title: Genetic variants associated with optic nerve vertical cup-to-disc ratio are risk factors for primary open angle glaucoma in a US Caucasian population.
abstract: OBJECTIVE
  Genetically complex disorders, such as primary open angle glaucoma (POAG), may include highly heritable quantitative traits as part of the overall phenotype, and mapping genes influencing the related quantitative traits may effectively identify genetic risk factors predisposing to the complex disease. Recent studies have identified SNPs associated with optic nerve area and vertical cup-to-disc ratio (VCDR). The purpose of this study was to evaluate the association between these SNPs and POAG in a US Caucasian case-control sample.
  
  
  METHODS
  Five SNPs previously associated with optic disc area, or VCDR, were genotyped in 539 POAG cases and 336 controls. Genotype data were analyzed for single SNP associations and SNP interactions with VCDR and POAG.
  
  
  RESULTS
  SNPs associated with VCDR rs1063192 (CDKN2B) and rs10483727 (SIX1/SIX6) were also associated with POAG (P = 0.0006 and P = 0.0043 for rs1063192 and rs10483727, respectively). rs1063192, associated with smaller VCDR, had a protective effect (odds ratio [OR] = 0.73; 95% confidence interval [CI], 0.58-0.90), whereas rs10483727, associated with larger VCDR, increased POAG risk (OR = 1.33; 95% CI, 1.08-1.65). POAG risk associated with increased VCDR was significantly influenced by the C allele of rs1900004 (ATOH7), associated with increased optic nerve area (P-interaction = 0.025; OR = 1.89; 95% CI, 1.22-2.94).
  
  
  CONCLUSIONS
  Genetic variants influencing VCDR are associated with POAG in a US Caucasian population. Variants associated with optic nerve area are not independently associated with disease but can influence the effects of VCDR variants suggesting that increased optic disc area can significantly contribute to POAG risk when coupled with risk factors controlling VCDR.
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA.
authors.forename: Bao Jian
authors.initials: BJ
authors.lastname: Fan
authors.forename: Dan Yi
authors.initials: DY
authors.lastname: Wang
authors.forename: Louis R
authors.initials: LR
authors.lastname: Pasquale
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.forename: Janey L
authors.initials: JL
authors.lastname: Wiggs
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D005260:Female; D005838:Genotype; D005902:Glaucoma, Open-Angle / Q000175:diagnosis / Q000235:genetics*; D018398:Homeodomain Proteins; D006801:Humans; D008297:Male; D008875:Middle Aged; D009898:Optic Disk / Q000473:pathology*; D009901:Optic Nerve Diseases / Q000175:diagnosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics; D012307:Risk Factors; D015534:Trans-Activators; D014481:United States; D044465:White People / Q000235:genetics*
chemical_list: C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D018398:Homeodomain Proteins; C099236:SIX1 protein, human; C491945:SIX6 protein, human; D015534:Trans-Activators