PMID- 25037249
OWN - NLM
STAT- MEDLINE
DCOM- 20141118
LR  - 20240213
IS  - 1432-1203 (Electronic)
IS  - 0340-6717 (Print)
IS  - 0340-6717 (Linking)
VI  - 133
IP  - 10
DP  - 2014 Oct
TI  - Hypothesis-independent pathway analysis implicates GABA and acetyl-CoA metabolism 
      in primary open-angle glaucoma and normal-pressure glaucoma.
PG  - 1319-30
LID - 10.1007/s00439-014-1468-7 [doi]
AB  - 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.
FAU - Bailey, Jessica N Cooke
AU  - Bailey JN
AD  - Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA.
FAU - Yaspan, Brian L
AU  - Yaspan BL
FAU - Pasquale, Louis R
AU  - Pasquale LR
FAU - Hauser, Michael A
AU  - Hauser MA
FAU - Kang, Jae H
AU  - Kang JH
FAU - Loomis, Stephanie J
AU  - Loomis SJ
FAU - Brilliant, Murray
AU  - Brilliant M
FAU - Budenz, Donald L
AU  - Budenz DL
FAU - Christen, William G
AU  - Christen WG
FAU - Fingert, John
AU  - Fingert J
FAU - Gaasterland, Douglas
AU  - Gaasterland D
FAU - Gaasterland, Terry
AU  - Gaasterland T
FAU - Kraft, Peter
AU  - Kraft P
FAU - Lee, Richard K
AU  - Lee RK
FAU - Lichter, Paul R
AU  - Lichter PR
FAU - Liu, Yutao
AU  - Liu Y
FAU - McCarty, Catherine A
AU  - McCarty CA
FAU - Moroi, Sayoko E
AU  - Moroi SE
FAU - Richards, Julia E
AU  - Richards JE
FAU - Realini, Tony
AU  - Realini T
FAU - Schuman, Joel S
AU  - Schuman JS
FAU - Scott, William K
AU  - Scott WK
FAU - Singh, Kuldev
AU  - Singh K
FAU - Sit, Arthur J
AU  - Sit AJ
FAU - Vollrath, Douglas
AU  - Vollrath D
FAU - Wollstein, Gadi
AU  - Wollstein G
FAU - Zack, Donald J
AU  - Zack DJ
FAU - Zhang, Kang
AU  - Zhang K
FAU - Pericak-Vance, Margaret A
AU  - Pericak-Vance MA
FAU - Allingham, R Rand
AU  - Allingham RR
FAU - Weinreb, Robert N
AU  - Weinreb RN
FAU - Haines, Jonathan L
AU  - Haines JL
FAU - Wiggs, Janey L
AU  - Wiggs JL
LA  - eng
GR  - R01 EY011671/EY/NEI NIH HHS/United States
GR  - T32 EY021453/EY/NEI NIH HHS/United States
GR  - R01 EY015473/EY/NEI NIH HHS/United States
GR  - EY009149/EY/NEI NIH HHS/United States
GR  - R01 EY022306/EY/NEI NIH HHS/United States
GR  - R01 EY013315/EY/NEI NIH HHS/United States
GR  - EY144428/EY/NEI NIH HHS/United States
GR  - U01 HG004728/HG/NHGRI NIH HHS/United States
GR  - T32EY021453/EY/NEI NIH HHS/United States
GR  - U01 HG004446/HG/NHGRI NIH HHS/United States
GR  - EY012118/EY/NEI NIH HHS/United States
GR  - UL1 TR000427/TR/NCATS NIH HHS/United States
GR  - R01 EY011008/EY/NEI NIH HHS/United States
GR  - P01 CA087969/CA/NCI NIH HHS/United States
GR  - R01 EY014448/EY/NEI NIH HHS/United States
GR  - EY18660/EY/NEI NIH HHS/United States
GR  - EY015473/EY/NEI NIH HHS/United States
GR  - P30 EY022589/EY/NEI NIH HHS/United States
GR  - EY015872/EY/NEI NIH HHS/United States
GR  - EY010886/EY/NEI NIH HHS/United States
GR  - CA87969/CA/NCI NIH HHS/United States
GR  - EY009847/EY/NEI NIH HHS/United States
GR  - U01 HG004424/HG/NHGRI NIH HHS/United States
GR  - R01 HL073389/HL/NHLBI NIH HHS/United States
GR  - EY011671/EY/NEI NIH HHS/United States
GR  - CA49449/CA/NCI NIH HHS/United States
GR  - EY13315/EY/NEI NIH HHS/United States
GR  - HG005259-01/HG/NHGRI NIH HHS/United States
GR  - EY015682/EY/NEI NIH HHS/United States
GR  - EY019126/EY/NEI NIH HHS/United States
