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

Disease areas:

• eye

Last updated:

2 July 2025

Author(s):

J. Willem L. Tideman, Olavi Pärssinen, Annechien E. G. Haarman, Anthony P. Khawaja, Juho Wedenoja, Katie M. Williams, Ginevra Biino, Xiaohu Ding, Mika Kähönen, Terho Lehtimäki, Olli T. Raitakari, Ching-Yu Cheng, Jost B. Jonas, Terri L. Young, Joan E. Bailey-Wilson, Jugnoo Rahi, Cathy Williams, Mingguang He, David A. Mackey, Jeremy A. Guggenheim, Adriana I. Iglesias, Akira Meguro, Akitaka Tsujikawa, Alex W. Hewitt, Veluchamy A. Barathi, Andres Metspalu, Andrew D. Paterson, Annechien E.G. Haarman, Anthony Musolf, Anthony P. Khawaja, Barbara E. Klein, Candace Middlebrooks, Caroline Hayward, Cathy Williams, Cécile Delcourt, Chi Pui Pang, Ching-Yu Cheng, Christopher J. Hammond, Claire L. Simpson, Cornelia M. van Duijn, David A. Mackey, Deyana Lewis, Dwight Stambolian, Emily Y. Chew, E-Shyong Tai, Ginevra Biino, Harry Campbell, Igor Rudan, J. Willem L. Tideman, Jaakko Kaprio, James F. Wilson, Jamie E. Craig, Jason C.S. Yam, Jeremy A. Guggenheim, Joan E. Bailey-Wilson, Jonathan H. Lass, Jost B. Jonas, Jugnoo S. Rahi, Juho Wedenoja, Kathryn P. Burdon, Katie M. Williams, Kenji Yamashiro, Konrad Oexle, Kris Lee, Leo-Pekka Lyytikäinen, Li Jia Chen, Margaret M. Deangelis, Masahiro Miyake, Maurice K.H. Yap, Maurizio Fossarello, Mika Kähönen, Milly S. Tedja, Mingguang He, Nicholas G. Martin, Ningli Wang, Nobuhisa Mizuki, Norbert Pfeiffer, Olavi Pärssinen, Olli Raitakari, Ozren Polasek, Paul J. Foster, Paul N. Baird, Pirro G. Hysi, Puya Gharahkhani, Qiao Fan, Qing Li, Quan Hoang, Robert P. Igo, Robert Wojciechowski, Seang-Mei Saw, Seyhan Yazar, Shea Ping Yip, Shi-Ming Li, Srujana Sahebjada, Stefan Nickels, Stuart MacGregor, Sudha K. Iyengar, Terho Lehtimäki, Terri L. Young, Toomas Haller, Veronique Vitart, Virginie J.M. Verhoeven, Wen Bin Wei, Xiangtian Zhou, Xiaobo Guo, Xiaohu Ding, Xikun Han, Ya Xing Wang, Naomi Allen, Tariq Aslam, Denize Atan, Sarah Barman, Jenny Barrett, Paul Bishop, Graeme Black, Catey Bunce, Roxana Carare, Usha Chakravarthy, Michelle Chan, Sharon Chua, Valentina Cipriani, Alexander Day, Parul Desai, Bal Dhillon, Andrew Dick, Alexander Doney, Cathy Egan, Sarah Ennis, Paul Foster, Marcus Fruttiger, John Gallacher, David Garway-Heath, Jane Gibson, Dan Gore, Jeremy Guggenheim, Chris Hammond, Alison Hardcastle, Simon Harding, Ruth Hogg, Pirro Hysi, Pearse A Keane, Peng Tee Khaw, Anthony Khawaja, Gerassimos Lascaratos, Thomas Littlejohns, Andrew Lotery, Phil Luthert, Tom Macgillivray, Sarah Mackie, Bernadette Mcguinness, Gareth Mckay, Martin Mckibbin, Danny Mitry, Tony Moore, James Morgan, Zaynah Muthy, Eoin O'sullivan, Chris Owen, Praveen Patel, Euan Paterson, Tunde Peto, Axel Petzold, Nikolas Pontikos, Jugnoo Rahi, Alicja Rudnicka, Jay Self, Panagiotis Sergouniotis, Sobha Sivaprasad, David Steel, Irene Stratton, Nicholas Strouthidis, Cathie Sudlow, Robyn Tapp, Caroline Thaung, Dhanes Thomas, Emanuele Trucco, Adnan Tufail, Stephen Vernon, Ananth Viswanathan, Katie Williams, Jayne Woodside, Max Yates, Jennifer Yip, Yalin Zheng

Publish date:

1 June 2021

Journal:

JAMA Ophthalmology

PubMed ID:

33830181

DOI:

10.1001/jamaophthalmol.2021.0497

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.