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Original Investigation
April 8, 2021

Evaluation of Shared Genetic Susceptibility to High and Low Myopia and Hyperopia

Author Affiliations
  • 1Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands
  • 2Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands
  • 3Gerontology Research Center and Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland
  • 4Department of Ophthalmology, Central Hospital of Central Finland, Jyväskylä, Finland
  • 5NIHR Biomedical Research Centre, Moorfields Eye Hospital National Health Service (NHS) Foundation Trust and UCL Institute of Ophthalmology, London, United Kingdom
  • 6Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
  • 7Department of Public Health, University of Helsinki, Helsinki, Finland
  • 8Section of Academic Ophthalmology, Faculty of Life Sciences and Medicine, King’s College London School of Life Course Sciences, London, United Kingdom
  • 9Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom
  • 10Institute of Molecular Genetics, National Research Council of Italy, Pavia, Italy
  • 11State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
  • 12Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
  • 13Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland
  • 14Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland
  • 15Department of Clinical Chemistry, Finnish Cardiovascular Research Center, Tampere, Finland
  • 16Centre for Population Health Research, University of Turku and Turku University Hospital, Finland
  • 17Research Centre of Applied and Preventive Medicine, University of Turku, Turku, Finland
  • 18Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
  • 19Duke-NUS Medical School, Singapore, Singapore
  • 20Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore
  • 21Department of Ophthalmology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
  • 22Beijing Institute of Ophthalmology, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China
  • 23Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison
  • 24Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland
  • 25UCL Great Ormond Street Institute of Child Health and Institute of Ophthalmology, University College London, London, United Kingdom
  • 26Centre for Academic Child Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
  • 27Centre for Eye Research Australia; Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, Victoria, Australia
  • 28Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Western Australia, Australia
  • 29Cardiff University School of Optometry and Vision Sciences, Cardiff, United Kingdom
JAMA Ophthalmol. 2021;139(6):601-609. doi:10.1001/jamaophthalmol.2021.0497
Key Points

Question  Is susceptibility to high and low myopia and hyperopia associated with a common set of genetic variants or with different sets of variants for each refractive error category?

Findings  In this genetic association study of 54 006 individuals, polygenic risk scores derived from a genome-wide association study for high myopia were predictive of high and low myopia and hyperopia. Polygenic risk scores from a genome-wide association study for hyperopia were predictive of high and low myopia.

Meaning  These results support a single set of common genetic variants being associated with susceptibility to high myopia, low myopia, and hyperopia (in addition to rare mutations for monogenic high myopia or high hyperopia, already known to exist).


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.

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