Genome-wide analyses identify 68 new loci associated with intraocular pressure and improve risk prediction for primary open-angle glaucoma

Khawaja, Anthony P.; Bailey, Jessica N. Cooke; Wareham, Nicholas J.; Scott, Robert A.; Simcoe, Mark James; Igo, Robert P.; Song, Yeunjoo E.; Wojciechowski, Robert; Cheng, Ching‐Yu; Khaw, Peng Tee; Pasquale, Louis R.; Haines, Jonathan L.; Foster, Paul J.; Wiggs, Janey L.; Hammond, Christopher J.; Hysi, Pirro G.; Eye, UK Biobank

doi:10.1038/s41588-018-0126-8

Cited by 234 publications

(316 citation statements)

References 58 publications

(79 reference statements)

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“…Both Tie2 and Angpt1 loss of function variants associate with risk of congenital glaucoma, and singlenucleotide polymorphisms in the Angpt1 promoter region significantly associate with primary openangle glaucoma risk (57)(58)(59). Consistent with immunofluorescence data in mice (60,61), our ssRNAseq data show that expression of Angpt1 in the conventional outflow tract is limited to TM cell clusters, while Tek (Tie2) and its antagonist, Angpt2 are expressed by lymphatic/endothelia cell clusters.…”

Section: Cell Type Specific Expression Of Glaucoma-related Genessupporting

confidence: 83%

Molecular taxonomy of human ocular outflow tissues defined by single cell transcriptomics

Patel

Fury

Yang

et al. 2020

Preprint

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The conventional outflow pathway is a complex tissue responsible for maintaining intraocular pressure (IOP) homeostasis. The coordinated effort of multiple cells with differing responsibilities ensure healthy outflow function and IOP maintenance. Dysfunction of one or more resident cell type results in ocular hypertension and risk for glaucoma, a leading cause of blindness. In this study, single cell RNA sequencing was performed to generate a comprehensive cell atlas of human conventional outflow tissues. We obtained 17757 genes expression profiles from 8758 cells from eight eyes of four donors representing the outflow cell transcriptome. Upon clustering analysis, 12 distinct cell types were identified, and region-specific expression of candidate genes were mapped in human tissues. Significantly, we identified two distinct expression patterns (myofibroblast and fibroblast) from cells located in the trabecular meshwork (TM), the primary structural component of the conventional outflow pathway. We also located neuron and macrophage signatures in the TM.The second primary component structure, Schlemm's canal displayed a unique combination of lymphatic/blood vascular gene expression. Other expression clusters corresponded to cells from neighboring tissues, predominantly in the ciliary muscle/scleral spur, which together correspond to the uveoscleral outflow path. Importantly, the utility of our atlas was demonstrated by mapping glaucomarelevant genes to outflow cell clusters. Our study provides a comprehensive molecular and cellular classification of conventional and unconventional outflow pathway structures responsible for IOP homeostasis. Significance statementOcular hypertension is the primary, and only modifiable risk factor for glaucoma, the leading cause of irreversible blindness. Intraocular pressure is regulated homeostatically by resistance to aqueous humor outflow through an architecturally complex tissue, the conventional/trabecular pathway. In this study, we generated a comprehensive cell atlas of the human trabecular meshwork and neighboring tissues using single cell, RNA sequencing. We identified 12 distinct cell types, and mapped regionspecific expression of candidate genes. The utility of our atlas was demonstrated by mapping glaucoma-relevant genes to conventional outflow cell clusters. Our study provides a comprehensive molecular and cellular classification of tissue structures responsible for intraocular pressure homeostasis in health, and dysregulation in disease.

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Section: Cell Type Specific Expression Of Glaucoma-related Genessupporting

confidence: 83%

Molecular taxonomy of human ocular outflow tissues defined by single cell transcriptomics

Patel

Fury

Yang

et al. 2020

Preprint

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“…As an example, the POAG phenotype may be defined in many different ways: by the associated traits (endophenotypes) cup‐to‐disc ratio (CDR), intraocular pressure (IOP), visual field (VF) loss, or by some combination of these (reviewed in Weinreb, Aung, & Medeiros, ). Fifteen loci have been identified as genetic risk modifiers of disease (Burdon et al., ; Chen et al., ; Cooke Bailey, Hoffman, et al., ; Gharahkhani et al., ; Hysi et al., ; Li et al., ; Thorleifsson et al., ; Wiggs et al., ), and numerous others identified in POAG endophenotypes have recently shown association with POAG (Gao, Huang, Nannini, Fan, & Kim, ; Khawaja et al., ; MacGregor et al., ). The genetic factors identified in studies of POAG and its component phenotypes (such as IOP, CDR, VF changes) overlap but are not identical.…”

Section: Critical Parameters and Complicating Factorsmentioning

confidence: 99%

Genetic Risk Scores

2019

Self Cite

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Genome‐wide variation data with millions of genetic markers have become commonplace. However, the potential for interpretation and application of these data for clinical assessment of outcomes of interest, and prediction of disease risk, is currently not fully realized. Many common complex diseases now have numerous, well‐established risk loci and likely harbor many genetic determinants with effects too small to be detected at genome‐wide levels of statistical significance. A simple and intuitive approach for converting genetic data to a predictive measure of disease susceptibility is to aggregate the effects of these loci into a single measure, the genetic risk score. Here, we describe some common methods and software packages for calculating genetic risk scores and polygenic risk scores, with focus on studies of common complex diseases. We review the basic information needed, as well as important considerations for constructing genetic risk scores, including specific requirements for phenotypic and genetic data, and limitations in their application. © 2019 by John Wiley & Sons, Inc.

