Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma

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, Tavé; Pasquale, Louis R.; Swaroop, Anand; Gharahkhani, Puya; Khawaja, Anthony P.; MacGregor, Stuart; Hewitt, Alex W.; Schuster, Alexander K.; Viswanathan, Ananth C.; Lotery, Andrew J.; Cree, Angela J.; Pang, Calvin P.; Brandl, Caroline; Klaver, Caroline C.W.; Hayward, Caroline; Khor, Chiea Chuen; Cheng, Ching Yu; Hammond, Christopher J.; van Duijn, Cornelia; Mackey, David A.; Stefansson, Einer; Vithana, Eranga N.; Pasutto, Francesca; Jonansson, Fridbert; Thorleifsson, Gudmar; Koh, Jacyline; Wilson, James F.; Craig, Jamie E.; Vergroesen, Joëlle E.; Fingert, John H.; Jonas, Jost B.; Stefánsson, Kári; Burdon, Kathryn P.; Chen, Li Jia; Kass, Michael; Jansonius, Nomdo M.; Pfeiffer, Norbert; Polašek, Ozren; Foster, Paul J.; Mitchell, Paul; Hysi, Pirro G.; Wojciechowski, Robert; Driessen, Sjoerd J.; Tompson, Stuart W.J.; Young, Terri L.; Wong, Tien Y.; Aung, Tin; Thorsteinsdottir, Unnur; de Vries, Victor A.; Ramdas, Wishal D.; Wang, Ya Xing; Chen, Rui; Vitart, Veronique; Sanes, Joshua R.; Wiggs, Janey L.; Segrè, Ayellet V.

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Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma

Titill:	Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma
Höfundur:	Hamel, Andrew R. Yan, Wenjun Rouhana, John M. Monovarfeshani, Aboozar Jiang, Xinyi Mehta, Puja A. Advani, Jayshree Luo, Yuyang Liang, Qingnan Rajasundaram, Skanda ... 60 fleiri höfundar Sýna alla höfunda Shrivastava, Arushi Duchinski, Katherine Mantena, Sreekar Wang, Jiali van Zyl, Tavé Pasquale, Louis R. Swaroop, Anand Gharahkhani, Puya Khawaja, Anthony P. MacGregor, Stuart Hewitt, Alex W. Schuster, Alexander K. Viswanathan, Ananth C. Lotery, Andrew J. Cree, Angela J. Pang, Calvin P. Brandl, Caroline Klaver, Caroline C.W. Hayward, Caroline Khor, Chiea Chuen Cheng, Ching Yu Hammond, Christopher J. van Duijn, Cornelia Mackey, David A. Stefansson, Einer Vithana, Eranga N. Pasutto, Francesca Jonansson, Fridbert Thorleifsson, Gudmar orcid.org/0000-0003-4623-9087 Koh, Jacyline Wilson, James F. Craig, Jamie E. Vergroesen, Joëlle E. Fingert, John H. Jonas, Jost B. Stefánsson, Kári Burdon, Kathryn P. Chen, Li Jia Kass, Michael Jansonius, Nomdo M. Pfeiffer, Norbert Polašek, Ozren Foster, Paul J. Mitchell, Paul Hysi, Pirro G. Wojciechowski, Robert Driessen, Sjoerd J. Tompson, Stuart W.J. Young, Terri L. Wong, Tien Y. Aung, Tin Thorsteinsdottir, Unnur de Vries, Victor A. Ramdas, Wishal D. Wang, Ya Xing Chen, Rui Vitart, Veronique Sanes, Joshua R. Wiggs, Janey L. Segrè, Ayellet V. 70 höfundar Sýna færri höfunda
Útgáfa:	2024-01-09
Tungumál:	Enska
Umfang:	4869889
Svið:	Health Sciences
Deild:	Faculty of Medicine
Birtist í:	Nature Communications; 15(1)
ISSN:	2041-1723
DOI:	10.1038/s41467-023-44380-y
Efnisorð:	Humans; Genome-Wide Association Study; Glaucoma, Open-Angle/genetics; Gene Expression Regulation; Causality; Glaucoma/genetics; General Chemistry; General Biochemistry,Genetics and Molecular Biology; General Physics and Astronomy
URI:	https://hdl.handle.net/20.500.11815/4810
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Tilvitnun: Hamel , A R , Yan , W , Rouhana , J M , Monovarfeshani , A , Jiang , X , Mehta , P A , Advani , J , Luo , Y , Liang , Q , Rajasundaram , S , Shrivastava , A , Duchinski , K , Mantena , S , Wang , J , van Zyl , T , Pasquale , L R , Swaroop , A , Gharahkhani , P , Khawaja , A P , MacGregor , S , Hewitt , A W , Schuster , A K , Viswanathan , A C , Lotery , A J , Cree , A J , Pang , C P , Brandl , C , Klaver , C C W , Hayward , C , Khor , C C , Cheng , C Y , Hammond , C J , van Duijn , C , Mackey , D A , Stefansson , E , Vithana , E N , Pasutto , F , Jonansson , F , Thorleifsson , G , Koh , J , Wilson , J F , Craig , J E , Vergroesen , J E , Fingert , J H , Jonas , J B , Stefánsson , K , Burdon , K P , Chen , L J , Kass , M , Jansonius , N M , Pfeiffer , N , Polašek , O , Foster , P J , Mitchell , P , Hysi , P G , Wojciechowski , R , Driessen , S J , Tompson , S W J , Young , T L , Wong , T Y , Aung , T , Thorsteinsdottir , U , de Vries , V A , Ramdas , W D , Wang , Y X , Chen , R , Vitart , V , Sanes , J R , Wiggs , J L & Segrè , A V 2024 , ' Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma ' , Nature Communications , vol. 15 , no. 1 , 396 , pp. 396 . https://doi.org/10.1038/s41467-023-44380-y
Útdráttur: 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.
Athugasemdir: © 2024. The Author(s).