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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Albertinazzi C, Za L, Paris S, de Curtis I (2003) ADP-ribosylation factor 6 and a functional PIX/p95-APP1 complex are required for Rac1B-mediated neurite outgrowth. Mol Biol Cell 14:1295–1307
Bringmann A, Grosche A, Pannicke T, Reichenbach A (2013) GABA and glutamate uptake and metabolism in retinal glial (Müller) cells. Front Endocrinol (Lausanne) 4:48
Burdon KP, Macgregor S, Hewitt AW, Sharma S, Chidlow G, Mills RA, Danoy P, Casson R, Viswanathan AC, Liu JZ, Landers J, Henders AK, Wood J, Souzeau E, Crawford A, Leo P, Wang JJ, Rochtchina E, Nyholt DR, Martin NG, Montgomery GW, Mitchell P, Brown MA, Mackey DA, Craig JE (2011) Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1. Nat Genet 43:574–578
Caprioli J, Varma R (2011) Intraocular pressure: modulation as treatment for glaucoma. Am J Ophthalmol 152:340–344
Chrysostomou V, Rezania F, Trounce IA, Crowston JG (2013) Oxidative stress and mitochondrial dysfunction in glaucoma. Curr Opin Pharmacol 13:12–25
Clayton LM, Devile M, Punte T, Haan GJ, Sander JW, Acheson JF, Sisodiya SM (2012) Patterns of peripapillary retinal nerve fiber layer thinning in vigabatrin-exposed individuals. Ophthalmol 119:2152–2160
Daniele LL, Adams RH, Durante DE, Pugh EN, Philp NJ (2007) Novel distribution of junctional adhesion molecule-C in the neural retina and retinal pigment epithelium. J Comp Neurol 505:166–176
Dapper JD, Crish SD, Pang IH, Calkins DJ (2013) Proximal inhibition of p38 MAPK stress signaling prevents distal axonopathy. Neurobiol Dis 59C:26–37
Fan BJ, Wiggs JL (2010) Glaucoma: genes, phenotypes, and new directions for therapy. J Clin Invest 120:3064–3072
Fokina VM, Frolova EI (2006) Expression patterns of Wnt genes during development of an anterior part of the chicken eye. Dev Dyn 235:496–505
Friedman DS, Wolfs RC, O’Colmain BJ, Klein BE, Taylor HR, West S, Leske MC, Mitchell P, Congdon N, Kempen J (2004) Prevalence of open-angle glaucoma among adults in the United States. Arch Ophthalmol 122:532–538
Gil-Carrasco F, Vargas-Alarcón G, Zúñiga J, Tinajero-Castañeda O, Hernández-Martinez B, Hernández-Pacheco G, Rodríguez-Reyna TS, Hesiquio R, Gamboa R, Granados J (1999) HLA-DRB and HLA-DQB loci in the genetic susceptibility to develop glaucoma in Mexicans. Am J Ophthalmol 128:297–300
Guo D, Standley C, Bellve K, Fogarty K, Bao ZZ (2012) Protein kinase Cα and integrin-linked kinase mediate the negative axon guidance effects of Sonic hedgehog. Mol Cell Neurosci 50:82–92
Kanehisa M, Goto S (2000) KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res 28:27–30
Lachke SA, Higgins AW, Inagaki M, Saadi I, Xi Q, Long M, Quade BJ, Talkowski ME, Gusella JF, Fujimoto A, Robinson ML, Yang Y, Duong QT, Shapira I, Motro B, Miyoshi J, Takai Y, Morton CC, Maas RL (2012) The cell adhesion gene PVRL3 is associated with congenital ocular defects. Hum Genet 131:235–250
Lawden MC, Eke T, Degg C, Harding GF, Wild JM (1999) Visual field defects associated with vigabatrin therapy. J Neurol Neurosurg Psychiatry 67:716–722
Lee JS, von der Hardt S, Rusch MA, Stringer SE, Stickney HL, Talbot WS, Geisler R, Nüsslein-Volhard C, Selleck SB, Chien CB, Roehl H (2004) Axon sorting in the optic tract requires HSPG synthesis by ext2 (dackel) and extl3 (boxer). Neuron 44:947–960
Lee S, Sheck L, Crowston JG, Van Bergen NJ, O’Neill EC, O’Hare F, Kong YX, Chrysostomou V, Vincent AL, Trounce IA (2012) Impaired complex-I-linked respiration and ATP synthesis in primary open-angle glaucoma patient lymphoblasts. Invest Ophthalmol Vis Sci 53:2431–2437
Liu JZ, McRae AF, Nyholt DR, Medland SE, Wray NR, Brown KM, Investigators AMFS, Hayward NK, Montgomery GW, Visscher PM, Martin NG, Macgregor S (2010) A versatile gene-based test for genome-wide association studies. Am J Hum Genet 87:139–145
