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. 2021 Jun 1;139(6):601-609.
doi: 10.1001/jamaophthalmol.2021.0497.

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

J Willem L Tideman  1   2 , Olavi Pärssinen  3   4 , Annechien E G Haarman  1   2 , Anthony P Khawaja  5 , Juho Wedenoja  6   7 , Katie M Williams  8   9 , Ginevra Biino  10 , Xiaohu Ding  11 , Mika Kähönen  12   13 , Terho Lehtimäki  12   14   15 , Olli T Raitakari  16   17   18 , Ching-Yu Cheng  19   20 , Jost B Jonas  21   22 , Terri L Young  23 , Joan E Bailey-Wilson  24 , Jugnoo Rahi  25 , Cathy Williams  26 , Mingguang He  11   27 , David A Mackey  28 , Jeremy A Guggenheim  29 ; UK Biobank Eye and Vision Consortium and the Consortium for Refractive Error and Myopia (CREAM Consortium)
Collaborators, Affiliations

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

J Willem L Tideman et al. JAMA Ophthalmol. .

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Khawaja 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.

Figures

Figure 1.
Figure 1.. Refractive Groups of European Ancestry Samples
Relative frequency distribution of refractive groups (n = 94 914). Genome-wide association studies (GWASs) were as follows: GWAS 1, high myopia (HM) vs emmetropia; GWAS 2, low myopia (LM) vs emmetropia; GWAS 3, hyperopia vs emmetropia; and GWAS 4, LM vs hyperopia.
Figure 2.
Figure 2.. Prediction of Refractive Error Categories Using Polygenic Risk Scores
Polygenic risk scores derived from specific case-control genome-wide association study (GWAS) analyses in individuals of European ancestry were used to predict all categories of refractive error in European ancestry and Asian ancestry replication samples. Error bars represent 95% CI. HM indicates high myopia; LM, low myopia.
Figure 3.
Figure 3.. Association Between Odds Ratio for Prediction and Difference in Refractive Error Between Groups
Results are presented for polygenic risk scores (PRSs) selected using a P value threshold of P < 1 × 10−5 in the clumping and thresholding step. Prediction was assessed in the European ancestry replication samples. Error bars represent 95% CIs. GWAS indicates genome-wide association study; HM, high myopia; LM, low myopia.
See this image and copyright information in PMC

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