title: Evaluation of the Myocilin Mutation Gln368Stop Demonstrates Reduced Penetrance for Glaucoma in European Populations.
abstract: Sequence variations in the myocilin (MYOC) gene account for approximately 2% to 4% of glaucoma cases. One particular MYOC mutation, Gln368Stop (dbSNP accession number: rs74315329), is the most common genetic mutation causing glaucoma by increasing intraocular pressure (IOP). The objective of this study was to evaluate the effect of this MYOC mutation on IOP using data from large-scale European population panels (directly sequenced and imputation based).
  
  
  
  Cross-sectional, cohort study.
  
  
  
  For this study, the penetrance of the variant rs74315329 was estimated in 2 population-based cohorts, the TwinsUK (N = 6092) and the Rotterdam Study (RS) (N =11 189).
  
  
  
  Carriers of the risk allele for rs74315329 were identified using whole-genome sequencing and imputation data (based on 1000 Genomes Project and Haplotype Reference Consortium panels). The penetrance of this variant was evaluated using IOP measurements and data on visual field testing/a diagnosis of glaucoma (if available).
  
  
  
  The penetrance of the variant rs74315329 was estimated from the percentage of the carriers of the risk allele of the variant who had high IOP (ocular hypertension) or glaucoma.
  
  
  
  In our study, the observed penetrance of the variant rs74315329 in relation to increased IOP was 12.5% and 19.4% in the TwinsUK and the RS, respectively. Thus, our study suggests a much lower penetrance for rs74315329 for ocular hypertension (and thus glaucoma), in comparison with that reported previously.
  
  
  
  The significance of this finding is that higher numbers of healthy individuals in the population are expected to be carriers of this mutation, which in turn reduces the utility of identifying carriers of this mutation as a screening tool for glaucoma.
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, St. Thomas' Hospital, London, United Kingdom.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Nag
authors.affiliation: King's Genomics Facilities, King's College London, London, United Kingdom.
authors.forename: Han
authors.initials: H
authors.lastname: Lu
authors.affiliation: King's Genomics Facilities, King's College London, London, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Arno
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Adriana I
authors.initials: AI
authors.lastname: Iglesias
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Pieter
authors.initials: P
authors.lastname: Bonnemaijer
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Linda
authors.initials: L
authors.lastname: Broer
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands; Netherlands Consortium for Healthy Ageing, Netherlands Genomic Initiative, the Hague, The Netherlands.
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Caroline C W
authors.initials: CC
authors.lastname: Klaver
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Cornelia
authors.initials: C
authors.lastname: van Duijn
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, St. Thomas' Hospital, London, United Kingdom; Department of Ophthalmology, King's College London, London, United Kingdom.
authors.forename: Pirro G
authors.initials: PG
authors.lastname: Hysi
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, St. Thomas' Hospital, London, United Kingdom; Department of Ophthalmology, King's College London, London, United Kingdom. Electronic address: chris.hammond@kcl.ac.uk.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Hammond
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D018388:Codon, Terminator / Q000235:genetics*; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D005902:Glaucoma, Open-Angle / Q000175:diagnosis / Q000235:genetics*; D006023:Glycoproteins / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007429:Intraocular Pressure; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009798:Ocular Hypertension / Q000175:diagnosis / Q000235:genetics; D019683:Penetrance; D044465:White People / Q000235:genetics*; D000099179:Myocilin
chemical_list: D018388:Codon, Terminator; D003598:Cytoskeletal Proteins; D005136:Eye Proteins; D006023:Glycoproteins; D000099179:Myocilin