Lux AL, Edwards SW, Hancock E, Johnson AL, Kennedy CR, Newton RW, O’Callaghan FJ, Verity CM, Osborne JP (2004) The United Kingdom Infantile Spasms Study comparing vigabatrin with prednisolone or tetracosactide at 14 days: a multicentre, randomised controlled trial. Lancet 364:1773–1778
Manolio TA, Brooks LD, Collins FS (2008) A HapMap harvest of insights into the genetics of common disease. J Clin Invest 118:1590–1605
Martinez G, Wijesinghe M, Turner K, Abud HE, Taketo MM, Noda T, Robinson ML, de Iongh RU (2009) Conditional mutations of beta-catenin and APC reveal roles for canonical Wnt signaling in lens differentiation. Invest Ophthalmol Vis Sci 50:4794–4806
Maurer GD, Brucker DP, Bähr O, Harter PN, Hattingen E, Walenta S, Mueller-Klieser W, Steinbach JP, Rieger J (2011) Differential utilization of ketone bodies by neurons and glioma cell lines: a rationale for ketogenic diet as experimental glioma therapy. BMC Cancer 11:315
Maurus D, Héligon C, Bürger-Schwärzler A, Brändli AW, Kühl M (2005) Noncanonical Wnt-4 signaling and EAF2 are required for eye development in Xenopus laevis. EMBO J 24:1181–1191
Moreno MC, de Zavalía N, Sande P, Jaliffa CO, Fernandez DC, Keller Sarmiento MI, Rosenstein RE (2008) Effect of ocular hypertension on retinal GABAergic activity. Neurochem Int 52:675–682
Nguyen D, Alavi MV, Kim KY, Kang T, Scott RT, Noh YH, Lindsey JD, Wissinger B, Ellisman MH, Weinreb RN, Perkins GA, Ju WK (2011) A new vicious cycle involving glutamate excitotoxicity, oxidative stress and mitochondrial dynamics. Cell Death Dis 2:e240
Okumichi H, Mizukami M, Kiuchi Y, Kanamoto T (2008) GABA A receptors are associated with retinal ganglion cell death induced by oxidative stress. Exp Eye Res 86:727–733
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575
Quigley HA (2011) Glaucoma. Lancet 377:1367–1377
Quigley HA, Broman AT (2006) The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 90:262–267
Racette L, Wilson MR, Zangwill LM, Weinreb RN, Sample PA (2003) Primary open-angle glaucoma in blacks: a review. Surv Ophthalmol 48:295–313
Ramdas WD, Wolfs RC, Kiefte-de Jong JC, Hofman A, de Jong PT, Vingerling JR, Jansonius NM (2012) Nutrient intake and risk of open-angle glaucoma: the Rotterdam Study. Eur J Epidemiol 27(5):385–393
Sedel F, Challe G, Mayer JM, Boutron A, Fontaine B, Saudubray JM, Brivet M (2008) Thiamine responsive pyruvate dehydrogenase deficiency in an adult with peripheral neuropathy and optic neuropathy. J Neurol Neurosurg Psychiatry 79:846–847
Shin DH, Becker B, Kolker AE (1977) Family history in primary open-angle glaucoma. Arch Ophthalmol 95:598–600
Sullivan TA, Geisert EE, Templeton JP, Rex TS (2012) Dose-dependent treatment of optic nerve crush by exogenous systemic mutant erythropoietin. Exp Eye Res 96:36–41
Suzuki M, Meguro A, Ota M, Nomura E, Kato T, Nomura N, Kashiwagi K, Mabuchi F, Iijima H, Kawase K, Yamamoto T, Nakamura M, Negi A, Sagara T, Nishida T, Inatani M, Tanihara H, Aihara M, Araie M, Fukuchi T, Abe H, Higashide T, Sugiyama K, Kanamoto T, Kiuchi Y, Iwase A, Ohno S, Inoko H, Mizuki N (2010) Genotyping HLA-DRB1 and HLA-DQB1 alleles in Japanese patients with normal tension glaucoma. Mol Vis 16:1874–1879
Thorleifsson G, Walters GB, Hewitt AW, Masson G, Helgason A, DeWan A, Sigurdsson A, Jonasdottir A, Gudjonsson SA, Magnusson KP, Stefansson H, Lam DS, Tam PO, Gudmundsdottir GJ, Southgate L, Burdon KP, Gottfredsdottir MS, Aldred MA, Mitchell P, St Clair D, Collier DA, Tang N, Sveinsson O, Macgregor S, Martin NG, Cree AJ, Gibson J, Macleod A, Jacob A, Ennis S, Young TL, Chan JC, Karwatowski WS, Hammond CJ, Thordarson K, Zhang M, Wadelius C, Lotery AJ, Trembath RC, Pang CP, Hoh J, Craig JE, Kong A, Mackey DA, Jonasson F, Thorsteinsdottir U, Stefansson K (2010) Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma. Nat Genet 42:906–909
van der Veen RL, Fuijkschot J, Willemsen MA, Cruysberg JR, Berendschot TT, Theelen T (2010) Patients with Sjögren–Larsson syndrome lack macular pigment. Ophthalmol 117:966–971
