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

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; IGGC International Glaucoma Genetics Consortium; Alex W. Hewitt; David A. Mackey; Jamie E. Craig; Kathryn P. Burdon; Paul J. Foster; Rui Chen; Veronique Vitart; Joshua R. Sanes; Janey L. Wiggs; Ayellet V. Segrè

doi:10.1038/s41467-023-44380-y

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

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 MacGregorIGGC International Glaucoma Genetics Consortium, Alex W. Hewitt, David A. Mackey, Jamie E. Craig, Kathryn P. Burdon, Paul J. Foster, Rui Chen, Veronique Vitart, Joshua R. Sanes, Janey L. Wiggs, Ayellet V. Segrè

College of Medicine and Public Health

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Abstract

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.

Original language	English
Article number	396
Number of pages	25
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-44380-y
Publication status	Published - 9 Jan 2024

Keywords

Functional genomics
Optic nerve diseases
Statistical methods

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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., ... Segrè, A. V. (2024). Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma. Nature Communications, 15(1), Article 396. https://doi.org/10.1038/s41467-023-44380-y

@article{f5fecdf8fc8d4cc78b3e400b4139b381,

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

abstract = "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.",

keywords = "Functional genomics, Optic nerve diseases, Statistical methods",

author = "Hamel, {Andrew R.} and Wenjun Yan and Rouhana, {John M.} and Aboozar Monovarfeshani and Xinyi Jiang and Mehta, {Puja A.} and Jayshree Advani and Yuyang Luo and Qingnan Liang and Skanda Rajasundaram and Arushi Shrivastava and Katherine Duchinski and Sreekar Mantena and Jiali Wang and {van Zyl}, Tav{\'e} and Pasquale, {Louis R.} and Anand Swaroop and Puya Gharahkhani and Khawaja, {Anthony P.} and Stuart MacGregor and {IGGC International Glaucoma Genetics Consortium} and Hewitt, {Alex W.} and Schuster, {Alexander K.} and Viswanathan, {Ananth C.} and Lotery, {Andrew J.} and Cree, {Angela J.} and Pang, {Calvin P.} and Caroline Brandl and Klaver, {Caroline C.W.} and Caroline Hayward and Khor, {Chiea Chuen} and Cheng, {Ching Yu} and Hammond, {Christopher J.} and {van Duijn}, Cornelia and Mackey, {David A.} and Einer Stefansson and Vithana, {Eranga N.} and Francesca Pasutto and Fridbert Jonansson and Gudmar Thorleifsson and Jacyline Koh and Wilson, {James F.} and Craig, {Jamie E.} and Vergroesen, {Jo{\"e}lle E.} and Fingert, {John H.} and Jonas, {Jost B.} and K{\'a}ri Stef{\'a}nsson and Burdon, {Kathryn P.} and Chen, {Li Jia} and Michael Kass and Jansonius, {Nomdo M.} and Norbert Pfeiffer and Ozren Pola{\v s}ek and Foster, {Paul J.} and Paul Mitchell and Hysi, {Pirro G.} and Robert Wojciechowski and Driessen, {Sjoerd J.} and Tompson, {Stuart W.J.} and Young, {Terri L.} and Wong, {Tien Y.} and Tin Aung and Unnur Thorsteinsdottir and {de Vries}, {Victor A.} and Ramdas, {Wishal D.} and Wang, {Ya Xing} and Rui Chen and Veronique Vitart and Sanes, {Joshua R.} and Wiggs, {Janey L.} and Segr{\`e}, {Ayellet V.}",

year = "2024",

month = jan,

day = "9",

doi = "10.1038/s41467-023-44380-y",

language = "English",

volume = "15",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature",

number = "1",

}

Hamel, AR, Yan, W, Rouhana, JM, Monovarfeshani, A, Jiang, X, Mehta, PA, Advani, J, Luo, Y, Liang, Q, Rajasundaram, S, Shrivastava, A, Duchinski, K, Mantena, S, Wang, J, van Zyl, T, Pasquale, LR, Swaroop, A, Gharahkhani, P, Khawaja, AP, MacGregor, S, IGGC International Glaucoma Genetics Consortium, Hewitt, AW, Mackey, DA, Craig, JE, Burdon, KP, Foster, PJ, Chen, R, Vitart, V, Sanes, JR, Wiggs, JL & Segrè, AV 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. https://doi.org/10.1038/s41467-023-44380-y

TY - JOUR

T1 - Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma

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 - IGGC International Glaucoma Genetics Consortium

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.

AU - Pfeiffer, Norbert

AU - Polašek, Ozren

AU - Foster, Paul J.

AU - Mitchell, Paul

AU - Hysi, Pirro G.

AU - Wojciechowski, Robert

AU - Driessen, Sjoerd J.

AU - Tompson, Stuart W.J.

AU - Young, Terri L.

AU - Wong, Tien Y.

AU - Aung, Tin

AU - Thorsteinsdottir, Unnur

AU - de Vries, Victor A.

AU - Ramdas, Wishal D.

AU - Wang, Ya Xing

AU - Chen, Rui

AU - Vitart, Veronique

AU - Sanes, Joshua R.

AU - Wiggs, Janey L.

AU - Segrè, Ayellet V.

PY - 2024/1/9

Y1 - 2024/1/9

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

IS - 1

M1 - 396

ER -

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

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