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Whole exome sequence analysis in 51 624 participants identifies novel genes and variants associated with refractive error and myopia.

  • Guggenheim, Jeremy A1
  • Clark, Rosie1
  • Cui, Jiangtian1
  • Terry, Louise1
  • Patasova, Karina2, 3
  • Haarman, Annechien E G4, 5
  • Musolf, Anthony M6
  • Verhoeven, Virginie J M4, 7
  • Klaver, Caroline C W4, 5, 8, 9
  • Bailey-Wilson, Joan E6
  • Hysi, Pirro G2, 3
  • Williams, Cathy10
  • 1 School of Optometry & Vision Sciences, Cardiff University, Cardiff, CF24 4HQ, UK.
  • 2 Section of Ophthalmology, School of Life Course Sciences, King's College London, WC2R 2LS, UK.
  • 3 Department of Twin Research and Genetic Epidemiology, School of Life Course Sciences, King's College London, WC2R 2LS, UK.
  • 4 Department of Ophthalmology, Erasmus Medical Center GD, 3015GD Rotterdam, The Netherlands. , (Netherlands)
  • 5 Department of Epidemiology, Erasmus Medical Center GD, 3015GD Rotterdam, The Netherlands. , (Netherlands)
  • 6 Statistical Genetics Section, Computational and Statistical Genomics Branch, Nation Human Genome Research Institute, National Institutes of Health, Baltimore, MD 21224, USA.
  • 7 Department of Clinical Genetics, Erasmus Medical Center GD, 3015GD Rotterdam, The Netherlands. , (Netherlands)
  • 8 Department of Ophthalmology, Radboud University Medical Center, 6525EX Nijmegen, The Netherlands. , (Netherlands)
  • 9 Institute of Molecular and Clinical Ophthalmology Basel, CH-4031 Basel, Switzerland. , (Switzerland)
  • 10 Centre for Academic Child Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 1NU, UK.
Published Article
Human Molecular Genetics
Oxford University Press
Publication Date
Jun 04, 2022
DOI: 10.1093/hmg/ddac004
PMID: 35022715


Refractive errors are associated with a range of pathological conditions, such as myopic maculopathy and glaucoma, and are highly heritable. Studies of missense and putative loss of function (pLOF) variants identified via whole exome sequencing (WES) offer the prospect of directly implicating potentially causative disease genes. We performed a genome-wide association study for refractive error in 51 624 unrelated adults, of European ancestry, aged 40-69 years from the UK and genotyped using WES. After testing 29 179 pLOF and 495 263 missense variants, 1 pLOF and 18 missense variants in 14 distinct genomic regions were taken forward for fine-mapping analysis. This yielded 19 putative causal variants of which 18 had a posterior inclusion probability >0.5. Of the 19 putative causal variants, 12 were novel discoveries. Specific variants were associated with a more myopic refractive error, while others were associated with a more hyperopic refractive error. Association with age of onset of spectacle wear (AOSW) was examined in an independent validation sample (38 100 early AOSW cases and 74 243 controls). Of 11 novel variants that could be tested, 8 (73%) showed evidence of association with AOSW status. This work identified COL4A4 and ATM as novel candidate genes associated with refractive error. In addition, novel putative causal variants were identified in the genes RASGEF1, ARMS2, BMP4, SIX6, GSDMA, GNGT2, ZNF652 and CRX. Despite these successes, the study also highlighted the limitations of community-based WES studies compared with high myopia case-control WES studies. © The Author(s) 2022. Published by Oxford University Press.

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