida, Jane Gibson, Jessica N Cooke Bailey, Eranga N Vithana, Puya Gharahkhani, Thibaud Boutin, Wishal D Ramdas, Tanja Zeller, Robert N Luben, Ekaterina Yonova-Doing, Ananth C Viswanathan & 63 others Seyhan Yazar, Angela J. Cree, Jonathan L Haines, Jia Yu Koh, Emmanuelle Souzeau, James F. Wilson, Najaf Amin, Christian Müller, Cristina Venturini, Lisa S Kearns, Jae Hee Kang, Yih Chung Tham, Tiger Zhou, Elisabeth M. Van Leeuwen, Stefan Nickels, Paul Sanfilippo, Jiemin Liao, Herma van der Linde, Wanting Zhao, Leonieke M E van Koolwijk, Li Zheng, Fernando Rivadeneira, Mani Baskaran, Sven J. Van Der Lee, Shamira Perera, Paulus T V M de Jong, Ben A. Oostra, André G. Uitterlinden, Qiao Fan, Albert Hofman, E-Shyong Tai, Johannes R Vingerling, Xueling Sim, Roger C W Wolfs, Yik Ying Teo, Hans G Lemij, Chiea Chuen Khor, Rob Willemsen, Karl J Lackner, Tin Aung, Nomdo M Jansonius, Grant W. Montgomery, Philipp S Wild, Terri L Young, Kathryn P. Burdon, Pirro G. Hysi, Louis R. Pasquale, Tien Yin Wong, Caroline C W Klaver, Alex W Hewitt, Jost B. Jonas, Paul Mitchell, Andrew J Lotery, Paul J Foster, Veronique Vitart, Norbert Pfeiffer, Jamie E. Craig, David A, Mackey, Christopher J. Hammond, Janey L. Wiggs, Ching Yu Cheng, Cornelia M. van Duijn, Stuart MacGregor

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Abstract

Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increased risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup-disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk.

Original languageEnglish
Pages (from-to)438-453
Number of pages16
JournalHuman Molecular Genetics
Volume26
Issue number2
DOIs
Publication statusPublished - 15 Jan 2017

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Optic Disk
Intraocular Pressure
Meta-Analysis
Primary Open Angle Glaucoma
Optic Nerve Diseases
Genome-Wide Association Study
Zebrafish
Optic Nerve
Genome

