A new polygenic score for refractive error improves detection of children at risk of high myopia but not the prediction of those at risk of myopic macular degeneration

CREAM Consortium, UK Biobank Eye and Vision Consortium

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Abstract

Background: High myopia (HM), defined as a spherical equivalent refractive error (SER) ≤ −6.00 diopters (D), is a leading cause of sight impairment, through myopic macular degeneration (MMD). We aimed to derive an improved polygenic score (PGS) for predicting children at risk of HM and to test if a PGS is predictive of MMD after accounting for SER. 

Methods: The PGS was derived from genome-wide association studies in participants of UK Biobank, CREAM Consortium, and Genetic Epidemiology Research on Adult Health and Aging. MMD severity was quantified by a deep learning algorithm. Prediction of HM was quantified as the area under the receiver operating curve (AUROC). Prediction of severe MMD was assessed by logistic regression. 

Findings: In independent samples of European, African, South Asian and East Asian ancestry, the PGS explained 19% (95% confidence interval 17–21%), 2% (1–3%), 8% (7–10%) and 6% (3–9%) of the variation in SER, respectively. The AUROC for HM in these samples was 0.78 (0.75–0.81), 0.58 (0.53–0.64), 0.71 (0.69–0.74) and 0.67 (0.62–0.72), respectively. The PGS was not associated with the risk of MMD after accounting for SER: OR = 1.07 (0.92–1.24). 

Interpretation: Performance of the PGS approached the level required for clinical utility in Europeans but not in other ancestries. A PGS for refractive error was not predictive of MMD risk once SER was accounted for. 

Funding: Supported by the Welsh Government and Fight for Sight ( 24WG201).

Original languageEnglish
Article number104551
Number of pages18
JournalEBioMedicine
Volume91
Early online date11 Apr 2023
DOIs
Publication statusPublished - May 2023

Bibliographical note

Funding Information:
Supported by the Welsh Government and Fight for Sight (24WG201).We acknowledge funding from the Welsh Government and Fight for Sight UK (24WG201), the National Health and Medical Research Council of Australia (5011549), and the United States National Eye Institute (R01EY027004 and R01EY033010). Data analysis was carried out using the HAWK computing cluster, maintained by Supercomputing Wales and Cardiff University ARCCA. UK Biobank: This research has been conducted using the UK Biobank Resource (application #17351). UK Biobank was established by the Wellcome Trust; the UK Medical Research Council; the Department for Health (London, UK); Scottish Government (Edinburgh, UK); and the Northwest Regional Development Agency (Warrington, UK). It also received funding from the Welsh Assembly Government (Cardiff, UK); the British Heart Foundation; and Diabetes UK. Collection of eye and vision data was supported by The Department for Health through an award made by the NIHR to the Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust, and UCL Institute of Ophthalmology, London, United Kingdom (grant no. BRC2_009). Additional support was provided by The Special Trustees of Moorfields Eye Hospital, London, United Kingdom (grant no. ST 12 09). ALSPAC: We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. This publication is the work of the authors and Jeremy Guggenheim and Cathy Williams will serve as guarantors for the contents of this paper. The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristolprovide core support for ALSPAC. GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. A comprehensive list of grants funding is available on the ALSPAC website: http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf; This research was specifically funded by Wellcome Trust and MRC grant 076467/Z/05/Z and Wellcome Trust grant WT088806. GERA: We are grateful to the Kaiser Permanente Northern California members who have generously agreed to participate in the Kaiser Permanente Research Program on Genes, Environment, and Health. Genotyping of the GERA cohort was funded by a grant from the National Institute on Aging, National Institute of Mental Health, and National Institutes of Health Common Fund (RC2AG036607). Support for GERA participant enrollment, survey completion, and biospecimen collection for the Research Program on Genes, Environment and Health was provided by the Robert Wood Johnson Foundation, the Wayne and Gladys Valley Foundation, the Ellison Medical Foundation, and Kaiser Permanente Community Benefit Programs. H.C. is supported by The National Eye Institute (R01EY027004 and R01EY033010). BHAS: The Pawsey Supercomputing Centre provided computation resources to carry out analyses required with funding from the Australian Government and the Government of Western Australia (WA). We thank the WA Country Health Service and the community of the City of Busselton for their ongoing support and participation. The BHAS is supported by grants from the Commonwealth of Australia Government (Preventative Health Policy Section, Department of Health), the Government of Western Australia (Office of Science, Department of Health), and the City of Busselton. Generation R: The Generation R Study is conducted by the Erasmus Medical Center in close collaboration with the School of Law and Faculty of Social Sciences of the Erasmus University Rotterdam; the Municipal Health Service Rotterdam area, Rotterdam; the Rotterdam Homecare Foundation, Rotterdam; and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond (STAR-MDC), Rotterdam. The authors gratefully acknowledge the contribution of children and parents, general practitioners, hospitals, midwives, and pharmacies in Rotterdam. We acknowledge funding from the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (grant 91815655) and the European Research Council Horizon 2020 (grant 648268).

