Genetic architecture of open angle glaucoma and related determinants

Wishal D Ramdas; Najaf Amin; Leonieke M E van Koolwijk; A Cecile J W Janssens; Ayse Demirkan; Paulus T V M de Jong; Yurii S Aulchenko; Roger C W Wolfs; Albert Hofman; Fernando Rivadeneira; Andre G Uitterlinden; Ben A Oostra; Hans G Lemij; Caroline C W Klaver; Johannes R Vingerling; Nomdo M Jansonius; Cornelia M van Duijn

doi:10.1136/jmg.2010.083337

Genetic architecture of open angle glaucoma and related determinants

Wishal D Ramdas, Najaf Amin, Leonieke M E van Koolwijk, A Cecile J W Janssens, Ayse Demirkan, Paulus T V M de Jong, Yurii S Aulchenko, Roger C W Wolfs, Albert Hofman, Fernando Rivadeneira, Andre G Uitterlinden, Ben A Oostra, Hans G Lemij, Caroline C W Klaver, Johannes R Vingerling, Nomdo M Jansonius, Cornelia M van Duijn

Research output: Contribution to journal › Article › Research › peer-review

Abstract

BACKGROUND: Although the vertical cup-disc ratio (VCDR) and intraocular pressure (IOP) are important determinants of open angle glaucoma (OAG), it is unclear to what extent the genetic origin of these traits overlap with those of OAG. We evaluated whether the same genes that determine VCDR and IOP also predict OAG.

METHODS: Genetic risk scores were constructed from single nucleotide polymorphisms (SNPs) using genome wide association data of 9326 participants from the Rotterdam Study cohorts (mean ± SD age: 64.6 ± 9.1 years). These risk scores were used to calculate the explained variance of VCDR and IOP in an independent cohort (Erasmus Rucphen Family study) consisting of 1646 participants (mean ± SD age: 46.8 ± 14.1 years) and the OAG risk in a subset of the Rotterdam Study cohorts. To evaluate false positive findings, we generated two new variables containing randomly sampled values to serve as a negative control.

RESULTS: The explained variance of VCDR increased when increasing the number of SNPs included in the risk score, suggesting a polygenic model. We found no clear evidence for a similar model for IOP, suggesting that a small number of SNPs determine the susceptibility to IOP. The SNPs related to IOP in terms of p values contributed little to VCDR. The risk scores associated with VCDR were also associated significantly with OAG. This suggests a common polygenic background for VCDR and OAG CONCLUSIONS: We found evidence for a polygenic model underlying one of the major traits of OAG, VCDR, and OAG itself. The IOP did not show any evidence for such a model.

Original language	English
Pages (from-to)	190-6
Number of pages	7
Journal	Journal of Medical Genetics
Volume	48
Issue number	3
DOIs	https://doi.org/10.1136/jmg.2010.083337
Publication status	Published - Mar 2011

Keywords

Adolescent
Adult
Age Distribution
Aged
Aged, 80 and over
Cohort Studies
Cross-Sectional Studies
Female
Genome-Wide Association Study
Glaucoma, Open-Angle/genetics
Humans
Intraocular Pressure
Male
Middle Aged
Phylogeny
Polymorphism, Single Nucleotide
Prospective Studies
Risk Factors
Sex Distribution
Young Adult

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10.1136/jmg.2010.083337

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Ramdas, W. D., Amin, N., van Koolwijk, L. M. E., Janssens, A. C. J. W., Demirkan, A., de Jong, P. T. V. M., Aulchenko, Y. S., Wolfs, R. C. W., Hofman, A., Rivadeneira, F., Uitterlinden, A. G., Oostra, B. A., Lemij, H. G., Klaver, C. C. W., Vingerling, J. R., Jansonius, N. M., & van Duijn, C. M. (2011). Genetic architecture of open angle glaucoma and related determinants. Journal of Medical Genetics, 48(3), 190-6. https://doi.org/10.1136/jmg.2010.083337

