title: WNT10A exonic variant increases the risk of keratoconus by decreasing corneal thickness.
abstract: Keratoconus is a degenerative eye condition which results from thinning of the cornea and causes vision distortion. Treatments such as ultraviolet (UV) cross-linking have proved effective for management of keratoconus when performed in early stages of the disease. The central corneal thickness (CCT) is a highly heritable endophenotype of keratoconus, and it is estimated that up to 95% of its phenotypic variance is due to genetics. Genome-wide association efforts of CCT have identified common variants (i.e. minor allele frequency (MAF) >5%). However, these studies typically ignore the large set of exonic variants whose MAF is usually low. In this study, we performed a CCT exome-wide association analysis in a sample of 1029 individuals from a population-based study in Western Australia. We identified a genome-wide significant exonic variant rs121908120 (P = 6.63 × 10(-10)) in WNT10A. This gene is 437 kb from a gene previously associated with CCT (USP37). We showed in a conditional analysis that the WNT10A variant completely accounts for the signal previously seen at USP37. We replicated our finding in independent samples from the Brisbane Adolescent Twin Study, Twin Eye Study in Tasmania and the Rotterdam Study. Further, we genotyped rs121908120 in 621 keratoconus cases and compared the frequency to a sample of 1680 unscreened controls from the Queensland Twin Registry. We found that rs121908120 increases the risk of keratoconus two times (odds ratio 2.03, P = 5.41 × 10(-5)).
authors.affiliation: Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Cuellar-Partida
authors.affiliation: Department of Ophthalmology, Department of Epidemiology.
authors.forename: Henriët
authors.initials: H
authors.lastname: Springelkamp
authors.affiliation: Menzies Institute for Medical Research.
authors.forename: Sionne E M
authors.initials: SE
authors.lastname: Lucas
authors.affiliation: Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia.
authors.forename: Seyhan
authors.initials: S
authors.lastname: Yazar
authors.affiliation: School of Medicine, Menzies Research Institute Tasmania, University of Tasmania, Hobart, Australia, Centre for Eye Research Australia, Melbourne University, Melbourne, Australia.
authors.forename: Alex W
authors.initials: AW
authors.lastname: Hewitt
authors.affiliation: Department of Ophthalmology, Department of Epidemiology.
authors.forename: Adriana I
authors.initials: AI
authors.lastname: Iglesias
authors.affiliation: Molecular Epidemiology.
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.affiliation: Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Australia and.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.affiliation: School of Women's and Infants' Health, University of Western Australia, Perth, Australia.
authors.forename: Craig E
authors.initials: CE
authors.lastname: Pennell
authors.affiliation: Department of Epidemiology.
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: van Leeuwen
authors.affiliation: Department of Ophthalmology, Department of Epidemiology.
authors.forename: Virginie J M
authors.initials: VJ
authors.lastname: Verhoeven
authors.affiliation: Department of Epidemiology, Netherlands Consortium for Healthy Ageing, Netherlands Genomics Initiative, the Hague 2593 CE, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Department of Epidemiology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands, Netherlands Consortium for Healthy Ageing, Netherlands Genomics Initiative, the Hague 2593 CE, The Netherlands.
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Department of Ophthalmology.
authors.forename: Wishal D
authors.initials: WD
authors.lastname: Ramdas
authors.affiliation: Department of Ophthalmology.
authors.forename: Roger C W
authors.initials: RC
authors.lastname: Wolfs
authors.affiliation: Department of Ophthalmology, Department of Epidemiology.
authors.forename: Johannes R
authors.initials: JR
authors.lastname: Vingerling
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Australia.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brown
authors.affiliation: Department of Ophthalmology, Flinders University, Adelaide, SA, Australia.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Mills
authors.affiliation: Department of Ophthalmology, Flinders University, Adelaide, SA, Australia.
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Craig
authors.affiliation: Department of Ophthalmology, Department of Epidemiology.
authors.forename: Caroline C W
authors.initials: CC
authors.lastname: Klaver
authors.affiliation: Department of Epidemiology.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.affiliation: Menzies Institute for Medical Research.
authors.forename: Kathryn P
authors.initials: KP
authors.lastname: Burdon
authors.affiliation: Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia, stuart.macgregor@qimrberghofer.edu.au.
authors.forename: Stuart
authors.initials: S
authors.lastname: MacGregor
authors.affiliation: Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Mackey
mesh_terms: D000328:Adult; D000368:Aged; D001315:Australia / Q000453:epidemiology; D003315:Cornea / Q000378:metabolism* / Q000473:pathology*; D005091:Exons; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007640:Keratoconus / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D051153:Wnt Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: C484142:WNT10A protein, human; D051153:Wnt Proteins