J Willem L Tideman1,2, Olavi Pärssinen3,4, Annechien E G Haarman1,2, Anthony P Khawaja5, Juho Wedenoja6,7, Katie M Williams8,9, Ginevra Biino10, Xiaohu Ding11, Mika Kähönen12,13, Terho Lehtimäki12,14,15, Olli T Raitakari16,17,18, Ching-Yu Cheng19,20, Jost B Jonas21,22, Terri L Young23, Joan E Bailey-Wilson24, Jugnoo Rahi25, Cathy Williams26, Mingguang He11,27, David A Mackey28, Jeremy A Guggenheim29. 1. Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands. 2. Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands. 3. Gerontology Research Center and Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland. 4. Department of Ophthalmology, Central Hospital of Central Finland, Jyväskylä, Finland. 5. NIHR Biomedical Research Centre, Moorfields Eye Hospital National Health Service (NHS) Foundation Trust and UCL Institute of Ophthalmology, London, United Kingdom. 6. Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. 7. Department of Public Health, University of Helsinki, Helsinki, Finland. 8. Section of Academic Ophthalmology, Faculty of Life Sciences and Medicine, King's College London School of Life Course Sciences, London, United Kingdom. 9. Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom. 10. Institute of Molecular Genetics, National Research Council of Italy, Pavia, Italy. 11. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China. 12. Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland. 13. Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland. 14. Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland. 15. Department of Clinical Chemistry, Finnish Cardiovascular Research Center, Tampere, Finland. 16. Centre for Population Health Research, University of Turku and Turku University Hospital, Finland. 17. Research Centre of Applied and Preventive Medicine, University of Turku, Turku, Finland. 18. Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland. 19. Duke-NUS Medical School, Singapore, Singapore. 20. Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore. 21. Department of Ophthalmology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. 22. Beijing Institute of Ophthalmology, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China. 23. Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison. 24. Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland. 25. UCL Great Ormond Street Institute of Child Health and Institute of Ophthalmology, University College London, London, United Kingdom. 26. Centre for Academic Child Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom. 27. Centre for Eye Research Australia; Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, Victoria, Australia. 28. Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Western Australia, Australia. 29. Cardiff University School of Optometry and Vision Sciences, Cardiff, United Kingdom.
Abstract
IMPORTANCE: Uncertainty currently exists about whether the same genetic variants are associated with susceptibility to low myopia (LM) and high myopia (HM) and to myopia and hyperopia. Addressing this question is fundamental to understanding the genetics of refractive error and has clinical relevance for genotype-based prediction of children at risk for HM and for identification of new therapeutic targets. OBJECTIVE: To assess whether a common set of genetic variants are associated with susceptibility to HM, LM, and hyperopia. DESIGN, SETTING, AND PARTICIPANTS: This genetic association study assessed unrelated UK Biobank participants 40 to 69 years of age of European and Asian ancestry. Participants 40 to 69 years of age living in the United Kingdom were recruited from January 1, 2006, to October 31, 2010. Of the total sample of 502 682 participants, 117 279 (23.3%) underwent an ophthalmic assessment. Data analysis was performed from December 12, 2019, to June 23, 2020. EXPOSURES: Four refractive error groups were defined: HM, -6.00 diopters (D) or less; LM, -3.00 to -1.00 D; hyperopia, +2.00 D or greater; and emmetropia, 0.00 to +1.00 D. Four genome-wide association study (GWAS) analyses were performed in participants of European ancestry: (1) HM vs emmetropia, (2) LM vs emmetropia, (3) hyperopia vs emmetropia, and (4) LM vs hyperopia. Polygenic risk scores were generated from GWAS summary statistics, yielding 4 sets of polygenic risk scores. Performance was assessed in independent replication samples of European and Asian ancestry. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) of polygenic risk scores in replication samples. RESULTS: A total of 51 841 unrelated individuals of European ancestry and 2165 unrelated individuals of Asian ancestry were assigned to a specific refractive error group and included in our analyses. Polygenic risk scores derived from all 4 GWAS analyses were predictive of all categories of refractive error in both European and Asian replication samples. For example, the polygenic risk score derived from the HM vs emmetropia GWAS was predictive in the European sample of HM vs emmetropia (OR, 1.58; 95% CI, 1.41-1.77; P = 1.54 × 10-15) as well as LM vs emmetropia (OR, 1.15; 95% CI, 1.07-1.23; P = 8.14 × 10-5), hyperopia vs emmetropia (OR, 0.83; 95% CI, 0.77-0.89; P = 4.18 × 10-7), and LM vs hyperopia (OR, 1.45; 95% CI, 1.33-1.59; P = 1.43 × 10-16). CONCLUSIONS AND RELEVANCE: Genetic risk variants were shared across HM, LM, and hyperopia and across European and Asian samples. Individuals with HM inherited a higher number of variants from among the same set of myopia-predisposing alleles and not different risk alleles compared with individuals with LM. These findings suggest that treatment interventions targeting common genetic risk variants associated with refractive error could be effective against both LM and HM.
