Common genetic variants associated with open-angle glaucoma

Wishal D Ramdas; Leonieke M E van Koolwijk; Hans G Lemij; Francesca Pasutto; Angela J Cree; Gudmar Thorleifsson; Sarah F Janssen; Ten Brink Jacoline; Najaf Amin; Fernando Rivadeneira; Roger C W Wolfs; G Bragi Walters; Fridbert Jonasson; Nicole Weisschuh; Christian Y Mardin; Jane Gibson; Richard H C Zegers; Albert Hofman; Paulus T V M de Jong; André G Uitterlinden; Ben A Oostra; Unnur Thorsteinsdottir; Eugen Gramer; Ulrich C Welgen-Lüssen; James F Kirwan; Arthur A B Bergen; André Reis; Kari Stefansson; Andrew J Lotery; Johannes R Vingerling; Nomdo M Jansonius; Caroline C W Klaver; Cornelia M van Duijn

doi:10.1093/hmg/ddr120

Common genetic variants associated with open-angle glaucoma

Wishal D Ramdas, Leonieke M E van Koolwijk, Hans G Lemij, Francesca Pasutto, Angela J Cree, Gudmar Thorleifsson, Sarah F Janssen, Ten Brink Jacoline, Najaf Amin, Fernando Rivadeneira, Roger C W Wolfs, G Bragi Walters, Fridbert Jonasson, Nicole Weisschuh, Christian Y Mardin, Jane Gibson, Richard H C Zegers, Albert Hofman, Paulus T V M de Jong, André G UitterlindenBen A Oostra, Unnur Thorsteinsdottir, Eugen Gramer, Ulrich C Welgen-Lüssen, James F Kirwan, Arthur A B Bergen, André Reis, Kari Stefansson, Andrew J Lotery, Johannes R Vingerling, Nomdo M Jansonius, Caroline C W Klaver, Cornelia M van Duijn

Research output: Contribution to journal › Review article › peer-review

Abstract

Open-angle glaucoma (glaucoma) is a major eye disorder characterized by optic disc pathology. Recent genome-wide association studies identified new loci associated with clinically relevant optic disc parameters, such as the optic disc area and vertical cup-disc ratio (VCDR). We examined to what extent these loci are involved in glaucoma. The loci studied include ATOH7, CDC7/TGFBR3 and SALL1 for optic disc area, and CDKN2B, SIX1, SCYL1/LTBP3, CHEK2, ATOH7 and DCLK1 for VCDR. We performed a meta-analysis using data from six independent studies including: the Rotterdam Study (n= 5736), Genetic Research in Isolated Populations combined with Erasmus Rucphen Family study (n= 1750), Amsterdam Glaucoma Study (n= 296) and cohorts from Erlangen and Tübingen (n= 1363), Southampton (n= 702) and deCODE (n= 36 151) resulting in a total of 3161 glaucoma cases and 42 837 controls. Of the eight loci, we found significant evidence (P= 1.41 × 10(-8)) for the association of CDKN2B with glaucoma [odds ratio (OR) for those homozygous for the risk allele: 0.76; 95% confidence interval (CI): 0.70-0.84], for the role of ATOH7 (OR: 1.28; 95% CI: 1.12-1.47) and for SIX1 (OR: 1.20; 95% CI: 1.10-1.31) when adjusting for the number of tested loci. Furthermore, there was a borderline significant association of CDC7/TGFBR3 and SALL1 (both P= 0.04) with glaucoma. In conclusion, we found consistent evidence for three common variants (CDKN2B, ATOH7 and SIX1) significantly associated with glaucoma. These findings may shed new light on the pathophysiological protein pathways leading to glaucoma, and point to pathways involved in the growth and development of the optic nerve.

Original language	English
Pages (from-to)	2464-71
Number of pages	8
Journal	Human Molecular Genetics
Volume	20
Issue number	12
DOIs	https://doi.org/10.1093/hmg/ddr120
Publication status	Published - 15 Jun 2011

Keywords

Basic Helix-Loop-Helix Transcription Factors/genetics
Cohort Studies
Cyclin-Dependent Kinase Inhibitor p15/genetics
Genetic Predisposition to Disease/genetics
Glaucoma, Open-Angle/genetics
Homeodomain Proteins/genetics
Humans
Logistic Models
Odds Ratio
Optic Disk/metabolism
Polymorphism, Single Nucleotide/genetics

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10.1093/hmg/ddr120

Cite this

Ramdas, W. D., van Koolwijk, L. M. E., Lemij, H. G., Pasutto, F., Cree, A. J., Thorleifsson, G., Janssen, S. F., Jacoline, T. B., Amin, N., Rivadeneira, F., Wolfs, R. C. W., Walters, G. B., Jonasson, F., Weisschuh, N., Mardin, C. Y., Gibson, J., Zegers, R. H. C., Hofman, A., de Jong, P. T. V. M., ... van Duijn, C. M. (2011). Common genetic variants associated with open-angle glaucoma. Human Molecular Genetics, 20(12), 2464-71. https://doi.org/10.1093/hmg/ddr120

