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

UK Biobank Eye and Vision Consortium and the Consortium for Refractive Error and Myopia (CREAM Consortium)

Research output: Contribution to journalArticle (Academic Journal)peer-review

21 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)601-609
Number of pages9
JournalJAMA Ophthalmology
Issue number6
Early online date8 Apr 2021
Publication statusPublished - 1 Jun 2021

Bibliographical note

Funding Information:
conducted using the UK Biobank Resource (applications 17351). UK Biobank was established by the Wellcome Trust, the UK Medical Research Council, the Department for Health (London, United Kingdom), Scottish Government (Edinburgh, United Kingdom), and the Northwest Regional Development Agency (Warrington, United Kingdom). It also received funding from the Welsh Assembly Government (Cardiff, United Kingdom), the British Heart Foundation, and Diabetes UK. Collection of eye and vision data was supported by grant BRC2_009 from the Department for Health through an award made by the National Institute for Health Research to the Biomedical Research Centre at Moorfields Eye Hospital National Health Service Foundation Trust and UCL Institute of Ophthalmology, London, United Kingdom. Additional support was provided by grant ST 12 09 from the Special Trustees of Moorfields Eye Hospital, London, United Kingdom. Data analysis was performed using the HAWK computing cluster, maintained by Supercomputing Wales and Cardiff University Advanced Research Computing at Cardiff. This work was supported by grant 24WG201 from the Welsh Government and Fight for Sight (Dr Guggenheim), the Silmäsäätiö Foundation and Evald and Hilda Nissi Foundation (Dr Pärssinen), grant R01EY014685 from the National Institutes of Health, National Eye Institute; a University of Wisconsin Centennial Scholars Award; and an unrestricted grant from Research to Prevent Blindness Inc to the Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison (Dr Young); and the Intramural Research Program of the National Institutes of Health (Dr Bailey-Wilson).

Funding Information:
reported receiving personal fees from Allergan, Novartis, Santen, Google Health, and Aerie outside the submitted work. Dr Jonas reported having a pending patent for use in the therapeutic or prophylactic treatment of myopia or hyperopia. Dr Young reported receiving grants from Research to Prevent Blindness Inc, University of Wisconsin Centennial Scholars Fund, and Research to Prevent Blindness Inc and consulting fees from Aerpio Pharmaceuticals Consultant outside the submitted work. Dr Guggenheim reported being an unpaid consultant for CooperVision Inc (consultancy fee paid directly by company to a charity selected by the company). No other disclosures were reported.

Publisher Copyright:
© 2021 American Medical Association. All rights reserved.


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