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  Monovarfeshan; 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; International Glaucoma Genetics Consortium (IGGC); 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 Monovarfeshan, 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 MacgregorInternational Glaucoma Genetics Consortium (IGGC), Rui Chen, Veronique Vitart, Joshua R Sanes, Janey L Wiggs, Ayellet V Segrè^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

Primary open-angle glaucoma (POAG), characterized by retinal ganglion cell death, is a leading cause of irreversible blindness worldwide; however, the 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 of overlapping expression and splicing quantitative trait loci (e/QTLs and sQTLs) in 49 GTEx tissues and retina prioritizesd causal genes for 60% of loci. These genes awere enriched in pathways implicated in extracellular matrix organization, cell adhesion, and vascular development. Analysis of single-nucleus RNA-seq of glaucoma-relevant eye tissues revealesd that the colocalizing genes and genome-wide POAG and IOP associations awere enriched in specific cell types in the aqueous outflow pathways, retina, optic nerve head, peripapillary sclera, and choroid. This study nominatesd IOP-dependent and independent regulatory mechanisms, genes, and cell types that may contribute to POAG pathogenesis.

Original language	English
Journal	Nature Communications
DOIs	https://doi.org/10.1038/s41467-023-44380-y
Publication status	Published - 9 Jan 2024

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Quantitative Traits in Health and Disease
Haley, C.
1/04/18 → 31/03/23
Project: Research

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Hamel, A. R., Yan, W., Rouhana, J. M., Monovarfeshan, A., Jiang, X., Mehta, P. A., Advani, J., Luo, Y., Liang, Q., Rajasundaram, S., Shrivastava, A., Duchinski, K., Mantena, S., Wang, J., Zyl, T. V., 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. https://doi.org/10.1038/s41467-023-44380-y

@article{c0d8e98e72fb45bcb94e619ca11ecc56,

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, the 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 of overlapping expression and splicing quantitative trait loci (e/QTLs and sQTLs) in 49 GTEx tissues and retina prioritizesd causal genes for 60% of loci. These genes awere enriched in pathways implicated in extracellular matrix organization, cell adhesion, and vascular development. Analysis of single-nucleus RNA-seq of glaucoma-relevant eye tissues revealesd that the colocalizing genes and genome-wide POAG and IOP associations awere enriched in specific cell types in the aqueous outflow pathways, retina, optic nerve head, peripapillary sclera, and choroid. This study nominatesd IOP-dependent and independent regulatory mechanisms, genes, and cell types that may contribute to POAG pathogenesis. ",

author = "Hamel, {Andrew R.} and Wenjun Yan and Rouhana, {John M} and Aboozar Monovarfeshan 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 Zyl, {Tav{\'e} van} and Pasquale, {Louis R.} and Anand Swaroop and Puya Gharahkhani and Khawaja, {Anthony P.} and Stuart Macgregor and (IGGC), {International Glaucoma Genetics Consortium} and Rui Chen and Veronique Vitart and Sanes, {Joshua R} and Wiggs, {Janey L} and Segr{\`e}, {Ayellet V}",

note = "Funding Information: We thank members of the Segr{\`e} lab for valuable comments and feedback, and Xiaoquan (William) Wen for helpful discussions on the interpretation of the colocalization results. This work was funded by NIH/NEI R01 EY031424 (A.V.S., A.R.H., J.M.R., P.A.M.), NIH/NEI P30 EY014104 (J.L.W., A.V.S.), NIH/NEI R01 EY032559 (J.L.W., A.V.S., L.R.P.), NIH/NEI R01 EY022305 (J.L.W.), and the Chan Zuckerberg Initiative (CZI) Seed Network for the Human Cell Atlas awards CZF2019-002459 (J.R.S., A.V.S., T.V.Z., W.Y., A.M.) and CZF2019-002425 (Q.L., R.C.). X.J. is supported by the University of Edinburgh and University of Helsinki joint PhD studentship program in Human Genomics. V.V. is supported by an MRC University Unit Programme grant (MC_UU_00007/10) (QTL in Health and Disease). Sr.M. was supported by NIH/NIGMS grant no. T32GM144273. P.G. is supported by an NHMRC Investigator Grant (#1173390). St.M. is supported by an NHMRC Senior Research Fellowship and an NHMRC Program Grant (APP1150144). A.P.K. is supported by a UK Research and Innovation Future Leaders Fellowship, an Alcon Research Institute Young Investigator Award and a Lister Institute for Preventive Medicine Award. This research was supported by the NIHR Biomedical Research Centre at Moorfields Eye Hospital and the UCL Institute of Ophthalmology (A.P.K.). This work is also supported by The Glaucoma Foundation (NYC) and an unrestricted challenge grant from Research to Prevent Blindness (L.R.P.), and intramural Research Program of National Eye Institute (ZIAEY000546 to A.S.). Publisher Copyright: {\textcopyright} 2024, The Author(s).",

