TY - JOUR
T1 - Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma
AU - International Glaucoma Genetics Consortium (IGGC)
AU - Hamel, Andrew R.
AU - Yan, Wenjun
AU - Rouhana, John M.
AU - Monovarfeshani, Aboozar
AU - Jiang, Xinyi
AU - Mehta, Puja A.
AU - Advani, Jayshree
AU - Luo, Yuyang
AU - Liang, Qingnan
AU - Rajasundaram, Skanda
AU - Shrivastava, Arushi
AU - Duchinski, Katherine
AU - Mantena, Sreekar
AU - Wang, Jiali
AU - van Zyl, Tavé
AU - Pasquale, Louis R.
AU - Swaroop, Anand
AU - Gharahkhani, Puya
AU - Khawaja, Anthony P.
AU - MacGregor, Stuart
AU - Hewitt, Alex W.
AU - Schuster, Alexander K.
AU - Viswanathan, Ananth C.
AU - Lotery, Andrew J.
AU - Cree, Angela J.
AU - Pang, Calvin P.
AU - Brandl, Caroline
AU - Klaver, Caroline C.W.
AU - Hayward, Caroline
AU - Khor, Chiea Chuen
AU - Cheng, Ching Yu
AU - Hammond, Christopher J.
AU - van Duijn, Cornelia
AU - Mackey, David A.
AU - Stefansson, Einer
AU - Vithana, Eranga N.
AU - Pasutto, Francesca
AU - Jonansson, Fridbert
AU - Thorleifsson, Gudmar
AU - Koh, Jacyline
AU - Wilson, James F.
AU - Craig, Jamie E.
AU - Vergroesen, Joëlle E.
AU - Fingert, John H.
AU - Jonas, Jost B.
AU - Stefánsson, Kári
AU - Burdon, Kathryn P.
AU - Chen, Li Jia
AU - Kass, Michael
AU - Jansonius, Nomdo M.
N1 - Publisher Copyright:
© 2024, The Author(s).
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
KW - Functional genomics
KW - Optic nerve diseases
KW - Statistical methods
UR - http://www.scopus.com/inward/record.url?scp=85181652198&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-44380-y
DO - 10.1038/s41467-023-44380-y
M3 - Article
C2 - 38195602
AN - SCOPUS:85181652198
SN - 2041-1723
VL - 15
JO - Nature Communications
JF - Nature Communications
M1 - 396
ER -