GR  - R01 EY012118/EY/NEI NIH HHS/United States
GR  - R01 EY015543/EY/NEI NIH HHS/United States
GR  - R56 EY011671/EY/NEI NIH HHS/United States
GR  - R01 EY008208/EY/NEI NIH HHS/United States
GR  - HG004608/HG/NHGRI NIH HHS/United States
GR  - HG004728/HG/NHGRI NIH HHS/United States
GR  - HHSN268200782096C/HG/NHGRI NIH HHS/United States
GR  - EY013178/EY/NEI NIH HHS/United States
GR  - R01 EY013178/EY/NEI NIH HHS/United States
GR  - EY09611/EY/NEI NIH HHS/United States
GR  - EY006827/EY/NEI NIH HHS/United States
GR  - R01 EY019126/EY/NEI NIH HHS/United States
GR  - R03 EY015682/EY/NEI NIH HHS/United States
GR  - R01 EY022305/EY/NEI NIH HHS/United States
GR  - HG004446/HG/NHGRI NIH HHS/United States
GR  - HL35464/HL/NHLBI NIH HHS/United States
GR  - R01 EY009611/EY/NEI NIH HHS/United States
GR  - R01 EY011405/EY/NEI NIH HHS/United States
GR  - EY011008/EY/NEI NIH HHS/United States
GR  - U10 EY010379/EY/NEI NIH HHS/United States
GR  - UM1 CA167552/CA/NCI NIH HHS/United States
GR  - R01 EY009580/EY/NEI NIH HHS/United States
GR  - R01 HL035464/HL/NHLBI NIH HHS/United States
GR  - U10 EY012118/EY/NEI NIH HHS/United States
GR  - R01 CA049449/CA/NCI NIH HHS/United States
GR  - P30 EY014104/EY/NEI NIH HHS/United States
GR  - R01 EY015872/EY/NEI NIH HHS/United States
GR  - R01 EY009847/EY/NEI NIH HHS/United States
GR  - R01 EY010886/EY/NEI NIH HHS/United States
GR  - U01 CA049449/CA/NCI NIH HHS/United States
GR  - HL073389/HL/NHLBI NIH HHS/United States
GR  - EY09580/EY/NEI NIH HHS/United States
GR  - HG004424/HG/NHGRI NIH HHS/United States
GR  - EY015543/EY/NEI NIH HHS/United States
GR  - EY008208/EY/NEI NIH HHS/United States
GR  - U01 HG004608/HG/NHGRI NIH HHS/United States
GR  - R01 EY023512/EY/NEI NIH HHS/United States
GR  - R01 EY018660/EY/NEI NIH HHS/United States
GR  - EY144448/EY/NEI NIH HHS/United States
GR  - U10 EY009149/EY/NEI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, American Recovery and Reinvestment Act
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140719
PL  - Germany
TA  - Hum Genet
JT  - Human genetics
JID - 7613873
RN  - 56-12-2 (gamma-Aminobutyric Acid)
RN  - 72-89-9 (Acetyl Coenzyme A)
SB  - IM
MH  - Acetyl Coenzyme A/*metabolism
MH  - Case-Control Studies
MH  - Cluster Analysis
MH  - Female
MH  - Genetic Predisposition to Disease
MH  - Glaucoma/*genetics/metabolism
MH  - Glaucoma, Open-Angle/*genetics/metabolism
MH  - Humans
MH  - Intraocular Pressure/genetics
MH  - Male
MH  - Metabolic Networks and Pathways/*genetics
MH  - Models, Genetic
MH  - Polymorphism, Single Nucleotide
MH  - gamma-Aminobutyric Acid/*metabolism
PMC - PMC4273559
MID - NIHMS647438
COIS- Conflict of interest The authors have no conflicts of interest relevant to the 
      material presented in this manuscript.
EDAT- 2014/07/20 06:00
MHDA- 2014/11/19 06:00
PMCR- 2015/10/01
CRDT- 2014/07/20 06:00
PHST- 2014/03/24 00:00 [received]
PHST- 2014/07/08 00:00 [accepted]
PHST- 2014/07/20 06:00 [entrez]
PHST- 2014/07/20 06:00 [pubmed]
PHST- 2014/11/19 06:00 [medline]
PHST- 2015/10/01 00:00 [pmc-release]
AID - 10.1007/s00439-014-1468-7 [doi]
PST - ppublish
SO  - Hum Genet. 2014 Oct;133(10):1319-30. doi: 10.1007/s00439-014-1468-7. Epub 2014 
      Jul 19.