title: Copy number variation at chromosome 5q21.2 is associated with intraocular pressure.
abstract: OBJECTIVE
  Glaucoma is a major cause of blindness in the world. Recent genome-wide association studies (GWAS) have identified common genetic variants for glaucoma, but still a significant heritability gap remains. We hypothesized that copy number variants (CNVs) might influence part of the susceptibility to glaucoma or its related quantitative endophenotypes.
  
  
  METHODS
  THIS STUDY EXAMINED THE ASSOCIATION BETWEEN CNVS AND INTRAOCULAR PRESSURE (IOP), THE MAJOR MODIFIABLE RISK FACTOR FOR PRIMARY OPEN-ANGLE GLAUCOMA (POAG), IN THREE POPULATION PANELS OF EUROPEAN ANCESTRY: the TwinsUK cohort (n = 1047), the Australian Twin Eye Study (n = 561), and the Wellcome Trust Case-Control Consortium 2 (WTCCC2)/Blue Mountains Eye Study (BMES) (n = 1660). We also used PCR-based assays to investigate a locus of interest that we found associated with IOP in a POAG case-control panel of European ancestry from London, United Kingdom.
  
  
  RESULTS
  WE IDENTIFIED ASSOCIATIONS BETWEEN IOP AND TWO CNV REGIONS IN THE TWINSUK COHORT: 5q21.2 (P = 0.003) overlapping the gene RAB9BP1 and 12p13.3 (P = 0.03) overlapping the genes SLC2A14 and SLC2A3. The Australian Twin Eye Study and BMES both replicated the 5q21.2 CNV association and direction of effect (P = 0.001 and P = 0.02, respectively). A meta-analysis across all the cohorts showed that presence of a copy number change at this locus increased IOP by 1.56 mm Hg (P = 1.24 × 10(-6)). In the case-control study, the 5q21.2 CNV locus did not show association with high-pressure (≥21 mm Hg) POAG cases.
  
  
  CONCLUSIONS
  The 5q21.2 CNV locus could represent a novel locus controlling IOP. Interestingly, this IOP locus is located in close vicinity to the previously widely replicated GLC1G linkage locus for glaucoma, for which subsequent studies have not reached consensus on the causal gene.
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.forename: Cristina
authors.initials: C
authors.lastname: Venturini
authors.forename: Pirro G
authors.initials: PG
authors.lastname: Hysi
authors.forename: Matthew
authors.initials: M
authors.lastname: Arno
authors.forename: Estibaliz
authors.initials: E
authors.lastname: Aldecoa-Otalora Astarloa
authors.forename: Stuart
authors.initials: S
authors.lastname: Macgregor
authors.forename: Alex W
authors.initials: AW
authors.lastname: Hewitt
authors.forename: Terri L
authors.initials: TL
authors.lastname: Young
authors.forename: Paul
authors.initials: P
authors.lastname: Mitchell
authors.forename: Ananth C
authors.initials: AC
authors.lastname: Viswanathan
authors.forename: David A
authors.initials: DA
authors.lastname: Mackey
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Hammond
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002895:Chromosomes, Human, Pair 5; D056915:DNA Copy Number Variations; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics; D055106:Genome-Wide Association Study; D005901:Glaucoma / Q000208:ethnology / Q000235:genetics*; D006801:Humans; D007429:Intraocular Pressure / Q000235:genetics*; D008297:Male; D008505:Medical Staff, Hospital; D008875:Middle Aged; D012307:Risk Factors; D044465:White People / Q000235:genetics / Q000706:statistics & numerical data; D055815:Young Adult
keywords: 5q21.2; copy number variation; intraocular pressure