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Towards the identification of causal genes for age-related macular degeneration

Fei-Fei Cheng, You-Yuan Zhuang, Xin-Ran Wen, Angli Xue, Jian Yang, View ORCID ProfileZi-Bing Jin
doi: https://doi.org/10.1101/778613
Fei-Fei Cheng
1Division of Ophthalmic Genetics, The Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China
2National Center for International Research in Regenerative Medicine and Neurogenetics, National Clinical Research Center for Ophthalmology, State Key Laboratory of Ophthalmology, Optometry and Visual Science, Wenzhou, 325027 China
3Institute for Advanced Research, Wenzhou Medical University, Wenzhou 325035, China
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You-Yuan Zhuang
1Division of Ophthalmic Genetics, The Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China
2National Center for International Research in Regenerative Medicine and Neurogenetics, National Clinical Research Center for Ophthalmology, State Key Laboratory of Ophthalmology, Optometry and Visual Science, Wenzhou, 325027 China
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Xin-Ran Wen
1Division of Ophthalmic Genetics, The Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China
2National Center for International Research in Regenerative Medicine and Neurogenetics, National Clinical Research Center for Ophthalmology, State Key Laboratory of Ophthalmology, Optometry and Visual Science, Wenzhou, 325027 China
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Angli Xue
4Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia
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Jian Yang
3Institute for Advanced Research, Wenzhou Medical University, Wenzhou 325035, China
4Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia
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  • For correspondence: jinzb@mail.eye.ac.cn jian.yang.qt@gmail.com
Zi-Bing Jin
1Division of Ophthalmic Genetics, The Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China
2National Center for International Research in Regenerative Medicine and Neurogenetics, National Clinical Research Center for Ophthalmology, State Key Laboratory of Ophthalmology, Optometry and Visual Science, Wenzhou, 325027 China
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  • ORCID record for Zi-Bing Jin
  • For correspondence: jinzb@mail.eye.ac.cn jian.yang.qt@gmail.com
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Abstract

Age-related macular degeneration (AMD) is a leading cause of visual impairment in ageing populations and has no radical treatment or prevention. Although genome-wide association studies (GWAS) have identified many susceptibility loci for AMD, the underlying causal genes remain elusive. Here, we prioritized nine putative causal genes by integrating expression quantitative trait locus (eQTL) data from blood (n = 2,765) with AMD GWAS data (16,144 cases vs. 17,832 controls) and replicated six of them using retina eQTL data (n = 523). Of the six genes, altering expression of cnn2, sarm1 and bloc1s1 led to ocular phenotype, impaired vision and retinal pigment epithelium (RPE) loss in zebrafish. Essential photoreceptor and RPE genes were downregulated in cnn2- and sarm1-knockdown zebrafishes. Through integration of GWAS and eQTL data followed by functional validation, our study reveals potential roles of CNN2, SARM1 and BLOC1S1 in AMD pathogenesis and demonstrates an efficient platform to prioritise causal genes for human complex diseases.

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  • ↵6 These authors jointly supervised this work.

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Posted September 23, 2019.
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Towards the identification of causal genes for age-related macular degeneration
Fei-Fei Cheng, You-Yuan Zhuang, Xin-Ran Wen, Angli Xue, Jian Yang, Zi-Bing Jin
bioRxiv 778613; doi: https://doi.org/10.1101/778613
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Towards the identification of causal genes for age-related macular degeneration
Fei-Fei Cheng, You-Yuan Zhuang, Xin-Ran Wen, Angli Xue, Jian Yang, Zi-Bing Jin
bioRxiv 778613; doi: https://doi.org/10.1101/778613

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