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Springelkamp, H., Iglesias, A. I., Mishra, A., Höhn, R., Wojciechowski, R., Khawaja, A. P., ... MacGregor, S. (2017). New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics. Human Molecular Genetics, 26(2), 438-453. https://doi.org/10.1093/hmg/ddw399
Springelkamp, Henriët ; Iglesias, Adriana I ; Mishra, Aniket ; Höhn, René ; Wojciechowski, Robert ; Khawaja, Anthony P ; Nag, Abhishek ; Wang, Ya Xing ; Wang, Jie Jin ; Cuellar-Partida, Gabriel ; Gibson, Jane ; Bailey, Jessica N Cooke ; Vithana, Eranga N ; Gharahkhani, Puya ; Boutin, Thibaud ; Ramdas, Wishal D ; Zeller, Tanja ; Luben, Robert N ; Yonova-Doing, Ekaterina ; Viswanathan, Ananth C ; Yazar, Seyhan ; Cree, Angela J. ; Haines, Jonathan L ; Koh, Jia Yu ; Souzeau, Emmanuelle ; Wilson, James F. ; Amin, Najaf ; Müller, Christian ; Venturini, Cristina ; Kearns, Lisa S ; Kang, Jae Hee ; Tham, Yih Chung ; Zhou, Tiger ; Van Leeuwen, Elisabeth M. ; Nickels, Stefan ; Sanfilippo, Paul ; Liao, Jiemin ; van der Linde, Herma ; Zhao, Wanting ; van Koolwijk, Leonieke M E ; Zheng, Li ; Rivadeneira, Fernando ; Baskaran, Mani ; Van Der Lee, Sven J. ; Perera, Shamira ; de Jong, Paulus T V M ; Oostra, Ben A. ; Uitterlinden, André G. ; Fan, Qiao ; Hofman, Albert ; Tai, E-Shyong ; Vingerling, Johannes R ; Sim, Xueling ; Wolfs, Roger C W ; Teo, Yik Ying ; Lemij, Hans G ; Khor, Chiea Chuen ; Willemsen, Rob ; Lackner, Karl J ; Aung, Tin ; Jansonius, Nomdo M ; Montgomery, Grant W. ; Wild, Philipp S ; Young, Terri L ; Burdon, Kathryn P. ; Hysi, Pirro G. ; Pasquale, Louis R. ; Wong, Tien Yin ; Klaver, Caroline C W ; Hewitt, Alex W ; Jonas, Jost B. ; Mitchell, Paul ; Lotery, Andrew J ; Foster, Paul J ; Vitart, Veronique ; Pfeiffer, Norbert ; Craig, Jamie E. ; Mackey, David A, ; Hammond, Christopher J. ; Wiggs, Janey L. ; Cheng, Ching Yu ; van Duijn, Cornelia M. ; MacGregor, Stuart. / New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics. In: Human Molecular Genetics. 2017 ; Vol. 26, No. 2. pp. 438-453.
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note = "{\circledC} The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.",
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Springelkamp, H, Iglesias, AI, Mishra, A, Höhn, R, Wojciechowski, R, Khawaja, AP, Nag, A, Wang, YX, Wang, JJ, Cuellar-Partida, G, Gibson, J, Bailey, JNC, Vithana, EN, Gharahkhani, P, Boutin, T, Ramdas, WD, Zeller, T, Luben, RN, Yonova-Doing, E, Viswanathan, AC, Yazar, S, Cree, AJ, Haines, JL, Koh, JY, Souzeau, E, Wilson, JF, Amin, N, Müller, C, Venturini, C, Kearns, LS, Kang, JH, Tham, YC, Zhou, T, Van Leeuwen, EM, Nickels, S, Sanfilippo, P, Liao, J, van der Linde, H, Zhao, W, van Koolwijk, LME, Zheng, L, Rivadeneira, F, Baskaran, M, Van Der Lee, SJ, Perera, S, de Jong, PTVM, Oostra, BA, Uitterlinden, AG, Fan, Q, Hofman, A, Tai, E-S, Vingerling, JR, Sim, X, Wolfs, RCW, Teo, YY, Lemij, HG, Khor, CC, Willemsen, R, Lackner, KJ, Aung, T, Jansonius, NM, Montgomery, GW, Wild, PS, Young, TL, Burdon, KP, Hysi, PG, Pasquale, LR, Wong, TY, Klaver, CCW, Hewitt, AW, Jonas, JB, Mitchell, P, Lotery, AJ, Foster, PJ, Vitart, V, Pfeiffer, N, Craig, JE, Mackey, DA, Hammond, CJ, Wiggs, JL, Cheng, CY, van Duijn, CM & MacGregor, S 2017, 'New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics' Human Molecular Genetics, vol. 26, no. 2, pp. 438-453. https://doi.org/10.1093/hmg/ddw399

New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics. / Springelkamp, Henriët; Iglesias, Adriana I; Mishra, Aniket; Höhn, René; Wojciechowski, Robert; Khawaja, Anthony P; Nag, Abhishek; Wang, Ya Xing; Wang, Jie Jin; Cuellar-Partida, Gabriel; Gibson, Jane; Bailey, Jessica N Cooke; Vithana, Eranga N; Gharahkhani, Puya; Boutin, Thibaud; Ramdas, Wishal D; Zeller, Tanja; Luben, Robert N; Yonova-Doing, Ekaterina; Viswanathan, Ananth C; Yazar, Seyhan; Cree, Angela J.; Haines, Jonathan L; Koh, Jia Yu; Souzeau, Emmanuelle; Wilson, James F.; Amin, Najaf; Müller, Christian; Venturini, Cristina; Kearns, Lisa S; Kang, Jae Hee; Tham, Yih Chung; Zhou, Tiger; Van Leeuwen, Elisabeth M.; Nickels, Stefan; Sanfilippo, Paul; Liao, Jiemin; van der Linde, Herma; Zhao, Wanting; van Koolwijk, Leonieke M E; Zheng, Li; Rivadeneira, Fernando; Baskaran, Mani; Van Der Lee, Sven J.; Perera, Shamira; de Jong, Paulus T V M; Oostra, Ben A.; Uitterlinden, André G.; Fan, Qiao; Hofman, Albert; Tai, E-Shyong; Vingerling, Johannes R; Sim, Xueling; Wolfs, Roger C W; Teo, Yik Ying; Lemij, Hans G; Khor, Chiea Chuen; Willemsen, Rob; Lackner, Karl J; Aung, Tin; Jansonius, Nomdo M; Montgomery, Grant W.; Wild, Philipp S; Young, Terri L; Burdon, Kathryn P.; Hysi, Pirro G.; Pasquale, Louis R.; Wong, Tien Yin; Klaver, Caroline C W; Hewitt, Alex W; Jonas, Jost B.; Mitchell, Paul; Lotery, Andrew J; Foster, Paul J; Vitart, Veronique; Pfeiffer, Norbert; Craig, Jamie E.; Mackey, David A,; Hammond, Christopher J.; Wiggs, Janey L.; Cheng, Ching Yu; van Duijn, Cornelia M.; MacGregor, Stuart.