@article{ca6206c6a2c74844a277a7aa86694d68,

title = "Genetic architecture of open angle glaucoma and related determinants",

abstract = "BACKGROUND: Although the vertical cup-disc ratio (VCDR) and intraocular pressure (IOP) are important determinants of open angle glaucoma (OAG), it is unclear to what extent the genetic origin of these traits overlap with those of OAG. We evaluated whether the same genes that determine VCDR and IOP also predict OAG.METHODS: Genetic risk scores were constructed from single nucleotide polymorphisms (SNPs) using genome wide association data of 9326 participants from the Rotterdam Study cohorts (mean ± SD age: 64.6 ± 9.1 years). These risk scores were used to calculate the explained variance of VCDR and IOP in an independent cohort (Erasmus Rucphen Family study) consisting of 1646 participants (mean ± SD age: 46.8 ± 14.1 years) and the OAG risk in a subset of the Rotterdam Study cohorts. To evaluate false positive findings, we generated two new variables containing randomly sampled values to serve as a negative control.RESULTS: The explained variance of VCDR increased when increasing the number of SNPs included in the risk score, suggesting a polygenic model. We found no clear evidence for a similar model for IOP, suggesting that a small number of SNPs determine the susceptibility to IOP. The SNPs related to IOP in terms of p values contributed little to VCDR. The risk scores associated with VCDR were also associated significantly with OAG. This suggests a common polygenic background for VCDR and OAG CONCLUSIONS: We found evidence for a polygenic model underlying one of the major traits of OAG, VCDR, and OAG itself. The IOP did not show any evidence for such a model.",

keywords = "Adolescent, Adult, Age Distribution, Aged, Aged, 80 and over, Cohort Studies, Cross-Sectional Studies, Female, Genome-Wide Association Study, Glaucoma, Open-Angle/genetics, Humans, Intraocular Pressure, Male, Middle Aged, Phylogeny, Polymorphism, Single Nucleotide, Prospective Studies, Risk Factors, Sex Distribution, Young Adult",

author = "Ramdas, {Wishal D} and Najaf Amin and {van Koolwijk}, {Leonieke M E} and Janssens, {A Cecile J W} and Ayse Demirkan and {de Jong}, {Paulus T V M} and Aulchenko, {Yurii S} and Wolfs, {Roger C W} and Albert Hofman and Fernando Rivadeneira and Uitterlinden, {Andre G} and Oostra, {Ben A} and Lemij, {Hans G} and Klaver, {Caroline C W} and Vingerling, {Johannes R} and Jansonius, {Nomdo M} and {van Duijn}, {Cornelia M}",

year = "2011",

month = mar,

doi = "10.1136/jmg.2010.083337",

language = "English",

volume = "48",

pages = "190--6",

number = "3",

}

Ramdas, WD, Amin, N, van Koolwijk, LME, Janssens, ACJW, Demirkan, A, de Jong, PTVM, Aulchenko, YS, Wolfs, RCW, Hofman, A, Rivadeneira, F, Uitterlinden, AG, Oostra, BA, Lemij, HG, Klaver, CCW, Vingerling, JR, Jansonius, NM & van Duijn, CM 2011, 'Genetic architecture of open angle glaucoma and related determinants', Journal of Medical Genetics, vol. 48, no. 3, pp. 190-6. https://doi.org/10.1136/jmg.2010.083337

