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 & 13 others 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. Wiggs

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1319-1330
Number of pages12
JournalHuman Genetics
Volume133
Issue number10
DOIs
StatePublished - Jan 1 2014

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Acetyl Coenzyme A
Glaucoma
gamma-Aminobutyric Acid
Pressure
National Eye Institute (U.S.)
Heparitin Sulfate
Medical Genetics
Cell Lineage
Blindness
HLA Antigens
Glycosaminoglycans
Phenylalanine
Tryptophan
Genes
Lysine
Single Nucleotide Polymorphism
Tyrosine
Primary Open Angle Glaucoma
Transcription Factors
Genome

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Bailey, J. N. C., Yaspan, B. L., Pasquale, L. R., Hauser, M. A., Kang, J. H., Loomis, S. J., ... Wiggs, J. L. (2014). Hypothesis-independent pathway analysis implicates GABA and Acetyl-CoA metabolism in primary open-angle glaucoma and normal-pressure glaucoma. Human Genetics, 133(10), 1319-1330. https://doi.org/10.1007/s00439-014-1468-7

Hypothesis-independent pathway analysis implicates GABA and Acetyl-CoA metabolism in primary open-angle glaucoma and normal-pressure glaucoma. / Bailey, Jessica N.Cooke; Yaspan, Brian L.; Pasquale, Louis R.; Hauser, Michael A.; Kang, Jae H.; Loomis, Stephanie J.; Brilliant, Murray; Budenz, Donald L.; Christen, William G.; Fingert, John; Gaasterland, Douglas; Gaasterland, Terry; Kraft, Peter; Lee, Richard K.; Lichter, Paul R.; Liu, Yutao; McCarty, Catherine A.; Moroi, Sayoko E.; Richards, Julia E.; Realini, Tony; Schuman, Joel S.; Scott, William K.; Singh, Kuldev; Sit, Arthur J.; Vollrath, Douglas; Wollstein, Gadi; Zack, Donald J.; Zhang, Kang; Pericak-Vance, Margaret A.; Allingham, R. Rand; Weinreb, Robert N.; Haines, Jonathan L.; Wiggs, Janey L.

In: Human Genetics, Vol. 133, No. 10, 01.01.2014, p. 1319-1330.

Research output: Contribution to journalArticle

Bailey, JNC, Yaspan, BL, Pasquale, LR, Hauser, MA, Kang, JH, Loomis, SJ, Brilliant, M, Budenz, DL, Christen, WG, Fingert, J, Gaasterland, D, Gaasterland, T, Kraft, P, Lee, RK, Lichter, PR, Liu, Y, McCarty, CA, Moroi, SE, Richards, JE, Realini, T, Schuman, JS, Scott, WK, Singh, K, Sit, AJ, Vollrath, D, Wollstein, G, Zack, DJ, Zhang, K, Pericak-Vance, MA, Allingham, RR, Weinreb, RN, Haines, JL & Wiggs, JL 2014, 'Hypothesis-independent pathway analysis implicates GABA and Acetyl-CoA metabolism in primary open-angle glaucoma and normal-pressure glaucoma', Human Genetics, vol. 133, no. 10, pp. 1319-1330. https://doi.org/10.1007/s00439-014-1468-7
Bailey, Jessica N.Cooke ; Yaspan, Brian L. ; Pasquale, Louis R. ; Hauser, Michael A. ; Kang, Jae H. ; Loomis, Stephanie J. ; Brilliant, Murray ; Budenz, Donald L. ; Christen, William G. ; Fingert, John ; Gaasterland, Douglas ; Gaasterland, Terry ; Kraft, Peter ; Lee, Richard K. ; Lichter, Paul R. ; Liu, Yutao ; McCarty, Catherine A. ; Moroi, Sayoko E. ; Richards, Julia E. ; Realini, Tony ; Schuman, Joel S. ; Scott, William K. ; Singh, Kuldev ; Sit, Arthur J. ; Vollrath, Douglas ; Wollstein, Gadi ; Zack, Donald J. ; Zhang, Kang ; Pericak-Vance, Margaret A. ; Allingham, R. Rand ; Weinreb, Robert N. ; Haines, Jonathan L. ; Wiggs, Janey L. / Hypothesis-independent pathway analysis implicates GABA and Acetyl-CoA metabolism in primary open-angle glaucoma and normal-pressure glaucoma. In: Human Genetics. 2014 ; Vol. 133, No. 10. pp. 1319-1330.
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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.",
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T1 - Hypothesis-independent pathway analysis implicates GABA and Acetyl-CoA metabolism in primary open-angle glaucoma and normal-pressure glaucoma

AU - Bailey, Jessica N.Cooke

AU - Yaspan, Brian L.

AU - Pasquale, Louis R.

AU - Hauser, Michael A.

AU - Kang, Jae H.

AU - Loomis, Stephanie J.

AU - Brilliant, Murray

AU - Budenz, Donald L.

AU - Christen, William G.

AU - Fingert, John

AU - Gaasterland, Douglas

AU - Gaasterland, Terry

AU - Kraft, Peter

AU - Lee, Richard K.

AU - Lichter, Paul R.

AU - Liu, Yutao

AU - McCarty, Catherine A.

AU - Moroi, Sayoko E.

AU - Richards, Julia E.

AU - Realini, Tony

AU - Schuman, Joel S.

AU - Scott, William K.

AU - Singh, Kuldev

AU - Sit, Arthur J.

AU - Vollrath, Douglas

AU - Wollstein, Gadi

AU - Zack, Donald J.

AU - Zhang, Kang

AU - Pericak-Vance, Margaret A.

AU - Allingham, R. Rand

AU - Weinreb, Robert N.

AU - Haines, Jonathan L.

AU - Wiggs, Janey L.

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