Dataset Information

NEIGHBOR-Methylation in POAG

ABSTRACT:

This is a case-control study of Primary Open Angle Glaucoma (POAG). POAG is a progressive optic neuropathy that eventually leads to blindness. More than 30 million people worldwide have Primary Open Angle Glaucoma (POAG), of which greater than 3 million are blind. Gene expression changes in the retina have been observed for POAG. Several recent studies, including the NEIGHBOR consortium (NEI Glaucoma Human genetic collaboration) have used GWAS to identify correlative regions of the genome. Despite this, the genetic basis of Glaucoma is not well understood. Epigenetic variation may account for low heritability and environmental effects on human disease. Despite the significant advances being made in understanding the role of epigenetics in gene regulation in other fields, little is known about the relationship between DNA methylation patterns, retinal gene expression, and retinal disease. The goal of this study is to identify differentially methylated regions in the peripheral blood of patients with POAG. The case identification is as per the NEIGHBOR description: Cases and controls were recruited from ophthalmology clinics and were examined by ophthalmologists. For cases the clinical exam included intraocular pressure measurements, optic nerve assessment and visual field evaluation. Controls had no family history of glaucoma, normal intraocular pressure and normal optic nerves. POAG and control samples come from two sources: Duke University and Massachusetts Eye and Ear Infirmary (MEEI). These samples were collected and genotyped as part of the NEIGHBOR study. From the 219 POAG cases contributed to NEIGHBOR by Duke, 75 samples were selected for exome sequencing by Dr. Terry Gaasterland (UCSD) as part of an ARRA grant. These samples were selected to mirror the distribution of the entire set of Duke patients for variables such as age, cup-to-disc ratio, CCT, and IOP. From these 75 patients, 43 were selected for our study and an additional seven patients chosen at random, for a total 50 patients from Duke. From the 219 Duke controls, 50 were selected to match the age (at the time of blood draw) and sex of the 50 Duke POAG patients. From the NEIGHBOR control samples from MEEI, 27 were selected who best matched the age (at blood draw), time since sample collection and sex of the POAG probands from GLAUGEN.

Additional individual-level phenotype and genotype data may be obtained through the authorized access portal of phs000238 (Neighbor - Glaucoma GWAS Study).

PROVIDER: phs000458 | dbGaP |

SECONDARY ACCESSION(S): PRJNA264565PRJNA85101

REPOSITORIES: dbGaP

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	GapExchange_phs000458.v1.p1.xml	Xml
	dbGaPEx2.1.5.xsd	Other
	Study_Report.phs000458.CIDR_POA_Glaucoma_Methylation.v1.p1.MULTI.pdf	Pdf
	manifest_phs000458.CIDR_POA_Glaucoma_Methylation.v1.p1.c1.GRU.pdf	Pdf
	manifest_phs000458.CIDR_POA_Glaucoma_Methylation.v1.p1.c2.DS-ED.pdf	Pdf

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Project description:This is a case-control study of Primary Open Angle Glaucoma (POAG). POAG is a progressive optic neuropathy that eventually leads to blindness. More than 30 million people worldwide have Primary Open Angle Glaucoma (POAG), of which greater than 3 million are blind. Gene expression changes in the retina have been observed for POAG. Several recent studies, including the GLAUGEN (Glaucoma Gene Environment) initiative have used GWAS to identify correlative regions of the genome. Despite this, the genetic basis of Glaucoma is not well understood. Epigenetic variation may account for low heritability and environmental effects on human disease. Despite the significant advances being made in understanding the role of epigenetics in gene regulation in other fields, little is known about the relationship between DNA methylation patterns, retinal gene expression, and retinal disease. The goal of this study is to identify differentially methylated regions in the peripheral blood of patients with POAG. The case identification is as per the GLAUGEN description: Cases and controls were recruited from ophthalmology clinics and were examined by ophthalmologists. For cases the clinical exam included intraocular pressure measurements, optic nerve assessment and visual field evaluation. Controls had no family history of glaucoma, normal intraocular pressure and normal optic nerves. POAG and control samples come from Massachusetts Eye and Ear Infirmary (MEEI). These samples were collected and genotyped as part of the GLAUGEN study. From the MEEI, 50 patients were selected from POAG pedigrees, to include all the probands genotyped by CIDR and are currently undergoing exome sequencing, and to include additional genotyped probands who belong to pedigrees of sufficient size and structure that parent of origin effects could be evaluated. Additional individual-level phenotype and genotype data may be obtained through the authorized access portal of <a href="./study.cgi?study_id=phs000308">phs000308</a> (Geneva - Glaugen GWAS Study).