@article{f2a0b560cd9d47fc95b1fdb688e4b442,

title = "Common genetic variants associated with open-angle glaucoma",

abstract = "Open-angle glaucoma (glaucoma) is a major eye disorder characterized by optic disc pathology. Recent genome-wide association studies identified new loci associated with clinically relevant optic disc parameters, such as the optic disc area and vertical cup-disc ratio (VCDR). We examined to what extent these loci are involved in glaucoma. The loci studied include ATOH7, CDC7/TGFBR3 and SALL1 for optic disc area, and CDKN2B, SIX1, SCYL1/LTBP3, CHEK2, ATOH7 and DCLK1 for VCDR. We performed a meta-analysis using data from six independent studies including: the Rotterdam Study (n= 5736), Genetic Research in Isolated Populations combined with Erasmus Rucphen Family study (n= 1750), Amsterdam Glaucoma Study (n= 296) and cohorts from Erlangen and T{\"u}bingen (n= 1363), Southampton (n= 702) and deCODE (n= 36 151) resulting in a total of 3161 glaucoma cases and 42 837 controls. Of the eight loci, we found significant evidence (P= 1.41 × 10(-8)) for the association of CDKN2B with glaucoma [odds ratio (OR) for those homozygous for the risk allele: 0.76; 95% confidence interval (CI): 0.70-0.84], for the role of ATOH7 (OR: 1.28; 95% CI: 1.12-1.47) and for SIX1 (OR: 1.20; 95% CI: 1.10-1.31) when adjusting for the number of tested loci. Furthermore, there was a borderline significant association of CDC7/TGFBR3 and SALL1 (both P= 0.04) with glaucoma. In conclusion, we found consistent evidence for three common variants (CDKN2B, ATOH7 and SIX1) significantly associated with glaucoma. These findings may shed new light on the pathophysiological protein pathways leading to glaucoma, and point to pathways involved in the growth and development of the optic nerve.",

keywords = "Basic Helix-Loop-Helix Transcription Factors/genetics, Cohort Studies, Cyclin-Dependent Kinase Inhibitor p15/genetics, Genetic Predisposition to Disease/genetics, Glaucoma, Open-Angle/genetics, Homeodomain Proteins/genetics, Humans, Logistic Models, Odds Ratio, Optic Disk/metabolism, Polymorphism, Single Nucleotide/genetics",

author = "Ramdas, {Wishal D} and {van Koolwijk}, {Leonieke M E} and Lemij, {Hans G} and Francesca Pasutto and Cree, {Angela J} and Gudmar Thorleifsson and Janssen, {Sarah F} and Jacoline, {Ten Brink} and Najaf Amin and Fernando Rivadeneira and Wolfs, {Roger C W} and Walters, {G Bragi} and Fridbert Jonasson and Nicole Weisschuh and Mardin, {Christian Y} and Jane Gibson and Zegers, {Richard H C} and Albert Hofman and {de Jong}, {Paulus T V M} and Uitterlinden, {Andr{\'e} G} and Oostra, {Ben A} and Unnur Thorsteinsdottir and Eugen Gramer and Welgen-L{\"u}ssen, {Ulrich C} and Kirwan, {James F} and Bergen, {Arthur A B} and Andr{\'e} Reis and Kari Stefansson and Lotery, {Andrew J} and Vingerling, {Johannes R} and Jansonius, {Nomdo M} and Klaver, {Caroline C W} and {van Duijn}, {Cornelia M}",

year = "2011",

month = jun,

day = "15",

doi = "10.1093/hmg/ddr120",

language = "English",

volume = "20",

pages = "2464--71",

number = "12",

}

Ramdas, WD, van Koolwijk, LME, Lemij, HG, Pasutto, F, Cree, AJ, Thorleifsson, G, Janssen, SF, Jacoline, TB, Amin, N, Rivadeneira, F, Wolfs, RCW, Walters, GB, Jonasson, F, Weisschuh, N, Mardin, CY, Gibson, J, Zegers, RHC, Hofman, A, de Jong, PTVM, Uitterlinden, AG, Oostra, BA, Thorsteinsdottir, U, Gramer, E, Welgen-Lüssen, UC, Kirwan, JF, Bergen, AAB, Reis, A, Stefansson, K, Lotery, AJ, Vingerling, JR, Jansonius, NM, Klaver, CCW & van Duijn, CM 2011, 'Common genetic variants associated with open-angle glaucoma', Human Molecular Genetics, vol. 20, no. 12, pp. 2464-71. https://doi.org/10.1093/hmg/ddr120

