Post-GWAS screening of candidate genes for refractive error in mutant zebrafish models
Abstract Genome-wide association studies (GWAS) have dissected numerous genetic factors underlying refractive errors (RE) such as myopia. Despite significant insights into understanding the genetic architecture of RE, few studies have validated and explored the functional role of candidate genes wit...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-02-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-28944-y |
| _version_ | 1811171780720590848 |
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| author | Wim H. Quint Kirke C. D. Tadema Nina C. C. J. Kokke Magda A. Meester-Smoor Adam C. Miller Rob Willemsen Caroline C. W. Klaver Adriana I. Iglesias |
| author_facet | Wim H. Quint Kirke C. D. Tadema Nina C. C. J. Kokke Magda A. Meester-Smoor Adam C. Miller Rob Willemsen Caroline C. W. Klaver Adriana I. Iglesias |
| author_sort | Wim H. Quint |
| collection | DOAJ |
| description | Abstract Genome-wide association studies (GWAS) have dissected numerous genetic factors underlying refractive errors (RE) such as myopia. Despite significant insights into understanding the genetic architecture of RE, few studies have validated and explored the functional role of candidate genes within these loci. To functionally follow-up on GWAS and characterize the potential role of candidate genes on the development of RE, we prioritized nine genes (TJP2, PDE11A, SHISA6, LAMA2, LRRC4C, KCNQ5, GNB3, RBFOX1, and GRIA4) based on biological and statistical evidence; and used CRISPR/cas9 to generate knock-out zebrafish mutants. These mutant fish were screened for abnormalities in axial length by spectral-domain optical coherence tomography and refractive status by eccentric photorefraction at the juvenile (2 months) and adult (4 months) developmental stage. We found a significantly increased axial length and myopic shift in refractive status in three of our studied mutants, indicating a potential involvement of the human orthologs (LAMA2, LRRC4C, and KCNQ5) in myopia development. Further, in-situ hybridization studies showed that all three genes are expressed throughout the zebrafish retina. Our zebrafish models provide evidence of a functional role of these three genes in refractive error development and offer opportunities to elucidate pathways driving the retina-to-sclera signaling cascade that leads to myopia. |
| first_indexed | 2024-04-10T17:19:46Z |
| format | Article |
| id | doaj.art-b9426aba4504409e8297e7c8a25dbb41 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-10T17:19:46Z |
| publishDate | 2023-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-b9426aba4504409e8297e7c8a25dbb412023-02-05T12:10:35ZengNature PortfolioScientific Reports2045-23222023-02-0113111110.1038/s41598-023-28944-yPost-GWAS screening of candidate genes for refractive error in mutant zebrafish modelsWim H. Quint0Kirke C. D. Tadema1Nina C. C. J. Kokke2Magda A. Meester-Smoor3Adam C. Miller4Rob Willemsen5Caroline C. W. Klaver6Adriana I. Iglesias7Department of Ophthalmology, Erasmus Medical CenterDepartment of Ophthalmology, Erasmus Medical CenterDepartment of Ophthalmology, Erasmus Medical CenterDepartment of Ophthalmology, Erasmus Medical CenterInstitute of Neuroscience, University of OregonDepartment of Clinical Genetics, Erasmus Medical CenterDepartment of Ophthalmology, Erasmus Medical CenterDepartment of Ophthalmology, Erasmus Medical CenterAbstract Genome-wide association studies (GWAS) have dissected numerous genetic factors underlying refractive errors (RE) such as myopia. Despite significant insights into understanding the genetic architecture of RE, few studies have validated and explored the functional role of candidate genes within these loci. To functionally follow-up on GWAS and characterize the potential role of candidate genes on the development of RE, we prioritized nine genes (TJP2, PDE11A, SHISA6, LAMA2, LRRC4C, KCNQ5, GNB3, RBFOX1, and GRIA4) based on biological and statistical evidence; and used CRISPR/cas9 to generate knock-out zebrafish mutants. These mutant fish were screened for abnormalities in axial length by spectral-domain optical coherence tomography and refractive status by eccentric photorefraction at the juvenile (2 months) and adult (4 months) developmental stage. We found a significantly increased axial length and myopic shift in refractive status in three of our studied mutants, indicating a potential involvement of the human orthologs (LAMA2, LRRC4C, and KCNQ5) in myopia development. Further, in-situ hybridization studies showed that all three genes are expressed throughout the zebrafish retina. Our zebrafish models provide evidence of a functional role of these three genes in refractive error development and offer opportunities to elucidate pathways driving the retina-to-sclera signaling cascade that leads to myopia.https://doi.org/10.1038/s41598-023-28944-y |
| spellingShingle | Wim H. Quint Kirke C. D. Tadema Nina C. C. J. Kokke Magda A. Meester-Smoor Adam C. Miller Rob Willemsen Caroline C. W. Klaver Adriana I. Iglesias Post-GWAS screening of candidate genes for refractive error in mutant zebrafish models Scientific Reports |
| title | Post-GWAS screening of candidate genes for refractive error in mutant zebrafish models |
| title_full | Post-GWAS screening of candidate genes for refractive error in mutant zebrafish models |
| title_fullStr | Post-GWAS screening of candidate genes for refractive error in mutant zebrafish models |
| title_full_unstemmed | Post-GWAS screening of candidate genes for refractive error in mutant zebrafish models |
| title_short | Post-GWAS screening of candidate genes for refractive error in mutant zebrafish models |
| title_sort | post gwas screening of candidate genes for refractive error in mutant zebrafish models |
| url | https://doi.org/10.1038/s41598-023-28944-y |
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