Abstract
Ammonia is a toxic by-product of protein catabolism and is involved in changes in glutamate metabolism. Therefore, ammonia metabolism genes may link a range of diseases involving glutamate signaling such as Alzheimer’s disease (AD), major depressive disorder (MDD), and type 2 diabetes (T2D). We analyzed data from a National Institute on Aging study with a family-based design to determine if 45 single nucleotide polymorphisms (SNPs) in glutaminase (GLS), carbamoyl phosphate synthetase 1 (CPS1), or glutamate-ammonia ligase (GLUL) genes were associated with AD, MDD, or T2D using PLINK software. HAPLOVIEW software was used to calculate linkage disequilibrium measures for the SNPs. Next, we analyzed the associated variations for potential effects on transcriptional control sites to identify possible functional effects of the SNPs. Of the SNPs that passed the quality control tests, four SNPs in the GLS gene were significantly associated with AD, two SNPs in the GLS gene were associated with T2D, and one SNP in the GLUL gene and three SNPs in the CPS1 gene were associated with MDD before Bonferroni correction. The in silico bioinformatic analysis suggested probable functional roles for six associated SNPs. Glutamate signaling pathways have been implicated in all these diseases, and other studies have detected similar brain pathologies such as cortical thinning in AD, MDD, and T2D. Taken together, these data potentially link GLS with AD, GLS with T2D, and CPS1 and GLUL with MDD and stimulate the generation of testable hypotheses that may help explain the molecular basis of pathologies shared by these disorders.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Akiyama H, McGeer PL, Itagaki S et al (1989) Loss of glutaminase-positive cortical neurons in Alzheimer’s disease. Neurochem Res 14(4):353–358. https://doi.org/10.1007/BF01000038
Ali S, Stone MA, Peters JL, Davies MJ, Khunti K (2006) The prevalence of co-morbid depression in adults with type 2 diabetes: a systematic review and meta-analysis. Diabet Med 23(11):1165–1173. https://doi.org/10.1111/j.1464-5491.2006.01943.x
Amidfar M, Khiabany M, Kohi A, Salardini E, Arbabi M, Roohi Azizi M, Zarrindast MR, Mohammadinejad P, Zeinoddini A, Akhondzadeh S (2017) Effect of memantine combination therapy on symptoms in patients with moderate-to-severe depressive disorder: randomized, double-blind, placebo-controlled study. J Clin Pharm Ther 42(1):44–50. https://doi.org/10.1111/jcpt.12469
Anderson RJ, Freedland KE, Clouse RE, Lustman PJ (2001) The prevalence of comorbid depression in adults with diabetes: a meta-analysis. Diabetes Care 24(6):1069–1078. https://doi.org/10.2337/diacare.24.6.1069
Angelin A, Gil-de-Gómez L, Dahiya S, Jiao J, Guo L, Levine MH, Wang Z, Quinn WJ III, Kopinski PK, Wang L, Akimova T, Liu Y, Bhatti TR, Han R, Laskin BL, Baur JA, Blair IA, Wallace DC, Hancock WW, Beier UH (2017) Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab 25(6):1282–1293.e7. https://doi.org/10.1016/j.cmet.2016.12.018
Ardawi MSM (1987) The maximal activity of phosphate-dependent glutaminase and glutamine metabolism in the colon and the small intestine of streptozotocin-diabetic rats. Diabetologia 30(2):109–114. https://doi.org/10.1007/bf00274581
Auron A, Brophy PD (2012) Hyperammonemia in review: pathophysiology, diagnosis, and treatment. Pediatr Nephrol 27(2):207–222. https://doi.org/10.1007/s00467-011-1838-5
Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21(2):263–265. https://doi.org/10.1093/bioinformatics/bth457
Bernard R, Kerman IA, Thompson RC, Jones EG, Bunney WE, Barchas JD, Schatzberg AF, Myers RM, Akil H, Watson SJ (2011) Altered expression of glutamate signaling, growth factor, and glia genes in the locus coeruleus of patients with major depression. Mol Psychiatry 16(6):634–646. https://doi.org/10.1038/mp.2010.44
Bovolenta LA, Acencio ML, Lemke N (2012) HTRIdb: an open-access database for experimentally verified human transcriptional regulation interactions. BMC Genomics 13(1):405. https://doi.org/10.1186/1471-2164-13-405
Burbaeva GS, Boksha IS, Tereshkina EB, Savushkina OK, Prokhorova TA, Vorobyeva EA (2014) Glutamate and GABA-metabolizing enzymes in post-mortem cerebellum in Alzheimer’s disease: phosphate-activated glutaminase and glutamic acid decarboxylase. Cerebellum 13(5):607–615. https://doi.org/10.1007/s12311-014-0573-4
Cantley J, Ashcroft FM (2015) Q&A: insulin secretion and type 2 diabetes: why do β-cells fail? BMC Biol 13(1):33. https://doi.org/10.1186/s12915-015-0140-6
Chandley MJ, Szebeni K, Szebeni A, Crawford J, Stockmeier A, Turecki G, Miguel-Hidalgo J, Ordway G (2013) Gene expression deficits in pontine locus coeruleus astrocytes in men with major depressive disorder. J Psychiatry Neurosci 38(4):276–284. https://doi.org/10.1503/jpn.120110
Choudary PV, Molnar M, Evans SJ, Tomita H, Li JZ, Vawter MP, Myers RM, Bunney WE, Akil H, Watson SJ, Jones EG (2005) Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. Proc Natl Acad Sci U S A 102(43):15653–15658. https://doi.org/10.1073/pnas.0507901102
Chung SJ, Kim M-J, Kim J, Ryu HS, Kim YJ, Kim SY, Lee JH (2015) Association of type 2 diabetes GWAS loci and the risk of Parkinson’s and Alzheimer’s diseases. Parkinsonism Relat Disord 21(12):1435–1440. https://doi.org/10.1016/j.parkreldis.2015.10.010
Cooper AJL, Jeitner TM (2016) Central role of glutamate metabolism in the maintenance of nitrogen homeostasis in normal and hyperammonemic brain. Biomol Ther 6(2). https://doi.org/10.3390/biom6020016
Crosby ME, Almasan A (2004) Opposing roles of E2Fs in cell proliferation and death. Cancer Biol Ther 3(12):1208–1211. https://doi.org/10.4161/cbt.3.12.1494
Desmet F-O, Hamroun D, Lalande M, Collod-Béroud G, Claustres M, Béroud C (2009) Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 37(9):e67–e67. https://doi.org/10.1093/nar/gkp215
Dimski DS (1994) Ammonia metabolism and the urea cycle: function and clinical implications. J Vet Intern Med 8(2):73–78. https://doi.org/10.1111/j.1939-1676.1994.tb03201.x
Dittmer J (2003) The biology of the Ets1 proto-oncogene. Mol Cancer 2(1):29. https://doi.org/10.1186/1476-4598-2-29
Drucker DJ, Sherman SI, Gorelick FS, Bergenstal RM, Sherwin RS, Buse JB (2010) Incretin-based therapies for the treatment of type 2 diabetes: evaluation of the risks and benefits. Diabetes Care 33(2):428–433. https://doi.org/10.2337/dc09-1499
Du A-T, Schuff N, Kramer JH et al (2007) Different regional patterns of cortical thinning in Alzheimer’s disease and frontotemporal dementia. Brain 130(4):1159–1166. https://doi.org/10.1093/brain/awm016
Esposito Z, Belli L, Toniolo S, Sancesario G, Bianconi C, Martorana A (2013) Amyloid B, glutamate, excitotoxicity in Alzheimer’s disease: are we on the right track? CNS Neurosci Ther 19(8):549–555. https://doi.org/10.1111/cns.12095
