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

被引：13

作者：

Hamel, Andrew R. ^{[1
,2
,3
]}

Yan, Wenjun ^{[4
,5
]}

Rouhana, John M. ^{[1
,2
,3
]}

Monovarfeshani, Aboozar ^{[4
,5
]}

Jiang, Xinyi ^{[6
,7
]}

Mehta, Puja A. ^{[1
,2
,3
]}

Advani, Jayshree ^{[8
]}

Luo, Yuyang ^{[1
,2
,3
]}

Liang, Qingnan ^{[9
]}

Rajasundaram, Skanda ^{[2
,10
,11
]}

Shrivastava, Arushi ^{[1
,2
,3
]}

Duchinski, Katherine ^{[1
,2
,3
,12
]}

Mantena, Sreekar ^{[1
,13
]}

Wang, Jiali ^{[1
,2
,3
]}

van Zyl, Tave ^{[4
,5
,14
]}

Pasquale, Louis R. ^{[15
]}

Swaroop, Anand ^{[8
]}

Gharahkhani, Puya ^{[16
]}

Khawaja, Anthony P. ^{[17
,18
]}

MacGregor, Stuart ^{[16
]}

Chen, Rui ^{[18
]}

Vitart, Veronique

Sanes, Joshua R.

Wiggs, Janey L.

Segre, Ayellet V. ^{[1
,2
,3
]}

机构：

[1] Massachusetts Eye & Ear, Dept Ophthalmol, Ocular Genom Inst, Boston, MA 02114 USA

[2] Harvard Med Sch, Dept Ophthalmol, Boston, MA 02115 USA

[3] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA

[4] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA

[5] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA

[6] Univ Edinburgh, Inst Genet & Canc, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland

[7] Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Edinburgh, Midlothian, Scotland

[8] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA

[9] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[10] Univ Oxford, Ctr Evidence Based Med, Oxford, England

[11] Imperial Coll London, Fac Med, London, England

[12] Harvard Med Sch, Bioinformat & Integrat Genom BIG PhD Program, Boston, MA 02115 USA

[13] Harvard Med Sch, Harvard MIT MD PhD Program, Boston, MA 02115 USA

[14] Yale Sch Med, Dept Ophthalmol & Visual Sci, New Haven, CT USA

[15] Icahn Sch Med Mt Sinai, Dept Ophthalmol, New York, NY USA

[16] QIMR Berghofer Med Res Inst, Brisbane, Qld 4029, Australia

[17] Moorfields Eye Hosp NHS Fdn Trust, NIHR Biomed Res Ctr, London, England

[18] UCL Inst Ophthalmol, London, England

来源：

NATURE COMMUNICATIONS | 2024年 / 15卷 / 01期

基金：

澳大利亚国家健康与医学研究理事会; 英国科研创新办公室;

关键词：

GENOME-WIDE ASSOCIATION; CENTRAL CORNEAL THICKNESS; OPTIC-NERVE HEAD; MENDELIAN RANDOMIZATION; RNA-SEQ; VARIANTS; COLOCALIZATION; PROGRESSION; PATHWAYS; TISSUES;

D O I：

10.1038/s41467-023-44380-y

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：25

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