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“…Reports have shown that incidence rate of glaucoma is higher in siblings compared with unrelated controls, indicating an important role of host genetics in predisposition to glaucoma. Recent genome wide association studies reveled role of ATP‐binding cassette transporter A1, actin filament‐associated protein 1, GDP‐mannose 4,6 dehydratase, phosphomannomutase 2, transforming growth factor beta receptor III, fibronectin type III domain containing 3B, rho guanine nucleotide exchange factor 12, growth arrest‐specific protein 7, forkhead box C1, ataxin‐2, thioredoxin reductase 2 with POAG, and PACG showed to be linked to ependymin related 1, choline acetyltransferase, gli‐similar protein 3, fermitin family member 2, and dolichyl‐phosphate mannosyltransferase subunit 2 . Furthermore, various candidate gene association studies presented association of single nucleotide polymorphisms with predisposition to development of POAG or PACG.…”

Section: Introductionmentioning

confidence: 99%

“…Recent genome wide association studies reveled role of ATP-binding cassette transporter A1, actin filament-associated protein 1, GDP-mannose 4,6 dehydratase, phosphomannomutase 2, transforming growth factor beta receptor III, fibronectin type III domain containing 3B, rho guanine nucleotide exchange factor 12, growth arrest-specific protein 7, forkhead box C1, ataxin-2, thioredoxin reductase 2 with POAG, and PACG showed to be linked to ependymin related 1, choline acetyltransferase, gli-similar protein 3, fermitin family member 2, and dolichyl-phosphate mannosyltransferase subunit 2. [6][7][8][9][10] Furthermore, various candidate gene association studies presented association of single nucleotide polymorphisms with predisposition to development of POAG or PACG. Role of matrix metalloproteinase-9 (MMP-9) variants have been well investigated in different populations as MMP-9 gene is responsible for remodeling of extracellular matrix.…”

Section: Introductionmentioning

confidence: 99%

Role of matrix metalloproteinase‐9 gene polymorphisms in glaucoma: A hospital‐based study in Chinese patients

Zhao

Fan

Huang

2019

Clinical Laboratory Analysis

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Background Glaucoma is the irreversible vision loss and contributes second leading cause of blindness worldwide. Matrix metalloproteinase‐9 (MMP‐9) is involved with remodeling and destruction of extracellular matrix. Elevated MMP‐9 levels and various functional variants of MMP‐9 have been associated with glaucoma in different population. In the current investigation, we tested association of MMP‐9 common variants with different clinical categories of glaucoma in Chinese population. Materials and Methods We enrolled total of 396 glaucoma patients those reported to hospital comprising of 212 primary angle closure glaucoma (PACG) cases and 184 primary open‐angle glaucoma POAG patients. In addition, 329 normal individuals from similar geographical areas were enrolled as healthy controls. Five common single nucleotide polymorphisms (rs3918242, rs3918254, rs2250889, rs3918249, and rs17576) were genotyped by PCR‐RFLP. Plasma levels of MMP‐9 were quantified by ELISA. Results Heterozygotes (GC) and allele “G” for rs2250889 polymorphism were more frequent in PACG cases compared with healthy controls (GC: P < .0001, OR = 2.26; G: P < .0001, OR = 1.19). Similarly, heterozygous mutant and minor allele for rs3918242 polymorphism were more prevalent in POAG in comparison with healthy controls. Interestingly, distribution of rs17576 variant was statistically higher in both PACG and POAG cases than healthy controls. Furthermore, analysis of plasma MMP‐9 with MMP‐9 polymorphisms revealed significant association of rs2250889, rs3918242, and rs17576 with plasma levels of the protein. Conclusions MMP‐9 mutants are associated with elevated plasma MMP‐9 and predisposed to development of glaucoma.

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Genome-wide analyses identify 68 new loci associated with intraocular pressure and improve risk prediction for primary open-angle glaucoma

Cited by 234 publications

References 58 publications

Molecular taxonomy of human ocular outflow tissues defined by single cell transcriptomics

Molecular taxonomy of human ocular outflow tissues defined by single cell transcriptomics

Genetic Risk Scores

Role of matrix metalloproteinase‐9 gene polymorphisms in glaucoma: A hospital‐based study in Chinese patients

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