Gabriel Cuellar-Partida1,2, Katie M Williams3,4, Seyhan Yazar5, Jeremy A Guggenheim6, Alex W Hewitt7, Cathy Williams8, Jie Jin Wang9, Pik-Fang Kho10, Seang Mei Saw11,12,13, Ching-Yu Cheng11,12,13, Tien Yin Wong11,12,13, Tin Aung11,12,13, Terri L Young14, J Willem L Tideman15, Jost B Jonas16,17, Paul Mitchell9, Robert Wojciechowski18, Dwight Stambolian19, Pirro Hysi4, Christopher J Hammond3,4, David A Mackey5, Robyn M Lucas20, Stuart MacGregor1. 1. Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. 2. University of Queensland Diamantina Institute, Translational Research Institute, University of Queensland, Brisbane, Queensland, Australia. 3. Department of Ophthalmology. 4. Department of Ophthalmology and Twin Research, King's College London, London, UK. 5. Lions Eye Institute, University of Western Australia, Perth, WA, Australia. 6. School of Optometry & Vision Sciences, Cardiff University, Cardiff, UK. 7. Menzies Research Institute Tasmania, University of Tasmania, Hobart, Australia. 8. School of Social and Community Medicine, University of Bristol, Bristol, UK. 9. Centre for Vision Research, Department of Ophthalmology and Westmead Institute for Medical Research, University of Sydney, Camperdown, NSW, Australia. 10. Department of Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, QLD,Australia. 11. Singapore Eye Research Institute, Singapore National Eye Centre, Singapore. 12. Ophthalmology and Visual Sciences Academic Clinical Programme, Duke-NUS Graduate Medical School. 13. Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. 14. Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI, USA. 15. Department of Ophthalmology and Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. 16. Beijing Institute of Ophthalmology, Capital University of Medical Science, Beijing Ophthalmology & Visual Sciences Key Laboratory, Beijing, China. 17. Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University Heidelberg, Seegartenklinik Heidelberg, Germany. 18. Wilmer Eye Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA. 19. Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA, USA. 20. National Centre for Epidemiology and Population Health, Research School of Population Health, The Australian National University, Canberra, Australia.
Abstract
Background: Myopia prevalence has increased in the past 20 years, with many studies linking the increase to reduced time spent outdoors. A number of recent observational studies have shown an inverse association between vitamin D [25(OH)D] serum levels and myopia. However, in such studies it is difficult to separate the effects of time outdoors and vitamin D levels. In this work we use Mendelian randomization (MR) to assess if genetically determined 25(OH)D levels contribute to the degree of myopia. Methods: We performed MR using results from a meta-analysis of refractive error (RE) genome-wide association study (GWAS) that included 37 382 and 8 376 adult participants of European and Asian ancestry, respectively, published by the Consortium for Refractive Error And Myopia (CREAM). We used single nucleotide polymorphisms (SNPs) in the DHCR7, CYP2R1, GC and CYP24A1 genes with known effects on 25(OH)D concentration as instrumental variables (IV). We estimated the effect of 25(OH)D on myopia level using a Wald-type ratio estimator based on the effect estimates from the CREAM GWAS. Results: Using the combined effect attributed to the four SNPs, the estimate for the effect of 25(OH)D on refractive error was -0.02 [95% confidence interval (CI) -0.09, 0.04] dioptres (D) per 10 nmol/l increase in 25(OH)D concentration in Caucasians and 0.01 (95% CI -0.17, 0.19) D per 10 nmol/l increase in Asians. Conclusions: The tight confidence intervals on our estimates suggest the true contribution of vitamin D levels to degree of myopia is very small and indistinguishable from zero. Previous findings from observational studies linking vitamin D levels to myopia were likely attributable to the effects of confounding by time spent outdoors.
Background: Myopia prevalence has increased in the past 20 years, with many studies linking the increase to reduced time spent outdoors. A number of recent observational studies have shown an inverse association between vitamin D [25(OH)D] serum levels and myopia. However, in such studies it is difficult to separate the effects of time outdoors and vitamin D levels. In this work we use Mendelian randomization (MR) to assess if genetically determined 25(OH)D levels contribute to the degree of myopia. Methods: We performed MR using results from a meta-analysis of refractive error (RE) genome-wide association study (GWAS) that included 37 382 and 8 376 adult participants of European and Asian ancestry, respectively, published by the Consortium for Refractive Error And Myopia (CREAM). We used single nucleotide polymorphisms (SNPs) in the DHCR7, CYP2R1, GC and CYP24A1 genes with known effects on 25(OH)D concentration as instrumental variables (IV). We estimated the effect of 25(OH)D on myopia level using a Wald-type ratio estimator based on the effect estimates from the CREAM GWAS. Results: Using the combined effect attributed to the four SNPs, the estimate for the effect of 25(OH)D on refractive error was -0.02 [95% confidence interval (CI) -0.09, 0.04] dioptres (D) per 10 nmol/l increase in 25(OH)D concentration in Caucasians and 0.01 (95% CI -0.17, 0.19) D per 10 nmol/l increase in Asians. Conclusions: The tight confidence intervals on our estimates suggest the true contribution of vitamin D levels to degree of myopia is very small and indistinguishable from zero. Previous findings from observational studies linking vitamin D levels to myopia were likely attributable to the effects of confounding by time spent outdoors.
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