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Human Genetics

, Volume 133, Issue 10, pp 1319–1330 | Cite as

Hypothesis-independent pathway analysis implicates GABA and Acetyl-CoA metabolism in primary open-angle glaucoma and normal-pressure glaucoma

  • Jessica N. Cooke Bailey
  • Brian L. Yaspan
  • Louis R. Pasquale
  • Michael A. Hauser
  • Jae H. Kang
  • Stephanie J. Loomis
  • Murray Brilliant
  • Donald L. Budenz
  • William G. Christen
  • John Fingert
  • Douglas Gaasterland
  • Terry Gaasterland
  • Peter Kraft
  • Richard K. Lee
  • Paul R. Lichter
  • Yutao Liu
  • Catherine A. McCarty
  • Sayoko E. Moroi
  • Julia E. Richards
  • Tony Realini
  • Joel S. Schuman
  • William K. Scott
  • Kuldev Singh
  • Arthur J. Sit
  • Douglas Vollrath
  • Gadi Wollstein
  • Donald J. Zack
  • Kang Zhang
  • Margaret A. Pericak-Vance
  • R. Rand Allingham
  • Robert N. Weinreb
  • Jonathan L. Haines
  • Janey L. WiggsEmail author
Original Investigation

Abstract

Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. Using genome-wide association single-nucleotide polymorphism data from the Glaucoma Genes and Environment study and National Eye Institute Glaucoma Human Genetics Collaboration comprising 3,108 cases and 3,430 controls, we assessed biologic pathways as annotated in the KEGG database for association with risk of POAG. After correction for genic overlap among pathways, we found 4 pathways, butanoate metabolism (hsa00650), hematopoietic cell lineage (hsa04640), lysine degradation (hsa00310) and basal transcription factors (hsa03022) related to POAG with permuted p < 0.001. In addition, the human leukocyte antigen (HLA) gene family was significantly associated with POAG (p < 0.001). In the POAG subset with normal-pressure glaucoma (NPG), the butanoate metabolism pathway was also significantly associated (p < 0.001) as well as the MAPK and Hedgehog signaling pathways (hsa04010 and hsa04340), glycosaminoglycan biosynthesis-heparan sulfate pathway (hsa00534) and the phenylalanine, tyrosine and tryptophan biosynthesis pathway (hsa0400). The butanoate metabolism pathway overall, and specifically the aspects of the pathway that contribute to GABA and acetyl-CoA metabolism, was the only pathway significantly associated with both POAG and NPG. Collectively these results implicate GABA and acetyl-CoA metabolism in glaucoma pathogenesis, and suggest new potential therapeutic targets.

Keywords

Glaucoma Human Leukocyte Antigen Retinal Ganglion Cell Vigabatrin Visual Field Loss 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

The Harvard Glaucoma Center of Excellence and Margolis fund (Boston, MA) support LRP and JLW. LRP, JER and JLW are also supported by Research to Prevent Blindness, Inc. (New York, NY). The Arthur Ashley Foundation also supports Dr. Pasquale. The Glaucoma Research Foundation (San Francisco, CA), American Health Assistance Foundation (Clarksburg, MD), and the Glaucoma Foundation (New York, NY) support YL. The following National Institutes of Health Grants support the maintenance of the Nurses Health Study and Health Professionals Follow-up, allowing these health professionals to contribute to this analysis: CA87969, CA49449, UM1 CA167552, and HL35464. The following Grants from the National Human Genome Research Institute (Bethesda, MD) supported GLAUGEN: HG004728 (LRP), HG004424 (Broad Institute to support genotyping), HG004446 (C. Laurie, U. Washington, to support genotype data cleaning and analysis). Genotyping services for the NEIGHBOR study were provided by the Center for Inherited Disease Research (CIDR) and were supported by the National Eye Institute through Grant HG005259-01 (JLW). In addition, CIDR is funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. The National Eye Institute (Bethesda, MD) through ARRA Grants EY015872 (JLW) and EY019126 (MAH) supported the collection and processing of samples for the NEIGHBOR dataset. Funding for the collection of cases and controls was provided by National Institutes of Health (Bethesda, MD) Grants: EY015543 (RRA), EY006827 (DG), HL073389 (Hauser, E), EY13315 (MAH), EY09611 (Hankinson, S), EY015473 (LRP), EY009149 (PRL), HG004608 (CAM), EY008208 (Medeiros, P.), EY015473 (LRP), EY012118 (MAP-V), EY015682 (TR), EY011671 (JER), EY09580 (JER), EY013178 (JSS), EY015872 (JLW), EY010886 (JLW), EY009847 (JLW), EY011008 (Zangwill, L), EY144428 (KZ), EY144448 (KZ), EY18660 (KZ). None of the authors have any commercial interests in the subject of the manuscript or in entities discussed in the manuscript. BL Yaspan and JN Cooke Bailey were supported in part by NIH Grant T32EY021453.