Project description:This is a case-control study of primary open angle glaucoma (POAG). POAG is an intraocular pressure (IOP) related progressive optic neuropathy that ultimately leads to blindness. For this study we have formed a collaborative consortium contributing 2170 POAG cases and 2347 controls with a unified definition of POAG (the NEIGHBOR consortium: NEI Glaucoma Human genetic collaBORation). The case definition has also been harmonized with an additional 976 cases and 1140 controls from the NHGRI supported GENEVA (gene-environment) study of glaucoma (GLAUGEN) (NIH/NHGRI U01HG004728, Pasquale PI). Cases and controls were recruited from ophthalmology clinics and were examined by ophthalmologists. For cases, the clinical exam included intraocular pressure measurements, optic nerve assessment and visual field evaluation. Controls had no family history of glaucoma, normal intraocular pressure and normal optic nerves. Cases and controls were also drawn from two clinical trial populations: Advanced Glaucoma Intervention Study (AGIS, NEI U10EY006827, D. Gaasterland PI) and Collaborative Initial Glaucoma Treatment Study (CIGTS, NEI U10 EY009149, P. Lichter PI). The NEIGHBOR consortium has two Co-Principal Investigators: J. Wiggs (Harvard, MEEI), and M. Hauser (Duke). The consortium includes eleven different centers where data collection and analysis take place. The eleven sites and investigators are: Harvard Medical School (Massachusetts Eye and Ear Infirmary) (J. Wiggs, L. Pasquale); Duke University Medical Center (M. Hauser, E. Hauser, R. Allingham, S. Schmidt); University of Michigan (J. Richards, S. Moroi, P. Lichter); University of Miami (M. Pericak-Vance, R. Lee, D. Budenz); Vanderbilt University (J. Haines); University of California San Diego (K. Zhang, R. Weinreb; T. Gaasterland); University of Pittsburgh (J. Schuman, G. Wollstein); University of West Virginia (A. Realini, J. Charlton, S. Zareparsi); Johns Hopkins University (D. Friedman, D. Zack); Stanford University (D. Vollrath, K. Singh), Eye Doctors of Washington (D. Gaasterland). Hemin Chin serves as the NEI Staff Collaborator. This national collaborative study is supported by multiple NIH grants: NEI R01 EY015543 (Allingham); NEI U10 EY006827 (D. Gaasterland); NHLBI R01 HL073389 (E. Hauser); NEI R01 EY13315 (M. Hauser); NEI U10 EY009149 (Lichter); NEI R01 EY015473 (Pasquale); NEI U10 EY012118 (Pericak-Vance); NEI R03 EY015682 (Realini); NEI R01 EY011671 (Richards); NEI R01 EY09580 (Richards); NEI R01 EY013178 (Schuman); NEI R01 EY015872 (Wiggs); NEI R01 EY009847 (Wiggs); NEI R01 EY010886 (Wiggs); NEI R01 EY144428 (Zhang); NEI R01 EY144448 (Zhang); NEI R01 EY18660 (Zhang). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the National Eye Institute (X01HG005259).

Project description:This is a study of primary open angle glaucoma (POAG) conducted through exome sequencing of cases and comparison of variant frequencies with general population frequencies available in dbGAP and controlled for sequencing platform artifact to minimize false positives. POAG is an intraocular pressure (IOP) related progressive optic neuropathy that ultimately leads to blindness. This study builds upon the efforts of an on-going collaborative consortium that studied 2,170 POAG cases and 2,347 controls with a unified definition of POAG (the NEIGHBOR consortium: NEI Glaucoma Human genetic collaBORation). The case definition for NEIGHBOR was harmonized with an additional 976 cases and 1140 controls from the NHGRI supported GENEVA (gene-environment) study of glaucoma (GLAUGEN) (NIH/NHGRI U01HG004728, Pasquale PI). In NEIGHBOR, cases and controls were recruited from ophthalmology clinics and were examined by ophthalmologists. For cases, the clinical exam included intraocular pressure measurements, optic nerve assessment and visual field evaluation. Controls had no family history of glaucoma, normal intraocular pressure and normal optic nerves. Cases and controls were also drawn from two clinical trial populations: Advanced Glaucoma Intervention Study (AGIS, NEI U10EY006827, D. Gaasterland PI) and Collaborative Initial Glaucoma Treatment Study (CIGTS, NEI U10 EY009149, P. Lichter PI). The Glaucoma Exome Sequencing study has one Principal Investigator: Theresa Gaasterland (UCSD) and two Co-Investigators: Robert Weinreb, MD, and Kang Zhang, MD, PhD, all of whom are part of the NEIGHBOR, subsequently NEIGHBORHOOD, consortium, which in turn has two Co-Principal Investigators: J. Wiggs (Harvard, MEEI), and M. Hauser (Duke). NEIGHBOR collaborators who contributed samples and/or expertise to the Glaucoma Exome Sequencing study included the following: Harvard Medical School (Massachusetts Eye and Ear Infirmary) (J. Wiggs, L. Pasquale); Duke University Medical Center (M. Hauser, E. Hauser, R. Allingham, S. Schmidt); University of Michigan (J. Richards, S. Moroi, P. Lichter); University of Miami (M. Pericak-Vance, R. Lee, D. Budenz); Vanderbilt University (J. Haines); University of California San Diego (K. Zhang, R. Weinreb; T. Gaasterland); University of Pittsburgh (J. Schuman, G. Wollenstein); University of West Virginia (A. Realini, J. Charlton, S. Zareparsi); Johns Hopkins University (D. Friedman); Stanford University (D. Vollrath, K. Singh), Eye Doctors of Washington (D. Gaasterland), Marshfield Clinic (Cathy McCarty). Hemin Chin serves as the NEI Staff Collaborator. This national collaborative study is supported by multiple NIH grants: NEI R01 EY015543 (Allingham); NEI U10 EY006827 (D. Gaasterland); NHLBI R01 HL073389 (E. Hauser); NEI R01 EY13315 (M. Hauser); NEI U10 EY009149 (Lichter); NEI R01 EY015473 (Pasquale); NEI U10 EY012118 (Pericak-Vance); NEI R03 EY015682 (Realini); NEI R01 EY011671 (Richards); NEI R01 EY09580 (Richards); NEI R01 EY013178 (Schuman); NEI R01 EY015872 (Wiggs); NEI R01 EY009847 (Wiggs); NEI R01 EY010886 (Wiggs); NEI R01 EY144428 (Zhang); NEI R01 EY144448 (Zhang); NEI R01 EY18660 (Zhang). Funding support for genotyping through exome sequencing, which was performed at the University of California, San Diego, was provided by the National Eye Institute (RC2 EY020678-01).

