title: Common genetic variants associated with open-angle glaucoma.
abstract: Open-angle glaucoma (glaucoma) is a major eye disorder characterized by optic disc pathology. Recent genome-wide association studies identified new loci associated with clinically relevant optic disc parameters, such as the optic disc area and vertical cup-disc ratio (VCDR). We examined to what extent these loci are involved in glaucoma. The loci studied include ATOH7, CDC7/TGFBR3 and SALL1 for optic disc area, and CDKN2B, SIX1, SCYL1/LTBP3, CHEK2, ATOH7 and DCLK1 for VCDR. We performed a meta-analysis using data from six independent studies including: the Rotterdam Study (n= 5736), Genetic Research in Isolated Populations combined with Erasmus Rucphen Family study (n= 1750), Amsterdam Glaucoma Study (n= 296) and cohorts from Erlangen and Tübingen (n= 1363), Southampton (n= 702) and deCODE (n= 36 151) resulting in a total of 3161 glaucoma cases and 42 837 controls. Of the eight loci, we found significant evidence (P= 1.41 × 10(-8)) for the association of CDKN2B with glaucoma [odds ratio (OR) for those homozygous for the risk allele: 0.76; 95% confidence interval (CI): 0.70-0.84], for the role of ATOH7 (OR: 1.28; 95% CI: 1.12-1.47) and for SIX1 (OR: 1.20; 95% CI: 1.10-1.31) when adjusting for the number of tested loci. Furthermore, there was a borderline significant association of CDC7/TGFBR3 and SALL1 (both P= 0.04) with glaucoma. In conclusion, we found consistent evidence for three common variants (CDKN2B, ATOH7 and SIX1) significantly associated with glaucoma. These findings may shed new light on the pathophysiological protein pathways leading to glaucoma, and point to pathways involved in the growth and development of the optic nerve.
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: Hans G
authors.initials: HG
authors.lastname: Lemij
authors.forename: Francesca
authors.initials: F
authors.lastname: Pasutto
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Cree
authors.forename: Gudmar
authors.initials: G
authors.lastname: Thorleifsson
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Janssen
authors.forename: Ten Brink
authors.initials: TB
authors.lastname: Jacoline
authors.forename: Najaf
authors.initials: N
authors.lastname: Amin
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.forename: Roger C W
authors.initials: RC
authors.lastname: Wolfs
authors.forename: G Bragi
authors.initials: GB
authors.lastname: Walters
authors.forename: Fridbert
authors.initials: F
authors.lastname: Jonasson
authors.forename: Nicole
authors.initials: N
authors.lastname: Weisschuh
authors.forename: Christian Y
authors.initials: CY
authors.lastname: Mardin
authors.forename: Jane
authors.initials: J
authors.lastname: Gibson
authors.forename: Richard H C
authors.initials: RH
authors.lastname: Zegers
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Paulus T V M
authors.initials: PT
authors.lastname: de Jong
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Ben A
authors.initials: BA
authors.lastname: Oostra
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.forename: Eugen
authors.initials: E
authors.lastname: Gramer
authors.forename: Ulrich C
authors.initials: UC
authors.lastname: Welgen-Lüssen
authors.forename: James F
authors.initials: JF
authors.lastname: Kirwan
authors.forename: Arthur A B
authors.initials: AA
authors.lastname: Bergen
authors.forename: André
authors.initials: A
authors.lastname: Reis
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lotery
authors.forename: Johannes R
authors.initials: JR
authors.lastname: Vingerling
authors.forename: Nomdo M
authors.initials: NM
authors.lastname: Jansonius
authors.forename: Caroline C W
authors.initials: CC
authors.lastname: Klaver
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D015331:Cohort Studies; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005902:Glaucoma, Open-Angle / Q000235:genetics* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D016015:Logistic Models; D016017:Odds Ratio; D009898:Optic Disk / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D018398:Homeodomain Proteins; C456975:ATOH7 protein, human; C493966:CDKN2B protein, human; C099236:SIX1 protein, human