Finckh U, Kohlschütter A, Schäfer H, Sperhake K, Colombo JP, Gal A (1998) Prenatal diagnosis of carbamoyl phosphate synthetase I deficiency by identification of a missense mutation in CPS1. Hum Mutat 12(3):206–211. https://doi.org/10.1002/(SICI)1098-1004(1998)12:3<206::AID-HUMU8>3.0.CO;2-E
Fisman M, Gordon B, Feleki V, Helmes E, Appell J, Rabheru K (1985) Hyperammonemia in Alzheimer’s disease. Am J Psychiatry 142(1):71–73. https://doi.org/10.1176/ajp.142.1.71
Gao L, Cui Z, Shen L, Ji H-F (2016) Shared genetic etiology between type 2 diabetes and Alzheimer’s disease identified by bioinformatics analysis. J Alzheimers Dis 50(1):13–17. https://doi.org/10.3233/JAD-150580
Gatz M, Pedersen NL, Berg S, et al (1997) Heritability for Alzheimer’s disease: the study of dementia in Swedish twins. J Gerontol 52:117–125
Geerlings MI, den Heijer T, Koudstaal PJ, Hofman A, Breteler MMB (2008) History of depression, depressive symptoms, and medial temporal lobe atrophy and the risk of Alzheimer disease. Neurology 70(15):1258–1264. https://doi.org/10.1212/01.wnl.0000308937.30473.d1
Gheni G, Ogura M, Iwasaki M, Yokoi N, Minami K, Nakayama Y, Harada K, Hastoy B, Wu X, Takahashi H, Kimura K, Matsubara T, Hoshikawa R, Hatano N, Sugawara K, Shibasaki T, Inagaki N, Bamba T, Mizoguchi A, Fukusaki E, Rorsman P, Seino S (2014) Glutamate acts as a key signal linking glucose metabolism to incretin/cAMP action to amplify insulin secretion. Cell Rep 9(2):661–673. https://doi.org/10.1016/j.celrep.2014.09.030
Gibson J, Russ TC, Adams MJ, Clarke TK, Howard DM, Hall LS, Fernandez-Pujals AM, Wigmore EM, Hayward C, Davies G, Murray AD, Smith BH, Porteous DJ, Deary IJ, McIntosh AM (2017) Assessing the presence of shared genetic architecture between Alzheimer’s disease and major depressive disorder using genome-wide association data. Transl Psychiatry 7(4):e1094. https://doi.org/10.1038/tp.2017.49
Gudala K, Bansal D, Schifano F, Bhansali A (2013) Diabetes mellitus and risk of dementia: a meta-analysis of prospective observational studies. J Diabetes Investig 4(6):640–650. https://doi.org/10.1111/jdi.12087
Gueli MC, Taibi G (2013) Alzheimer’s disease: amino acid levels and brain metabolic status. Neurol Sci 34(9):1575–1579. https://doi.org/10.1007/s10072-013-1289-9
Hao K, Di Narzo AF, Ho L et al (2015) Shared genetic etiology underlying Alzheimer’s disease and type 2 diabetes. Mol Asp Med 43–44:66–76. https://doi.org/10.1016/j.mam.2015.06.006
Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science (80) 256:184–185
Herrup K (2015) The case for rejecting the amyloid cascade hypothesis. Nat Neurosci 18(6):794–799. https://doi.org/10.1038/nn.4017
Hollenhorst PC, Chandler KJ, Poulsen RL, Johnson WE, Speck NA, Graves BJ (2009) DNA specificity determinants associate with distinct transcription factor functions. PLoS Genet 5(12):e1000778. https://doi.org/10.1371/journal.pgen.1000778
Hoyer S, Nitsch R, Oesterreich K (1990) Ammonia is endogenously generated in the brain in the presence of presumed and verified dementia of Alzheimer type. Neurosci Lett 117(3):358–362. https://doi.org/10.1016/0304-3940(90)90691-2
Huang X-T, Li C, Peng X-P, Guo J, Yue SJ, Liu W, Zhao FY, Han JZ, Huang YH, Yang-Li, Cheng QM, Zhou ZG, Chen C, Feng DD, Luo ZQ (2017) An excessive increase in glutamate contributes to glucose-toxicity in β-cells via activation of pancreatic NMDA receptors in rodent diabetes. Sci Rep 7:44120. https://doi.org/10.1038/srep44120
