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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 A. ORCID:, Clark, Rosie, Cui, Jiangtian, Terry, Louise ORCID:, Patasova, Karina, Haarman, Annechien E. G., Musolf, Anthony M., Verhoeven, Virginie J. M., Klaver, Caroline C. W., Bailey-Wilson, Joan E., Hysi, Pirro G. and Williams, Cathy 2022. Whole exome sequence analysis in 51?624 participants identifies novel genes and variants associated with refractive error and myopia. Human Molecular Genetics 31 (11) , pp. 1909-1919. 10.1093/hmg/ddac004

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Optometry and Vision Sciences
Additional Information: This is an Open Access article distributed under the terms of the Creative Commons Attribution License (
Publisher: Oxford University Press
ISSN: 0964-6906
Funders: Cardiff University; Welsh Government and Fight for Sight (24WG201)
Date of First Compliant Deposit: 2 March 2022
Date of Acceptance: 4 January 2022
Last Modified: 06 Jan 2024 02:19

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