Funding Information:
We acknowledge funding from the Welsh Government and Fight for Sight UK ( 24WG201 ), the National Health and Medical Research Council of Australia ( 5011549 ), and the United States National Eye Institute ( R01EY027004 and R01EY033010 ). Data analysis was carried out using the HAWK computing cluster, maintained by Supercomputing Wales and Cardiff University ARCCA. UK Biobank : This research has been conducted using the UK Biobank Resource (application #17351). UK Biobank was established by the Wellcome Trust ; the UK Medical Research Council ; the Department for Health (London, UK); Scottish Government (Edinburgh, UK); and the Northwest Regional Development Agency (Warrington, UK). It also received funding from the Welsh Assembly Government (Cardiff, UK); the British Heart Foundation ; and Diabetes UK. Collection of eye and vision data was supported by The Department for Health through an award made by the NIHR to the Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust, and UCL Institute of Ophthalmology, London, United Kingdom (grant no. BRC2_009 ). Additional support was provided by The Special Trustees of Moorfields Eye Hospital, London, United Kingdom (grant no. ST 12 09 ). ALSPAC : We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. This publication is the work of the authors and Jeremy Guggenheim and Cathy Williams will serve as guarantors for the contents of this paper. The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z ) and the University of Bristolprovide core support for ALSPAC. GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. A comprehensive list of grants funding is available on the ALSPAC website: http://www.bristol.ac.uk/alspac/external/documents/ grant-acknowledgements.pdf; This research was specifically funded by Wellcome Trust and MRC grant 076467/Z/05/Z and Wellcome Trust grant WT088806 . GERA : We are grateful to the Kaiser Permanente Northern California members who have generously agreed to participate in the Kaiser Permanente Research Program on Genes, Environment, and Health. Genotyping of the GERA cohort was funded by a grant from the National Institute on Aging , National Institute of Mental Health , and National Institutes of Health Common Fund ( RC2AG036607 ). Support for GERA participant enrollment, survey completion, and biospecimen collection for the Research Program on Genes, Environment and Health was provided by the Robert Wood Johnson Foundation , the Wayne and Gladys Valley Foundation , the Ellison Medical Foundation , and Kaiser Permanente Community Benefit Programs. H.C. is supported by The National Eye Institute ( R01EY027004 and R01EY033010 ). BHAS : The Pawsey Supercomputing Centre provided computation resources to carry out analyses required with funding from the Australian Government and the Government of Western Australia (WA). We thank the WA Country Health Service and the community of the City of Busselton for their ongoing support and participation. The BHAS is supported by grants from the Commonwealth of Australia Government (Preventative Health Policy Section , Department of Health ), the Government of Western Australia ( Office of Science , Department of Health ), and the City of Busselton. Generation R : The Generation R Study is conducted by the Erasmus Medical Center in close collaboration with the School of Law and Faculty of Social Sciences of the Erasmus University Rotterdam; the Municipal Health Service Rotterdam area, Rotterdam; the Rotterdam Homecare Foundation , Rotterdam; and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond (STAR-MDC) , Rotterdam. The authors gratefully acknowledge the contribution of children and parents, general practitioners, hospitals, midwives, and pharmacies in Rotterdam. We acknowledge funding from the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (grant 91815655 ) and the European Research Council Horizon 2020 (grant 648268 ).

Publisher Copyright:
© 2023 The Author(s)

Keywords

  • ALSPAC
  • Generation R
  • Myopia
  • Polygenic score
  • UK Biobank

ASJC Scopus subject areas

  • General Biochemistry,Genetics and Molecular Biology

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