Project description:Glaucoma is a group of diseases characterized by progressive optic nerve damage leading to irreversible visual field loss, often associated with elevated intraocular pressure (IOP). However, the specific underlying factors or molecular mechanisms distinguishing various glaucoma subtypes are still not fully understood. In this study, we enrolled a total of 27 subjects, comprising 5 exfoliation syndrome (XFS), 4 exfoliation glaucoma (XFG), 11 primary open-angle glaucoma (POAG), and 7 cataract patients (Control) for a comparative multi-omics analysis including both proteomics and metabolomics of the aqueous humor (AH). The AH proteome and metabolome were analyzed separately using data-independent acquisition (DIA) and data-dependent acquisition (DDA) methods, after which the results were additionally integrated for a comprehensive analysis. The comparative proteomics analysis led to the identification of differentially expressed proteins (DEPs) related to lipid metabolism, complement activation, and extracellular matrix (ECM) regulation, which were commonly up-regulated in both XFG and POAG groups. The metabolomics analysis revealed differentially expressed metabolites (DEMs) particularly those involved in amino acids, suggesting their role in antioxidative processes. Thus, bioinformatic analysis suggested significant substances, such as VTN, APOA1, C6, and L-phenylalanine, that showed quantitative alterations in glaucoma patients. In addition, the integrating the individual omics analyses revealed interaction networks involving PLG, APOA1, and L-phenylalanine, or C3, APOD, and L-valine, suggesting the quantitative relationship in protein-metabolite interactions related to inflammation and lipid metabolism within the AH of glaucoma patients. Furthermore, the correlation approach identified a relationship between FGG and L-phenylalanine, and VTN and inosine, implying potential interactions among compounds not previously identified. These findings would provide valuable insights into the complex molecular mechanism differentiating glaucoma subtypes and may benefit further research into the clinical application of AH proteome and metabolome.

Project description:Primary Open-Angle Glaucoma (POAG) and Pseudoexfoliation Glaucoma (PEXG) are forms of glaucoma with distinct etiologies, but they share a common type of optic neurodegeneration that leads to irreversible loss of retinal ganglion cells, visual field and blindness if left untreated. The main objective in the present study was to explore whether differential-proteomic analysis of blood serum from patients with POAG or PEXG could lead to the identification of candidate biomarkers of glaucoma and provide clues to pathogenic mechanisms. A total of 202 blood samples from medically treated patients with POAG (n=73), PEXG (n=59), and cataracts (control, n=70) were collected and analyzed following a proteomic workflow that involved two phases: discovery and validation. In the discovery phase, differential-proteomics (2D-DIGE) methodology led to the identification of a panel of 35 proteins that were altered (i.e., over- or under-expressed) in serum samples of glaucoma patients. Functional pathway analysis suggested a potential involvement of these proteins in immunological and inflammatory pathways. In the validation phase, ELISA assays of the top-17-ranked proteins confirmed that most of them were over-expressed in the glaucoma groups. Stepwise discriminant analysis of the ELISA data resulted in a six-protein panel (APOA4, TF, C3, APOL1, IGHG2, C4A) that was used to generate multivariate predictive models. These models achieved a diagnostic efficiency of 81% (correct assignment), specificity of 83%, and sensitivity of 92%. Specifically, 100% efficacy was reached in the discrimination of the POAG group from control, and 86% efficacy in the discrimination of POAG from PEXG. Overall, these data demonstrate the discovery of a panel of serum biomarkers that could be used in large-scale multiplexed screenings for the diagnosis of POAG and PEXG patients. Furthermore, these biomarkers may have a role in the pathogenesis, and association to immune-inflammatory processes with glaucoma.

Dataset Information

NEIGHBOR-Methylation in POAG

Dataset's files

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