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

Jeremy A. Guggenheim*, Rosie Clark, Jiangtian Cui, Louise Terry, Karina Patasova, Annechien E.G. Haarman, Anthony M. Musolf, Virginie J.M. Verhoeven, Caroline C.W. Klaver, Joan E. Bailey-Wilson, Pirro G. Hysi, Cathy Williams

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Pages (from-to)1909-1919
Number of pages11
JournalHuman Molecular Genetics
Issue number11
Publication statusPublished - 1 Jun 2022

Bibliographical note

This work was supported by Cardiff University, the
Welsh Government and Fight for Sight (JAG/CW; Ref:
24WG201), an NIHR Senior Research Fellowship award
SRF-2015-08-005 (C.W.), Oogfonds, ODAS, Uitzicht (grant
2017-28), LSBS, MaculaFonds, Netherlands Organization
for Scientific Research (NWO), Grant 91617076 (V.J.M.V.) and Grant 91815655 (C.C.W.K.), the European Research
Council (ERC) under the European Union’s Horizon
2020 research and innovation programme grant 648268
(C.C.W.K.) and the Intramural Research Program of the
National Human Genome Research Institute, National
Institutes of Health (A.M.M./J.E.B.-W.). The sponsor or
funding organizations had no role in the design or
conduct of this research.

Publisher Copyright:
© 2022 The Author(s). Published by Oxford University Press.


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