New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics
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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; 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; NEIGHBORHOOD Consortium.
In: HUM MOL GENET, Vol. 26, No. 2, 15.01.2017, p. 438-453.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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
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
AU - NEIGHBORHOOD Consortium
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 - Cyclin-Dependent Kinase Inhibitor p21/genetics
KW - Female
KW - Genome, Human
KW - Genome-Wide Association Study
KW - Glaucoma, Open-Angle/genetics
KW - Homeodomain Proteins/genetics
KW - Humans
KW - Intraocular Pressure/genetics
KW - Male
KW - Middle Aged
KW - Optic Disk/pathology
KW - Optic Nerve Diseases/genetics
KW - Tonometry, Ocular
KW - Zebrafish Proteins/genetics
U2 - 10.1093/hmg/ddw399
DO - 10.1093/hmg/ddw399
M3 - SCORING: Journal article
C2 - 28073927
VL - 26
SP - 438
EP - 453
JO - HUM MOL GENET
JF - HUM MOL GENET
SN - 0964-6906
IS - 2
ER -