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

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Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma
Nature Communications ( IF 14.7 ) Pub Date : 2024-01-09 , DOI: 10.1038/s41467-023-44380-y
Andrew R Hamel _{1,

2,

3} , Wenjun Yan ₄ , John M Rouhana _{1,

2,

3} , Aboozar Monovarfeshani ₄ , Xinyi Jiang _{5,

6} , Puja A Mehta _{1,

2,

3} , Jayshree Advani ₇ , Yuyang Luo _{1,

2,

3} , Qingnan Liang ₈ , Skanda Rajasundaram _{2,

9,

10} , Arushi Shrivastava _{1,

2,

3} , Katherine Duchinski _{1,

2,

3,

11} , Sreekar Mantena _{1,

12} , Jiali Wang _{1,

2,

3} , Tavé van Zyl _{4,

13} , Louis R Pasquale ₁₄ , Anand Swaroop ₇ , Puya Gharahkhani ₁₅ , Anthony P Khawaja ₁₆ , Stuart MacGregor ₁₅ , , Rui Chen ₈ , Veronique Vitart ₅ , Joshua R Sanes ₄ , Janey L Wiggs _{1,

2,

3} , Ayellet V Segrè _{1,

2,

3}

Affiliation

Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA, USA.
Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, MA, USA.
MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK.
Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK.
Neurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MA, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Centre for Evidence-Based Medicine, University of Oxford, Oxford, UK.
Faculty of Medicine, Imperial College London, London, UK.
Bioinformatics and Integrative Genomics (BIG) PhD Program, Harvard Medical School, Boston, MA, USA.
Harvard/MIT MD-PhD Program, Harvard Medical School, Boston, MA, USA.
Department of Ophthalmology and Visual Sciences, Yale School of Medicine, New Haven, CT, USA.
Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4029, Australia.
NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK.

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.

中文翻译：

将遗传调控和单细胞表达与 GWAS 相结合优先考虑青光眼的致病基因和细胞类型

原发性开角型青光眼（POAG）以视网膜神经节细胞死亡为特征，是全球不可逆失明的主要原因。然而，其分子和细胞原因尚不清楚。眼压（IOP）升高是一个主要危险因素，但许多患者的眼压正常。>240 POAG 和 IOP 全基因组关联研究（GWAS）基因座的共定位和孟德尔随机化分析以及 49 个 GTEx 组织和视网膜中的重叠表达和剪接数量性状基因座（e/sQTLs）优先考虑 60% 的基因座的致病基因。这些基因在与细胞外基质组织、细胞粘附和血管发育有关的通路中富集。对青光眼相关眼组织的单核 RNA-seq 的分析表明，POAG 和 IOP 共定位基因和全基因组关联在房流出途径、视网膜、视神经头、周围巩膜和脉络膜的特定细胞类型中富集。本研究指定了可能导致 POAG 发病机制的 IOP 依赖性和独立调节机制、基因和细胞类型。

更新日期：2024-01-09

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