Inagaki N, Kuromi H, Gonoi T, Okamoto Y, Ishida H, Seino Y, Kaneko T, Iwanaga T, Seino S (1995) Expression and role of ionotropic glutamate receptors in pancreatic islet cells. FASEB 9(8):686–691. https://doi.org/10.1096/fasebj.9.8.7768362
Iwanami J, Mogi M, Tsukuda K, Jing F, Ohshima K, Wang XL, Nakaoka H, Kan-no H, Chisaka T, Bai HY, Min LJ, Horiuchi M (2014) Possible synergistic effect of direct angiotensin II type 2 receptor stimulation by compound 21 with memantine on prevention of cognitive decline in type 2 diabetic mice. Eur J Pharmacol 724:9–15. https://doi.org/10.1016/j.ejphar.2013.12.015
Janson J, Laedtke T, Parisi JE, et al (2004) Increased risk of type 2 diabetes in Alzheimer disease
Katon W, Lyles CR, Parker MM, Karter AJ, Huang ES, Whitmer RA (2012) Association of depression with increased risk of dementia in patients with type 2 diabetes. Arch Gen Psychiatry 69(4):410–417. https://doi.org/10.1001/archgenpsychiatry.2011.154
Klaus V, Vermeulen T, Minassian B, Israelian N, Engel K, Lund AM, Roebrock K, Christensen E, Häberle J (2009) Highly variable clinical phenotype of carbamylphosphate synthetase 1 deficiency in one family: an effect of allelic variation in gene expression? Clin Genet 76(3):263–269. https://doi.org/10.1111/j.1399-0004.2009.01216.x
Kulijewicz-Nawrot M, Syková E, Chvátal A, Verkhratsky A, Rodríguez JJ (2013) Astrocytes and glutamate homoeostasis in Alzheimer’s disease: a decrease in glutamine synthetase, but not in glutamate transporter-1, in the prefrontal cortex. ASN Neuro 5(4):273–282. https://doi.org/10.1042/AN20130017
Lau A, Tymianski M (2010) Glutamate receptors, neurotoxicity and neurodegeneration. Eur J Phys 460(2):525–542. https://doi.org/10.1007/s00424-010-0809-1
Lee JH, Cheng R, Graff-Radford N, Foroud T, Mayeux R, National Institute on Aging Late-Onset Alzheimer’s Disease Family Study Group (2008) Analyses of the National Institute on Aging Late-Onset Alzheimer’s Disease Family Study: implication of additional loci. Arch Neurol 65(11):1518–1526. https://doi.org/10.1001/archneur.65.11.1518
Lee Y, Son H, Kim G, Kim S, Lee DH, Roh GS, Kang SS, Cho GJ, Choi WS, Kim HJ (2013) Glutamine deficiency in the prefrontal cortex increases depressive-like behaviours in male mice. J Psychiatry Neurosci 38(3):183–191. https://doi.org/10.1503/jpn.120024
Li X, Song D, Leng SX (2015) Link between type 2 diabetes and Alzheimer’s disease: from epidemiology to mechanism and treatment. Clin Interv Aging 10:549–560. https://doi.org/10.2147/CIA.S74042
Litovchick L, Sadasivam S, Florens L, Zhu X, Swanson SK, Velmurugan S, Chen R, Washburn MP, Liu XS, DeCaprio JA (2007) Evolutionarily conserved multisubunit RBL2/p130 and E2F4 protein complex represses human cell cycle-dependent genes in quiescence. Mol Cell 26(4):539–551. https://doi.org/10.1016/j.molcel.2007.04.015
Liu Z-P, Wu C, Miao H, Wu H (2015) RegNetwork: an integrated database of transcriptional and post-transcriptional regulatory networks in human and mouse. Database 2015:bav095. https://doi.org/10.1093/database/bav095
Luchsinger JA, Reitz C, Honig LS, Tang MX, Shea S, Mayeux R (2005) Aggregation of vascular risk factors and risk of incident Alzheimer disease. Neurology 65(4):545–551. https://doi.org/10.1212/01.wnl.0000172914.08967.dc
