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Genetic architecture of open angle glaucoma and related determinants
  1. Wishal D Ramdas1,2,
  2. Najaf Amin1,
  3. Leonieke M E van Koolwijk1,3,
  4. A Cecile J W Janssens1,
  5. Ayse Demirkan1,
  6. Paulus T V M de Jong4,5,
  7. Yurii S Aulchenko1,
  8. Roger C W Wolfs1,2,
  9. Albert Hofman1,
  10. Fernando Rivadeneira1,6,
  11. Andre G Uitterlinden1,6,7,
  12. Ben A Oostra7,
  13. Hans G Lemij3,
  14. Caroline C W Klaver1,2,
  15. Johannes R Vingerling1,2,
  16. Nomdo M Jansonius1,8,
  17. Cornelia M van Duijn1
  1. 1Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands
  2. 2Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands
  3. 3Glaucoma service, The Rotterdam Eye Hospital, Rotterdam, the Netherlands
  4. 4Department of Ophthalmogenetics, The Netherlands Institute for Neuroscience, RNAAS, Amsterdam, the Netherlands
  5. 5Department of Ophthalmology, Academic Medical Center, Amsterdam, the Netherlands
  6. 6Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands
  7. 7Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands
  8. 8Department of Ophthalmology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
  1. Correspondence to Professor Johannes R Vingerling, Department Ophthalmology and Epidemiology, Erasmus Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands; j.vingerling{at}


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.

  • Genetics
  • vertical cup-disc ratio
  • intraocular pressure
  • open angle glaucoma
  • polygenomic
  • genetic epidemiology
  • ophthalmology
  • glaucoma
  • epidemiology

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  • Funding The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The generation and management of genome-wide association studies (GWAS) genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO)/Netherlands Consortium for Healthy Ageing (NCHA) project nr. 050-060-810. The genetic study in the Erasmus Rucphen (ERF) Study was supported by the Center for Medical Systems Biology (CMSB) of NGI. The ophthalmic part of the Rotterdam Study and ERF are supported by the Netherlands Organization for Health Research and Development (ZonMw) grant 2200.0035; Lijf en Leven, Krimpen a/d Lek; MD Fonds, Utrecht. Oogfonds Nederland, Utrecht; Stichting Nederlands Oogheelkundig Onderzoek, Nijmegen/Rotterdam; Swart van Essen, Rotterdam; Netherlands Organisation for Scientific Research (NWO); Bevordering van Volkskracht, Rotterdam; Blindenhulp, The Hague; Landelijke Stichting voor Blinden en Slechtzienden (LSBS), Utrecht; Rotterdamse Vereniging voor Blindenbelangen, Rotterdam; OOG, The Hague; Algemene Nederlandse Vereniging ter Voorkoming van Blindheid (ANVVB), Doorn; The Rotterdam Eye Hospital Research Foundation (Stichting Wetenschappelijk Onderzoek Het Oogziekenhuis [SWOO] Prof. Dr. HJ Flieringa, Rotterdam); Laméris Ootech BV, Nieuwegein; Topcon Europe BV, Capelle aan de IJssel, all in the Netherlands, and Heidelberg Engineering, Dossenheim, Germany. The sponsors or funding organisations had no role in the design, conduct, analysis or publication of this research.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the Medical Ethics Committee of the Erasmus University.

  • Provenance and peer review Not commissioned; externally peer reviewed.