TY - JOUR

T1 - Genetic architecture of open angle glaucoma and related determinants

AU - Ramdas, Wishal D

AU - Amin, Najaf

AU - van Koolwijk, Leonieke M E

AU - Janssens, A Cecile J W

AU - Demirkan, Ayse

AU - de Jong, Paulus T V M

AU - Aulchenko, Yurii S

AU - Wolfs, Roger C W

AU - Hofman, Albert

AU - Rivadeneira, Fernando

AU - Uitterlinden, Andre G

AU - Oostra, Ben A

AU - Lemij, Hans G

AU - Klaver, Caroline C W

AU - Vingerling, Johannes R

AU - Jansonius, Nomdo M

AU - van Duijn, Cornelia M

PY - 2011/3

Y1 - 2011/3

N2 - BACKGROUND: Although the vertical cup-disc ratio (VCDR) and intraocular pressure (IOP) are important determinants of open angle glaucoma (OAG), it is unclear to what extent the genetic origin of these traits overlap with those of OAG. We evaluated whether the same genes that determine VCDR and IOP also predict OAG.METHODS: Genetic risk scores were constructed from single nucleotide polymorphisms (SNPs) using genome wide association data of 9326 participants from the Rotterdam Study cohorts (mean ± SD age: 64.6 ± 9.1 years). These risk scores were used to calculate the explained variance of VCDR and IOP in an independent cohort (Erasmus Rucphen Family study) consisting of 1646 participants (mean ± SD age: 46.8 ± 14.1 years) and the OAG risk in a subset of the Rotterdam Study cohorts. To evaluate false positive findings, we generated two new variables containing randomly sampled values to serve as a negative control.RESULTS: The explained variance of VCDR increased when increasing the number of SNPs included in the risk score, suggesting a polygenic model. We found no clear evidence for a similar model for IOP, suggesting that a small number of SNPs determine the susceptibility to IOP. The SNPs related to IOP in terms of p values contributed little to VCDR. The risk scores associated with VCDR were also associated significantly with OAG. This suggests a common polygenic background for VCDR and OAG CONCLUSIONS: We found evidence for a polygenic model underlying one of the major traits of OAG, VCDR, and OAG itself. The IOP did not show any evidence for such a model.

AB - BACKGROUND: Although the vertical cup-disc ratio (VCDR) and intraocular pressure (IOP) are important determinants of open angle glaucoma (OAG), it is unclear to what extent the genetic origin of these traits overlap with those of OAG. We evaluated whether the same genes that determine VCDR and IOP also predict OAG.METHODS: Genetic risk scores were constructed from single nucleotide polymorphisms (SNPs) using genome wide association data of 9326 participants from the Rotterdam Study cohorts (mean ± SD age: 64.6 ± 9.1 years). These risk scores were used to calculate the explained variance of VCDR and IOP in an independent cohort (Erasmus Rucphen Family study) consisting of 1646 participants (mean ± SD age: 46.8 ± 14.1 years) and the OAG risk in a subset of the Rotterdam Study cohorts. To evaluate false positive findings, we generated two new variables containing randomly sampled values to serve as a negative control.RESULTS: The explained variance of VCDR increased when increasing the number of SNPs included in the risk score, suggesting a polygenic model. We found no clear evidence for a similar model for IOP, suggesting that a small number of SNPs determine the susceptibility to IOP. The SNPs related to IOP in terms of p values contributed little to VCDR. The risk scores associated with VCDR were also associated significantly with OAG. This suggests a common polygenic background for VCDR and OAG CONCLUSIONS: We found evidence for a polygenic model underlying one of the major traits of OAG, VCDR, and OAG itself. The IOP did not show any evidence for such a model.

KW - Adolescent

KW - Adult

KW - Age Distribution

KW - Aged

KW - Aged, 80 and over

KW - Cohort Studies

KW - Cross-Sectional Studies

KW - Female

KW - Genome-Wide Association Study

KW - Glaucoma, Open-Angle/genetics

KW - Humans

KW - Intraocular Pressure

KW - Male

KW - Middle Aged

KW - Phylogeny

KW - Polymorphism, Single Nucleotide

KW - Prospective Studies

KW - Risk Factors

KW - Sex Distribution

KW - Young Adult

U2 - 10.1136/jmg.2010.083337

DO - 10.1136/jmg.2010.083337

M3 - Article

C2 - 21059592

SN - 0022-2593

VL - 48

SP - 190

EP - 196

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

IS - 3

ER -

Genetic architecture of open angle glaucoma and related determinants

Abstract

Keywords

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