Marquard J, Otter S, Welters A, Stirban A, Fischer A, Eglinger J, Herebian D, Kletke O, Klemen MS, Stožer A, Wnendt S, Piemonti L, Köhler M, Ferrer J, Thorens B, Schliess F, Rupnik MS, Heise T, Berggren PO, Klöcker N, Meissner T, Mayatepek E, Eberhard D, Kragl M, Lammert E (2015) Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment. Nat Med 21(4):363–372. https://doi.org/10.1038/nm.3822
McGeer EG, McGeer PL, Akiyama H, Harrop R (1989) Cortical glutaminase, beta-glucuronidase and glucose utilization in Alzheimer’s disease. Can J Neurol Sci 16(S4):511–515. https://doi.org/10.1017/S0317167100029851
Miguel-Hidalgo JJ, Waltzer R, Whittom AA, Austin MC, Rajkowska G, Stockmeier CA (2010) Glial and glutamatergic markers in depression, alcoholism, and their comorbidity. J Affect Disord 127(1-3):230–240. https://doi.org/10.1016/j.jad.2010.06.003
Mirza Z, Kamal MA, Buzenadah AM et al (2014) Establishing genomic/transcriptomic links between Alzheimer’s disease and type 2 diabetes mellitus by meta-analysis approach. CNS Neurol Disord Drug Targets 13(3):501–516. https://doi.org/10.2174/18715273113126660154
Miulli DE, Norwell DY, Schwartz FN (1993) Plasma concentrations of glutamate and its metabolites in patients with Alzheimer’s disease. J Am Osteopath Assoc 93(6):670–676
Myhrer T (1998) Adverse psychological impact, glutamatergic dysfunction, and risk factors for Alzheimer’s disease. Neurosci Biobehav Rev 23(1):131–139. https://doi.org/10.1016/S0149-7634(98)00039-6
Ott A, Stolk RP, van Harskamp F, Pols HAP, Hofman A, Breteler MMB (1999) Diabetes mellitus and the risk of dementia: the Rotterdam Study. Neurology 53(9):1937–1942. https://doi.org/10.1212/WNL.53.9.1937
Proitsi P, Lupton MK, Velayudhan L, Hunter G, Newhouse S, Lin K, Fogh I, Tsolaki M, Daniilidou M, Pritchard M, Craig D, Todd S, Johnston JA, McGuinness B, Kloszewska I, Soininen H, Mecocci P, Vellas B, Passmore PA, Sims R, Williams J, Brayne C, Stewart R, Sham P, Lovestone S, Powell JF (2014) Alleles that increase risk for type 2 diabetes mellitus are not associated with increased risk for Alzheimer’s disease. Neurobiol Aging 35:2883.e3–2882883.e10. doi: https://doi.org/10.1016/j.neurobiolaging.2014.07.023, 12
Prudente S, Shah H, Bailetti D, Pezzolesi M, Buranasupkajorn P, Mercuri L, Mendonca C, de Cosmo S, Niewczas M, Trischitta V, Doria A (2015) Genetic variant at the GLUL locus predicts all-cause mortality in patients with type 2 diabetes. Diabetes 64(7):2658–2663. https://doi.org/10.2337/db14-1653
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, Maller J, Sklar P, de Bakker PIW, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81(3):559–575. https://doi.org/10.1086/519795
Raabe W (1987) Synaptic transmission in ammonia intoxication. Neurochem Pathol 6(1-2):145–166. https://doi.org/10.1007/BF02833604
Robinson SR (2000) Neuronal expression of glutamine synthetase in Alzheimer’s disease indicates a profound impairment of metabolic interactions with astrocytes. Neurochem Int 36(4-5):471–482. https://doi.org/10.1016/S0197-0186(99)00150-3
Rojas J, Teran-Angel G, Barbosa L, Peterson DL, Berrueta L, Salmen S (2016) Activation-dependent mitochondrial translocation of Foxp3 in human hepatocytes. Exp Cell Res 343(2):159–167. https://doi.org/10.1016/j.yexcr.2016.04.008
Sanacora G, Treccani G, Popoli M (2012) Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology 62(1):63–77. https://doi.org/10.1016/j.neuropharm.2011.07.036