TY - JOUR

T1 - Common genetic variants associated with open-angle glaucoma

AU - Ramdas, Wishal D

AU - van Koolwijk, Leonieke M E

AU - Lemij, Hans G

AU - Pasutto, Francesca

AU - Cree, Angela J

AU - Thorleifsson, Gudmar

AU - Janssen, Sarah F

AU - Jacoline, Ten Brink

AU - Amin, Najaf

AU - Rivadeneira, Fernando

AU - Wolfs, Roger C W

AU - Walters, G Bragi

AU - Jonasson, Fridbert

AU - Weisschuh, Nicole

AU - Mardin, Christian Y

AU - Gibson, Jane

AU - Zegers, Richard H C

AU - Hofman, Albert

AU - de Jong, Paulus T V M

AU - Uitterlinden, André G

AU - Oostra, Ben A

AU - Thorsteinsdottir, Unnur

AU - Gramer, Eugen

AU - Welgen-Lüssen, Ulrich C

AU - Kirwan, James F

AU - Bergen, Arthur A B

AU - Reis, André

AU - Stefansson, Kari

AU - Lotery, Andrew J

AU - Vingerling, Johannes R

AU - Jansonius, Nomdo M

AU - Klaver, Caroline C W

AU - van Duijn, Cornelia M

PY - 2011/6/15

Y1 - 2011/6/15

N2 - Open-angle glaucoma (glaucoma) is a major eye disorder characterized by optic disc pathology. Recent genome-wide association studies identified new loci associated with clinically relevant optic disc parameters, such as the optic disc area and vertical cup-disc ratio (VCDR). We examined to what extent these loci are involved in glaucoma. The loci studied include ATOH7, CDC7/TGFBR3 and SALL1 for optic disc area, and CDKN2B, SIX1, SCYL1/LTBP3, CHEK2, ATOH7 and DCLK1 for VCDR. We performed a meta-analysis using data from six independent studies including: the Rotterdam Study (n= 5736), Genetic Research in Isolated Populations combined with Erasmus Rucphen Family study (n= 1750), Amsterdam Glaucoma Study (n= 296) and cohorts from Erlangen and Tübingen (n= 1363), Southampton (n= 702) and deCODE (n= 36 151) resulting in a total of 3161 glaucoma cases and 42 837 controls. Of the eight loci, we found significant evidence (P= 1.41 × 10(-8)) for the association of CDKN2B with glaucoma [odds ratio (OR) for those homozygous for the risk allele: 0.76; 95% confidence interval (CI): 0.70-0.84], for the role of ATOH7 (OR: 1.28; 95% CI: 1.12-1.47) and for SIX1 (OR: 1.20; 95% CI: 1.10-1.31) when adjusting for the number of tested loci. Furthermore, there was a borderline significant association of CDC7/TGFBR3 and SALL1 (both P= 0.04) with glaucoma. In conclusion, we found consistent evidence for three common variants (CDKN2B, ATOH7 and SIX1) significantly associated with glaucoma. These findings may shed new light on the pathophysiological protein pathways leading to glaucoma, and point to pathways involved in the growth and development of the optic nerve.

AB - Open-angle glaucoma (glaucoma) is a major eye disorder characterized by optic disc pathology. Recent genome-wide association studies identified new loci associated with clinically relevant optic disc parameters, such as the optic disc area and vertical cup-disc ratio (VCDR). We examined to what extent these loci are involved in glaucoma. The loci studied include ATOH7, CDC7/TGFBR3 and SALL1 for optic disc area, and CDKN2B, SIX1, SCYL1/LTBP3, CHEK2, ATOH7 and DCLK1 for VCDR. We performed a meta-analysis using data from six independent studies including: the Rotterdam Study (n= 5736), Genetic Research in Isolated Populations combined with Erasmus Rucphen Family study (n= 1750), Amsterdam Glaucoma Study (n= 296) and cohorts from Erlangen and Tübingen (n= 1363), Southampton (n= 702) and deCODE (n= 36 151) resulting in a total of 3161 glaucoma cases and 42 837 controls. Of the eight loci, we found significant evidence (P= 1.41 × 10(-8)) for the association of CDKN2B with glaucoma [odds ratio (OR) for those homozygous for the risk allele: 0.76; 95% confidence interval (CI): 0.70-0.84], for the role of ATOH7 (OR: 1.28; 95% CI: 1.12-1.47) and for SIX1 (OR: 1.20; 95% CI: 1.10-1.31) when adjusting for the number of tested loci. Furthermore, there was a borderline significant association of CDC7/TGFBR3 and SALL1 (both P= 0.04) with glaucoma. In conclusion, we found consistent evidence for three common variants (CDKN2B, ATOH7 and SIX1) significantly associated with glaucoma. These findings may shed new light on the pathophysiological protein pathways leading to glaucoma, and point to pathways involved in the growth and development of the optic nerve.

KW - Basic Helix-Loop-Helix Transcription Factors/genetics

KW - Cohort Studies

KW - Cyclin-Dependent Kinase Inhibitor p15/genetics

KW - Genetic Predisposition to Disease/genetics

KW - Glaucoma, Open-Angle/genetics

KW - Homeodomain Proteins/genetics

KW - Humans

KW - Logistic Models

KW - Odds Ratio

KW - Optic Disk/metabolism

KW - Polymorphism, Single Nucleotide/genetics

U2 - 10.1093/hmg/ddr120

DO - 10.1093/hmg/ddr120

M3 - Review article

C2 - 21427129

SN - 0964-6906

VL - 20

SP - 2464

EP - 2471

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 12

ER -

Common genetic variants associated with open-angle glaucoma

Abstract

Keywords

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