title: Hypothesis-independent pathway analysis implicates GABA and acetyl-CoA metabolism in primary open-angle glaucoma and normal-pressure glaucoma.
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.
authors.affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA.
authors.forename: Jessica N Cooke
authors.initials: JN
authors.lastname: Bailey
authors.forename: Brian L
authors.initials: BL
authors.lastname: Yaspan
authors.forename: Louis R
authors.initials: LR
authors.lastname: Pasquale
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hauser
authors.forename: Jae H
authors.initials: JH
authors.lastname: Kang
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Loomis
authors.forename: Murray
authors.initials: M
authors.lastname: Brilliant
authors.forename: Donald L
authors.initials: DL
authors.lastname: Budenz
authors.forename: William G
authors.initials: WG
authors.lastname: Christen
authors.forename: John
authors.initials: J
authors.lastname: Fingert
authors.forename: Douglas
authors.initials: D
authors.lastname: Gaasterland
authors.forename: Terry
authors.initials: T
authors.lastname: Gaasterland
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.forename: Richard K
authors.initials: RK
authors.lastname: Lee
authors.forename: Paul R
authors.initials: PR
authors.lastname: Lichter
authors.forename: Yutao
authors.initials: Y
authors.lastname: Liu
authors.forename: Catherine A
authors.initials: CA
authors.lastname: McCarty
authors.forename: Sayoko E
authors.initials: SE
authors.lastname: Moroi
authors.forename: Julia E
authors.initials: JE
authors.lastname: Richards
authors.forename: Tony
authors.initials: T
authors.lastname: Realini
authors.forename: Joel S
authors.initials: JS
authors.lastname: Schuman
authors.forename: William K
authors.initials: WK
authors.lastname: Scott
authors.forename: Kuldev
authors.initials: K
authors.lastname: Singh
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Sit
authors.forename: Douglas
authors.initials: D
authors.lastname: Vollrath
authors.forename: Gadi
authors.initials: G
authors.lastname: Wollstein
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Zack
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.forename: R Rand
authors.initials: RR
authors.lastname: Allingham
authors.forename: Robert N
authors.initials: RN
authors.lastname: Weinreb
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.forename: Janey L
authors.initials: JL
authors.lastname: Wiggs
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism*; D016022:Case-Control Studies; D016000:Cluster Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D005901:Glaucoma / Q000235:genetics* / Q000378:metabolism; D005902:Glaucoma, Open-Angle / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007429:Intraocular Pressure / Q000235:genetics; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D005680:gamma-Aminobutyric Acid; D000105:Acetyl Coenzyme A