PUBLICATION
Exome-wide association study identifies KDELR3 mutations in extreme myopia
- Authors
- Yuan, J., Zhuang, Y.Y., Liu, X., Zhang, Y., Li, K., Chen, Z.J., Li, D., Chen, H., Liang, J., Yao, Y., Yu, X., Zhuo, R., Zhao, F., Zhou, X., Myopia Associated Genetics and Intervention Consortium, Yu, X., Qu, J., Su, J.
- ID
- ZDB-PUB-240808-7
- Date
- 2024
- Source
- Nature communications 15: 67036703 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Child
- Exome Sequencing*
- Single-Cell Analysis
- Extracellular Matrix/genetics
- Extracellular Matrix/metabolism
- Young Adult
- Female
- Genome-Wide Association Study
- Mutation*
- Zebrafish*/genetics
- Sclera/metabolism
- Sclera/pathology
- Exome/genetics
- Myopia/genetics
- Myopia/metabolism
- Myopia/pathology
- Humans
- Fibroblasts/metabolism
- Case-Control Studies
- Adult
- Animals
- Male
- Genetic Predisposition to Disease
- PubMed
- 39112444 Full text @ Nat. Commun.
Citation
Yuan, J., Zhuang, Y.Y., Liu, X., Zhang, Y., Li, K., Chen, Z.J., Li, D., Chen, H., Liang, J., Yao, Y., Yu, X., Zhuo, R., Zhao, F., Zhou, X., Myopia Associated Genetics and Intervention Consortium, Yu, X., Qu, J., Su, J. (2024) Exome-wide association study identifies KDELR3 mutations in extreme myopia. Nature communications. 15:67036703.
Abstract
Extreme myopia (EM), defined as a spherical equivalent (SE) ≤ -10.00 diopters (D), is one of the leading causes of sight impairment. Known EM-associated variants only explain limited risk and are inadequate for clinical decision-making. To discover risk genes, we performed a whole-exome sequencing (WES) on 449 EM individuals and 9606 controls. We find a significant excess of rare protein-truncating variants (PTVs) in EM cases, enriched in the retrograde vesicle-mediated transport pathway. Employing single-cell RNA-sequencing (scRNA-seq) and a single-cell polygenic burden score (scPBS), we pinpointed PI16 + /SFRP4+ fibroblasts as the most relevant cell type. We observed that KDELR3 is highly expressed in scleral fibroblast and involved in scleral extracellular matrix (ECM) organization. The zebrafish model revealed that kdelr3 downregulation leads to elongated ocular axial length and increased lens diameter. Together, our study provides insight into the genetics of EM in humans and highlights KDELR3's role in EM pathogenesis.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping