生物
全基因组关联研究
计算生物学
遗传学
基因表达
基因
生物信息学
细胞
单核苷酸多态性
基因型
作者
Andrew R. Hamel,Wenjun Yan,John M. Rouhana,Aboozar Monovarfeshani,Xinyi Jiang,Puja A. Mehta,Jayshree Advani,Yuyang Luo,Qingnan Liang,Skanda Rajasundaram,Arushi Shrivastava,Katherine Duchinski,Sreekar Mantena,Jiali Wang,Tavé van Zyl,Louis R. Pasquale,Anand Swaroop,Puya Gharahkhani,Anthony P. Khawaja,Stuart MacGregor
标识
DOI:10.1038/s41467-023-44380-y
摘要
Primary open-angle glaucoma (POAG), characterized by retinal ganglion cell death, is a leading cause of irreversible blindness worldwide. However, its molecular and cellular causes are not well understood. Elevated intraocular pressure (IOP) is a major risk factor, but many patients have normal IOP. Colocalization and Mendelian randomization analysis of >240 POAG and IOP genome-wide association study (GWAS) loci and overlapping expression and splicing quantitative trait loci (e/sQTLs) in 49 GTEx tissues and retina prioritizes causal genes for 60% of loci. These genes are enriched in pathways implicated in extracellular matrix organization, cell adhesion, and vascular development. Analysis of single-nucleus RNA-seq of glaucoma-relevant eye tissues reveals that the POAG and IOP colocalizing genes and genome-wide associations are enriched in specific cell types in the aqueous outflow pathways, retina, optic nerve head, peripapillary sclera, and choroid. This study nominates IOP-dependent and independent regulatory mechanisms, genes, and cell types that may contribute to POAG pathogenesis.
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