Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma.
Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma.
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DOI：
10.1038/s41467-023-44380-y
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发表时间：
2024-01-09
影响因子：
16.6
通讯作者：
Segre, Ayellet V.
中科院分区：
文献类型：
--
作者：
Hamel, Andrew R.;Yan, Wenjun;Rouhana, John M.;Monovarfeshani, Aboozar;Jiang, Xinyi;Mehta, Puja A.;Advani, Jayshree;Luo, Yuyang;Liang, Qingnan;Rajasundaram, Skanda;Shrivastava, Arushi;Duchinski, Katherine;Mantena, Sreekar;Wang, Jiali;van Zyl, Tave;Pasquale, Louis R.;Swaroop, Anand;Gharahkhani, Puya;Khawaja, Anthony P.;MacGregor, Stuart;Chen, Rui;Vitart, Veronique;Sanes, Joshua R.;Wiggs, Janey L.;Segre, Ayellet V.
原发性开角型青光眼（Primary open-angle glaucoma，POAG）是一种以视网膜神经节细胞死亡为特征的致盲性疾病。然而，其分子和细胞原因还不清楚。眼内压（IOP）升高是一个主要的风险因素，但许多患者的IOP正常。共定位和孟德尔随机化分析>240 POAG和IOP全基因组关联研究（GWAS）基因座和49个GTEx组织和视网膜中的重叠表达和剪接数量性状基因座（e/sQTL），优先考虑60%基因座的致病基因。这些基因在细胞外基质组织、细胞粘附和血管发育的途径中富集。青光眼相关眼组织的单核RNA-seq分析揭示，POAG和IOP共定位基因和全基因组关联在房水流出通路、视网膜、视神经乳头、视乳头周围巩膜和脉络膜中的特定细胞类型中富集。这项研究提名IOP依赖性和独立的调节机制，基因和细胞类型，可能有助于POAG的发病机制。青光眼的分子和细胞原因还不清楚。在这里，作者将GWAS与多个眼组织的遗传调控和单细胞表达相结合，以确定影响青光眼发病机制的基因和关键细胞类型。
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. The molecular and cellular causes of glaucoma are not well understood. Here, the authors integrate GWAS with genetic regulation and single cell expression from multiple eye tissues to identify genes and key cell types that affect glaucoma pathogenesis.
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影响因子：
3.5
作者：
Gao, X. Raymond;Huang, Hua;Kim, Heejin
通讯作者：
Kim, Heejin
遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
2.1
作者：
Bowden J;Davey Smith G;Haycock PC;Burgess S
通讯作者：
Burgess S
影响因子：
9.8
作者：
Alipanahi B;Hormozdiari F;Behsaz B;Cosentino J;McCaw ZR;Schorsch E;Sculley D;Dorfman EH;Foster PJ;Peng LH;Phene S;Hammel N;Carroll A;Khawaja AP;McLean CY
通讯作者：
McLean CY
影响因子：
30.8
作者：
Finucane HK;Bulik-Sullivan B;Gusev A;Trynka G;Reshef Y;Loh PR;Anttila V;Xu H;Zang C;Farh K;Ripke S;Day FR;ReproGen Consortium;Schizophrenia Working Group of the Psychiatric Genomics Consortium;RACI Consortium;Purcell S;Stahl E;Lindstrom S;Perry JR;Okada Y;Raychaudhuri S;Daly MJ;Patterson N;Neale BM;Price AL
通讯作者：
Price AL