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

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 -