IMPORTANCE: Uncertainty currently exists about whether the same genetic variants are associated with susceptibility to low myopia (LM) and high myopia (HM) and to myopia and hyperopia. Addressing this question is fundamental to understanding the genetics of refractive error and has clinical relevance for genotype-based prediction of children at risk for HM and for identification of new therapeutic targets. OBJECTIVE: To assess whether a common set of genetic variants are associated with susceptibility to HM, LM, and hyperopia. DESIGN, SETTING, AND PARTICIPANTS: This genetic association study assessed unrelated UK Biobank participants 40 to 69 years of age of European and Asian ancestry. Participants 40 to 69 years of age living in the United Kingdom were recruited from January 1, 2006, to October 31, 2010. Of the total sample of 502 682 participants, 117 279 (23.3%) underwent an ophthalmic assessment. Data analysis was performed from December 12, 2019, to June 23, 2020. EXPOSURES: Four refractive error groups were defined: HM, -6.00 diopters (D) or less; LM, -3.00 to -1.00 D; hyperopia, +2.00 D or greater; and emmetropia, 0.00 to +1.00 D. Four genome-wide association study (GWAS) analyses were performed in participants of European ancestry: (1) HM vs emmetropia, (2) LM vs emmetropia, (3) hyperopia vs emmetropia, and (4) LM vs hyperopia. Polygenic risk scores were generated from GWAS summary statistics, yielding 4 sets of polygenic risk scores. Performance was assessed in independent replication samples of European and Asian ancestry. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) of polygenic risk scores in replication samples. RESULTS: A total of 51 841 unrelated individuals of European ancestry and 2165 unrelated individuals of Asian ancestry were assigned to a specific refractive error group and included in our analyses. Polygenic risk scores derived from all 4 GWAS analyses were predictive of all categories of refractive error in both European and Asian replication samples. For example, the polygenic risk score derived from the HM vs emmetropia GWAS was predictive in the European sample of HM vs emmetropia (OR, 1.58; 95% CI, 1.41-1.77; P = 1.54 × 10-15) as well as LM vs emmetropia (OR, 1.15; 95% CI, 1.07-1.23; P = 8.14 × 10-5), hyperopia vs emmetropia (OR, 0.83; 95% CI, 0.77-0.89; P = 4.18 × 10-7), and LM vs hyperopia (OR, 1.45; 95% CI, 1.33-1.59; P = 1.43 × 10-16). CONCLUSIONS AND RELEVANCE: Genetic risk variants were shared across HM, LM, and hyperopia and across European and Asian samples. Individuals with HM inherited a higher number of variants from among the same set of myopia-predisposing alleles and not different risk alleles compared with individuals with LM. These findings suggest that treatment interventions targeting common genetic risk variants associated with refractive error could be effective against both LM and HM.
Authors: Jeremy A Guggenheim; Rosie Clark; Jiangtian Cui; Louise Terry; Karina Patasova; Annechien E G Haarman; Anthony M Musolf; Virginie J M Verhoeven; Caroline C W Klaver; Joan E Bailey-Wilson; Pirro G Hysi; Cathy Williams Journal: Hum Mol Genet Date: 2022-06-04 Impact factor: 5.121