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 RealiniJoel 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

14 Scopus citations

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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Bailey, J. N. C., Yaspan, B. L., Pasquale, L. R., Hauser, M. A., Kang, J. H., Loomis, S. J., Brilliant, M., Budenz, D. L., Christen, W. G., Fingert, J., Gaasterland, D., Gaasterland, T., Kraft, P., Lee, R. K., Lichter, P. R., Liu, Y., McCarty, C. A., Moroi, S. E., Richards, J. E., ... 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