In: Human Molecular Genetics, Vol. 26, No. 2, 15.01.2017, p. 438-453.

Research output: Contribution to journalArticle

TY - JOUR

T1 - New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics

AU - Springelkamp, Henriët

AU - Iglesias, Adriana I

AU - Mishra, Aniket

AU - Höhn, René

AU - Wojciechowski, Robert

AU - Khawaja, Anthony P

AU - Nag, Abhishek

AU - Wang, Ya Xing

AU - Wang, Jie Jin

AU - Cuellar-Partida, Gabriel

AU - Gibson, Jane

AU - Bailey, Jessica N Cooke

AU - Vithana, Eranga N

AU - Gharahkhani, Puya

AU - Boutin, Thibaud

AU - Ramdas, Wishal D

AU - Zeller, Tanja

AU - Luben, Robert N

AU - Yonova-Doing, Ekaterina

AU - Viswanathan, Ananth C

AU - Yazar, Seyhan

AU - Cree, Angela J.

AU - Haines, Jonathan L

AU - Koh, Jia Yu

AU - Souzeau, Emmanuelle

AU - Wilson, James F.

AU - Amin, Najaf

AU - Müller, Christian

AU - Venturini, Cristina

AU - Kearns, Lisa S

AU - Kang, Jae Hee

AU - Tham, Yih Chung

AU - Zhou, Tiger

AU - Van Leeuwen, Elisabeth M.

AU - Nickels, Stefan

AU - Sanfilippo, Paul

AU - Liao, Jiemin

AU - van der Linde, Herma

AU - Zhao, Wanting

AU - van Koolwijk, Leonieke M E

AU - Zheng, Li

AU - Rivadeneira, Fernando

AU - Baskaran, Mani

AU - Van Der Lee, Sven J.

AU - Perera, Shamira

AU - de Jong, Paulus T V M

AU - Oostra, Ben A.

AU - Uitterlinden, André G.

AU - Fan, Qiao

AU - Hofman, Albert

AU - Tai, E-Shyong

AU - Vingerling, Johannes R

AU - Sim, Xueling

AU - Wolfs, Roger C W

AU - Teo, Yik Ying

AU - Lemij, Hans G

AU - Khor, Chiea Chuen

AU - Willemsen, Rob

AU - Lackner, Karl J

AU - Aung, Tin

AU - Jansonius, Nomdo M

AU - Montgomery, Grant W.

AU - Wild, Philipp S

AU - Young, Terri L

AU - Burdon, Kathryn P.

AU - Hysi, Pirro G.

AU - Pasquale, Louis R.

AU - Wong, Tien Yin

AU - Klaver, Caroline C W

AU - Hewitt, Alex W

AU - Jonas, Jost B.

AU - Mitchell, Paul

AU - Lotery, Andrew J

AU - Foster, Paul J

AU - Vitart, Veronique

AU - Pfeiffer, Norbert

AU - Craig, Jamie E.

AU - Mackey, David A,

AU - Hammond, Christopher J.

AU - Wiggs, Janey L.

AU - Cheng, Ching Yu

AU - van Duijn, Cornelia M.

AU - MacGregor, Stuart

N1 - © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

PY - 2017/1/15

Y1 - 2017/1/15

N2 - Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increased risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup-disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk.

AB - Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increased risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup-disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk.

KW - Journal Article

U2 - 10.1093/hmg/ddw399

DO - 10.1093/hmg/ddw399

M3 - Article

VL - 26

SP - 438

EP - 453

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 2

ER -