Conflict of interest

The authors have no conflicts of interest relevant to the material presented in this manuscript.

Supplementary material

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Supplementary material 1 (TIFF 640 kb)
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Supplementary material 3 (DOCX 38 kb)
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Supplementary material 4 (DOCX 38 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Jessica N. Cooke Bailey
    • 1
    • 25
  • Brian L. Yaspan
    • 1
    • 26
  • Louis R. Pasquale
    • 2
    • 3
  • Michael A. Hauser
    • 4
    • 5
  • Jae H. Kang
    • 3
  • Stephanie J. Loomis
    • 2
    • 3
  • Murray Brilliant
    • 6
  • Donald L. Budenz
    • 7
  • William G. Christen
    • 8
  • John Fingert
    • 9
    • 10
  • Douglas Gaasterland
    • 11
  • Terry Gaasterland
    • 12
  • Peter Kraft
    • 13
  • Richard K. Lee
    • 14
  • Paul R. Lichter
    • 15
  • Yutao Liu
    • 4
    • 5
  • Catherine A. McCarty
    • 16
  • Sayoko E. Moroi
    • 15
  • Julia E. Richards
    • 15
  • Tony Realini
    • 17
  • Joel S. Schuman
    • 18
  • William K. Scott
    • 19
  • Kuldev Singh
    • 20
  • Arthur J. Sit
    • 21
  • Douglas Vollrath
    • 22
  • Gadi Wollstein
    • 18
  • Donald J. Zack
    • 23
  • Kang Zhang
    • 24
  • Margaret A. Pericak-Vance
    • 19
  • R. Rand Allingham
    • 4
  • Robert N. Weinreb
    • 24
  • Jonathan L. Haines
    • 1
    • 25
  • Janey L. Wiggs
    • 2
    Email author
  1. 1.Center for Human Genetics ResearchVanderbilt UniversityNashvilleUSA
  2. 2.Department of Ophthalmology, Harvard Medical SchoolMassachusetts Eye and Ear InfirmaryBostonUSA
  3. 3.Channing Division of Network MedicineBrigham and Women’s Hospital, Harvard Medical SchoolBostonUSA
  4. 4.Department of OphthalmologyDuke University Medical CenterDurhamUSA
  5. 5.Department of MedicineDuke University Medical CenterDurhamUSA
  6. 6.Center for Human GeneticsMarshfield Clinic Research FoundationMarshfieldUSA
  7. 7.Department of OphthalmologyUniversity of North CarolinaChapel HillUSA
  8. 8.Department of MedicineBrigham and Women’s HospitalBostonUSA
  9. 9.Department of Ophthalmology, College of MedicineUniversity of IowaIowa CityUSA
  10. 10.Department of Anatomy/Cell Biology, College of MedicineUniversity of IowaIowa CityUSA
  11. 11.Eye Doctors of WashingtonChevy ChaseUSA
  12. 12.Scripps Genome CenterUniversity of California at San DiegoSan DiegoUSA
  13. 13.Department of BiostatisticsHarvard School of Public HealthBostonUSA
  14. 14.Bascom Palmer Eye InstituteUniversity of Miami Miller School of MedicineMiamiUSA
  15. 15.Department of Ophthalmology and Visual SciencesUniversity of MichiganAnn ArborUSA
  16. 16.Essentia Institute of Rural HealthDuluthUSA
  17. 17.Department of OphthalmologyWVU Eye InstituteMorgantownUSA
  18. 18.Department of Ophthalmology, UPMC Eye CenterUniversity of PittsburghPittsburghUSA
  19. 19.Institute for Human GenomicsUniversity of Miami Miller School of MedicineMiamiUSA
  20. 20.Department of OphthalmologyStanford UniversityPalo AltoUSA
  21. 21.Department of OphthalmologyMayo ClinicRochesterUSA
  22. 22.Department of GeneticsStanford UniversityPalo AltoUSA
  23. 23.Wilmer Eye InstituteJohns Hopkins University HospitalBaltimoreUSA
  24. 24.Department of Ophthalmology, Hamilton Eye CenterUniversity of CaliforniaSan DiegoUSA
  25. 25.Department of Epidemiology and Biostatistics, Institute of Computational BiologyCase Western Reserve University School of MedicineClevelandUSA
  26. 26.Genentech, IncSouth San FranciscoUSA

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