title: Clinical implications of old and new genes for open-angle glaucoma.
abstract: OBJECTIVE
  Genome-wide association studies have revealed new insights into the genetic determinants of open-angle glaucoma (OAG). This study was performed to determine to what extent variants within established genes (MYOC, OPTN, and WDR36) and newly identified common genetic variants (ATOH7, CDKN2B, and SIX1) contribute to the risk of OAG.
  
  
  METHODS
  Population-based setting, family-based setting, and a case-control study.
  
  
  METHODS
  The Rotterdam Study I cohort (N = 5312; mean age±standard deviation [SD], 68.0±8.4 years). Findings were replicated in the Genetic Research in Isolated Populations combined with the Erasmus Rucphen Family study (N = 1750; mean age±SD, 48.3±15.2 years), and a cohort from Southampton (N = 702; mean age±SD, 72.5±10.7 years).
  
  
  METHODS
  After identifying common variants associated with OAG within the established genes, the risk of OAG was analyzed using logistic regression. Discriminative accuracy was assessed by comparing the area under the receiver operator characteristic curve (AUC) for models, including the number of risk alleles, intraocular pressure, age, and gender, with the AUC for the same model but without the risk alleles.
  
  
  METHODS
  Odds ratios and AUCs of individual and combined risk alleles.
  
  
  RESULTS
  No consistent significant associations for the established genes (MYOC, OPTN, and WDR36) with OAG were found. However, when comparing the load of risk variants between cases and controls, 2 of 3 studies showed a significant increased risk of OAG for participants carrying more risk alleles of the 3 established genes. When combining all 6 genes, participants carrying a high number of risk alleles (highest tertile) had a 2.29-fold to 3.19-fold increase in risk of OAG compared with those carrying only a few risk alleles. The addition of the newly identified genes to IOP, age, and gender resulted in a higher AUC compared with the AUC without the newly identified genes (P = 0.027).
  
  
  CONCLUSIONS
  A significant contribution to the risk of OAG was found for the new common variants identified by recent genome-wide association studies, but not for variants within the established genes. Participants carrying a high number of risk alleles had an approximately 3-fold increase in the risk of OAG compared with those with a low number of risk alleles.
  
  
  BACKGROUND
  The author(s) have no proprietary or commercial interest in any materials discussed in this article.
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Wishal D
authors.initials: WD
authors.lastname: Ramdas
authors.forename: Leonieke M E
authors.initials: LM
authors.lastname: van Koolwijk
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Cree
authors.forename: A Cecile J W
authors.initials: AC
authors.lastname: Janssens
authors.forename: Najaf
authors.initials: N
authors.lastname: Amin
authors.forename: Paulus T V M
authors.initials: PT
authors.lastname: de Jong
authors.forename: Roger C W
authors.initials: RC
authors.lastname: Wolfs
authors.forename: Jane
authors.initials: J
authors.lastname: Gibson
authors.forename: James F
authors.initials: JF
authors.lastname: Kirwan
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.forename: Ben A
authors.initials: BA
authors.lastname: Oostra
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Sarah
authors.initials: S
authors.lastname: Ennis
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lotery
authors.forename: Hans G
authors.initials: HG
authors.lastname: Lemij
authors.forename: Caroline C W
authors.initials: CC
authors.lastname: Klaver
authors.forename: Johannes R
authors.initials: JR
authors.lastname: Vingerling
authors.forename: Nomdo M
authors.initials: NM
authors.lastname: Jansonius
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D019540:Area Under Curve; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D016022:Case-Control Studies; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D060005:Genotyping Techniques; D005902:Glaucoma, Open-Angle / Q000175:diagnosis / Q000235:genetics*; D006023:Glycoproteins / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007429:Intraocular Pressure / Q000235:genetics; D008297:Male; D026901:Membrane Transport Proteins; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012372:ROC Curve; D012307:Risk Factors; D035582:Transcription Factor TFIIIA / Q000235:genetics; D014792:Visual Acuity / Q000502:physiology; D000099179:Myocilin
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D003598:Cytoskeletal Proteins; D005136:Eye Proteins; D006023:Glycoproteins; D018398:Homeodomain Proteins; D026901:Membrane Transport Proteins; D035582:Transcription Factor TFIIIA; D000099179:Myocilin; C456975:ATOH7 protein, human; C493966:CDKN2B protein, human; C409460:OPTN protein, human; C099236:SIX1 protein, human; C502341:WDR36 protein, human