Wan G, Mathur R, Hu X, Liu Y, Zhang X, Peng G, Lu X (2013) Long non-coding RNA ANRIL (CDKN2B-AS) is induced by the ATM-E2F1 signaling pathway. Cell Signal 25:1086–1095
Wax MB (2011) The case for autoimmunity in glaucoma. Exp Eye Res 93:187–190
Wiggs JL, Kang JH, Yaspan BL, Mirel DB, Laurie C, Crenshaw A, Brodeur W, Gogarten S, Olson LM, Abdrabou W, DelBono E, Loomis S, Haines JL, Pasquale LR, GENEVA Consortium (2011) Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma in Caucasians from the USA. Hum Mol Genet 20:4707–4713
Wiggs JL, Yaspan BL, Hauser MA, Kang JH, Allingham RR, Olson LM, Abdrabou W, Fan BJ, Wang DY, Brodeur W, Budenz DL, Caprioli J, Crenshaw A, Crooks K, Delbono E, Doheny KF, Friedman DS, Gaasterland D, Gaasterland T, Laurie C, Lee RK, Lichter PR, Loomis S, Liu Y, Medeiros FA, McCarty C, Mirel D, Moroi SE, Musch DC, Realini A, Rozsa FW, Schuman JS, Scott K, Singh K, Stein JD, Trager EH, Vanveldhuisen P, Vollrath D, Wollstein G, Yoneyama S, Zhang K, Weinreb RN, Ernst J, Kellis M, Masuda T, Zack D, Richards JE, Pericak-Vance M, Pasquale LR, Haines JL (2012) Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma. PLoS Genet 8:e1002654
Wiggs JL, Hauser MA, Abdrabou W, Allingham RR, Budenz DL, Delbono E, Friedman DS, Kang JH, Gaasterland D, Gaasterland T, Lee RK, Lichter PR, Loomis S, Liu Y, McCarty C, Medeiros FA, Moroi SE, Olson LM, Realini A, Richards JE, Rozsa FW, Schuman JS, Singh K, Stein JD, Vollrath D, Weinreb RN, Wollstein G, Yaspan BL, Yoneyama S, Zack D, Zhang K, Pericak-Vance M, Pasquale LR, Haines JL (2013) The NEIGHBOR consortium primary open-angle glaucoma genome-wide association study: rationale, study design, and clinical variables. J Glaucoma 22:517–525
Willer CJ, Li Y, Abecasis GR (2010) METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26:2190–2191
Wyatt AW, Osborne RJ, Stewart H, Ragge NK (2010) Bone morphogenetic protein 7 (BMP7) mutations are associated with variable ocular, brain, ear, palate, and skeletal anomalies. Hum Mutat 31:781–787
Yaspan BL, Bush WS, Torstenson ES, Ma D, Pericak-Vance MA, Ritchie MD, Sutcliffe JS, Haines JL (2011) Genetic analysis of biological pathway data through genomic randomization. Hum Genet 129:563–571
Yu DY, Cringle SJ, Balaratnasingam C, Morgan WH, Yu PK, Su EN (2013) Retinal ganglion cells: energetics, compartmentation, axonal transport, cytoskeletons and vulnerability. Prog Retin Eye Res 36:217–246
Zhang C, McCall MA (2012) Receptor targets of amacrine cells. Vis Neurosci 29:11–29
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.
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J. N. C. Bailey, B. L. Yaspan, J. L. Haines and J. L. Wiggs contributed equally.
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Supplemental Fig. 1A. Principal component analysis for primary open-angle cases and the normal-pressure primary open-angle glaucoma subgroup versus controls for the NEIGHBOR cohort. Results are shown for eigenvectors 1 vs 2, 2 vs 3, 3 vs 4 and 4 vs 5. In the original NEIGHBOR GWAS (Wiggs et al. 2012) eigenvectors 1 and 2 were included in the logistic regression model.
Supplemental Fig. 1B. Principal component analysis for primary open-angle glaucoma cases and the normal-pressure primary open-angle glaucoma subgroup cases versus controls for the GLAUGEN cohort. Results are shown for eigenvectors 1 vs 2, 2 vs 3, 3 vs 4 and 4 vs 5. In the original GLAUGEN GWAS (Wiggs et al. 2012) eigenvectors 1, 2 and 6 were included in the logistic regression model.
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Bailey, J.N.C., Yaspan, B.L., Pasquale, L.R. et al. Hypothesis-independent pathway analysis implicates GABA and Acetyl-CoA metabolism in primary open-angle glaucoma and normal-pressure glaucoma. Hum Genet 133, 1319–1330 (2014). https://doi.org/10.1007/s00439-014-1468-7
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DOI: https://doi.org/10.1007/s00439-014-1468-7