year = "2024",

month = jan,

day = "9",

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

language = "English",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Hamel, AR, Yan, W, Rouhana, JM, Monovarfeshan, A, Jiang, X, Mehta, PA, Advani, J, Luo, Y, Liang, Q, Rajasundaram, S, Shrivastava, A, Duchinski, K, Mantena, S, Wang, J, Zyl, TV, Pasquale, LR, Swaroop, A, Gharahkhani, P, Khawaja, AP, Macgregor, S, (IGGC), IGGC, 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. 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 - Monovarfeshan, 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 - Zyl, Tavé van

AU - Pasquale, Louis R.

AU - Swaroop, Anand

AU - Gharahkhani, Puya

AU - Khawaja, Anthony P.

AU - Macgregor, Stuart

AU - (IGGC), International Glaucoma Genetics Consortium

AU - Chen, Rui

AU - Vitart, Veronique

AU - Sanes, Joshua R

AU - Wiggs, Janey L

AU - Segrè, Ayellet V

N1 - Funding Information: We thank members of the Segrè lab for valuable comments and feedback, and Xiaoquan (William) Wen for helpful discussions on the interpretation of the colocalization results. This work was funded by NIH/NEI R01 EY031424 (A.V.S., A.R.H., J.M.R., P.A.M.), NIH/NEI P30 EY014104 (J.L.W., A.V.S.), NIH/NEI R01 EY032559 (J.L.W., A.V.S., L.R.P.), NIH/NEI R01 EY022305 (J.L.W.), and the Chan Zuckerberg Initiative (CZI) Seed Network for the Human Cell Atlas awards CZF2019-002459 (J.R.S., A.V.S., T.V.Z., W.Y., A.M.) and CZF2019-002425 (Q.L., R.C.). X.J. is supported by the University of Edinburgh and University of Helsinki joint PhD studentship program in Human Genomics. V.V. is supported by an MRC University Unit Programme grant (MC_UU_00007/10) (QTL in Health and Disease). Sr.M. was supported by NIH/NIGMS grant no. T32GM144273. P.G. is supported by an NHMRC Investigator Grant (#1173390). St.M. is supported by an NHMRC Senior Research Fellowship and an NHMRC Program Grant (APP1150144). A.P.K. is supported by a UK Research and Innovation Future Leaders Fellowship, an Alcon Research Institute Young Investigator Award and a Lister Institute for Preventive Medicine Award. This research was supported by the NIHR Biomedical Research Centre at Moorfields Eye Hospital and the UCL Institute of Ophthalmology (A.P.K.). This work is also supported by The Glaucoma Foundation (NYC) and an unrestricted challenge grant from Research to Prevent Blindness (L.R.P.), and intramural Research Program of National Eye Institute (ZIAEY000546 to A.S.). Publisher Copyright: © 2024, The Author(s).

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, the 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 of overlapping expression and splicing quantitative trait loci (e/QTLs and sQTLs) in 49 GTEx tissues and retina prioritizesd causal genes for 60% of loci. These genes awere enriched in pathways implicated in extracellular matrix organization, cell adhesion, and vascular development. Analysis of single-nucleus RNA-seq of glaucoma-relevant eye tissues revealesd that the colocalizing genes and genome-wide POAG and IOP associations awere enriched in specific cell types in the aqueous outflow pathways, retina, optic nerve head, peripapillary sclera, and choroid. This study nominatesd 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, the 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 of overlapping expression and splicing quantitative trait loci (e/QTLs and sQTLs) in 49 GTEx tissues and retina prioritizesd causal genes for 60% of loci. These genes awere enriched in pathways implicated in extracellular matrix organization, cell adhesion, and vascular development. Analysis of single-nucleus RNA-seq of glaucoma-relevant eye tissues revealesd that the colocalizing genes and genome-wide POAG and IOP associations awere enriched in specific cell types in the aqueous outflow pathways, retina, optic nerve head, peripapillary sclera, and choroid. This study nominatesd IOP-dependent and independent regulatory mechanisms, genes, and cell types that may contribute to POAG pathogenesis.

U2 - 10.1038/s41467-023-44380-y

DO - 10.1038/s41467-023-44380-y

M3 - Article

SN - 2041-1723

JO - Nature Communications

JF - Nature Communications

ER -

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

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