Population-based meta-analysis in Caucasians confirms association with COL5A1 and ZNF469 but not COL8A2 with central corneal thickness
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Central corneal thickness (CCT) has become an endophenotype of major interest for the genetically complex disorder glaucoma. CCT has a high heritability, and thin CCT is an independent risk factor for the diagnosis and progression of open-angle glaucoma. Genome-wide association studies thus provide genetic loci associated with CCT and potentially related to open-angle glaucoma. The distribution of CCT and prevalence of glaucoma in population-based studies have demonstrated ethnic differences suggesting ethnic-dependent variations in the genetic determinants of CCT. We conducted a genome-wide association study in Caucasians (n = 3,931) from the Gutenberg Health Study (Germany) followed by replication of 30 genome-wide significant SNPs or SNPs of interest (P < 10−5) in the Rotterdam Study (The Netherlands, n = 1,418). In a combined analysis, we confirmed quantitative trait loci on chromosomes 9q34 and 16q24 for association with CCT. On chromosome 16q24, the locus is located in an intergenic region near the ZNF469 gene (top SNP: rs9938149, P = 1.45 × 10−12). ZNF469 missense mutation is involved in a syndrome with very thin cornea (brittle cornea syndrome). The second locus on chromosome 9q34 represents the intergenic region between the RXRA and COL5A1 gene (top SNP: rs3132306, P = 2.71 × 10−10). Collagen type 5 determines the diameter of the corneal collagen fibrils. In our Caucasian population-based GWA study, we reinforce the involvement of collagen-related genes influencing CCT in Caucasians. We could not confirm the collagen type 8 locus on chromosome 1 as reported in Asian studies.
KeywordsGlaucoma Central Corneal Thickness Keratoconus Discovery Cohort ZNF469 Gene
We would like to acknowledge the following agencies and persons: The Gutenberg Health Study is funded through the government of Rheinland-Pfalz (“Stiftung Rheinland Pfalz für Innovation” [AZ961386261733]; the research programs “Wissen schafft Zukunft” and “Schwerpunkt Vaskuläre Prävention” of the Johannes Gutenberg-University of Mainz; Boehringer Ingelheim; PHILIPS Medical Systems; National Genome Network “NGFNplus” by the Federal Ministry of Education and Research, Germany [A301GS0833]. The Gutenberg Health Study thanks Dagmar Laubert-Reh for her assistance with the statistics and all technical assistants for sample processing and genotyping. The Rotterdam Study was supported by the Netherlands Organisation of Scientific Research (NWO) [Vidi 91796357]; Erasmus Medical Center and Erasmus University, Rotterdam, The Netherlands; Netherlands Organization for Health Research and Development (ZonMw); UitZicht; the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission (DG XII); the Municipality of Rotterdam; the Netherlands Genomics Initiative/NWO; Center for Medical Systems Biology of NGI; Lijf en Leven; M.D. Fonds; Henkes Stichting; Stichting Nederlands Oogheelkundig Onderzoek; Swart van Essen; Bevordering van Volkskracht; Blindenhulp; Landelijke Stichting voor Blinden en Slechtzienden; Rotterdamse Vereniging voor Blindenbelangen; OOG; Algemene Nederlandse Vereniging ter Voorkoming van Blindheid; the Rotterdam Eye Hospital Research Foundation; Laméris Ootech; Topcon Europe; and Heidelberg Engineering. The Rotterdam Study thanks Johannes R. Vingerling, Fernando Rivadeneira, Albert Hofman, Paulus T.V.M. de Jong, Ada Hooghart, Corina Brussee, Riet Bernaerts-Biskop, Patricia van Hilten, Pascal Arp, Jeanette Vergeer, Marijn Verkerk and Sander Bervoets.
The experiments comply with the current laws in which they were performed.
Conflicts of interest
The authors declare that they have no conflict of interest.
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