Seiler N (1993) Is ammonia a pathogenetic factor in Alzheimer’s disease? Neurochem Res 18(3):235–245. https://doi.org/10.1007/BF00969079
Seiler N (2002) Ammonia and Alzheimer’s disease. Neurochem Int 41(2-3):189–207. https://doi.org/10.1016/S0197-0186(02)00041-4
Suárez I, Bodega G, Fernández B (2002) Glutamine synthetase in brain: effect of ammonia. Neurochem Int 41(2-3):123–142. https://doi.org/10.1016/S0197-0186(02)00033-5
Sullivan PF, Neale MC, Kendler KS (2000) Genetic epidemiology of major depression: review and meta-analysis. Am J Psychiatry 157:1552–1562. https://doi.org/10.1176/appi.ajp.157.10.1552
Suzuki Y, Matsushima A, Ohtake A, Mori M, Tatibana M, Orii T (1986) Carbamyl phosphate synthetase I deficiency with no detectable mRNA activity. Eur J Pediatr 145(5):406–408. https://doi.org/10.1007/BF00439249
Szylberg Ł, Karbownik D, Marszałek A (2016) The role of FOXP3 in human cancers. Anticancer Res 36(8):3789–3794
Tu P-C, Chen L-F, Hsieh J-C, Bai YM, Li CT, Su TP (2012) Regional cortical thinning in patients with major depressive disorder: a surface-based morphometry study. Psychiatry Res Neuroimaging 202(3):206–213. https://doi.org/10.1016/j.pscychresns.2011.07.011
Uhlén M, Fagerberg L, Hallström BM, et al (2015) Tissue-based map of the human proteome
Vent-Schmidt J, Han JM, MacDonald KG, Levings MK (2014) The role of FOXP3 in regulating immune responses. Int Rev Immunol 33(2):110–128. https://doi.org/10.3109/08830185.2013.811657
Willemsen G, Ward KJ, Bell CG, et al (2015) The concordance and heritability of type 2 diabetes in 34,166 twin pairs from international twin registers: the Discordant Twin (DISCOTWIN) Consortium. Twin Res Hum Genet 18:762–771. https://doi.org/10.1017/thg.2015.83
Xu J, Begley P, Church SJ, Patassini S, Hollywood KA, Jüllig M, Curtis MA, Waldvogel HJ, Faull RLM, Unwin RD, Cooper GJS (2016) Graded perturbations of metabolism in multiple regions of human brain in Alzheimer’s disease: snapshot of a pervasive metabolic disorder. Biochim Biophys Acta - Mol Basis Dis 1862(6):1084–1092. https://doi.org/10.1016/j.bbadis.2016.03.001
Yokoi N, Gheni G, Takahashi H, Seino S (2016) β-Cell glutamate signaling: its role in incretin-induced insulin secretion. J Diabetes Investig 7(Suppl 1):38–43. https://doi.org/10.1111/jdi.12468
Yoon S, Cho H, Kim J, Lee DW, Kim GH, Hong YS, Moon S, Park S, Lee S, Lee S, Bae S, Simonson DC, Lyoo IK (2017) Brain changes in overweight/obese and normal-weight adults with type 2 diabetes mellitus. Diabetologia 60(7):1–11. https://doi.org/10.1007/s00125-017-4266-7
Zhou Y, Danbolt NC (2014) Glutamate as a neurotransmitter in the healthy brain. J Neural Transm 121(8):799–817. https://doi.org/10.1007/s00702-014-1180-8
Acknowledgments
We acknowledge the NIH GWAS Data Repository, the Contributing Investigator(s) who contributed the phenotype data and DNA samples from his/her original study, and the primary funding organization that supported the contributing study “National Institute on Aging—Late Onset Alzheimer’s Disease Family Study: Genome-Wide Association Study for Susceptibility Loci.” The datasets used for analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000219.v1.p1. Funding support for the “Genetic Consortium for Late Onset Alzheimer’s Disease” was provided through the Division of Neuroscience, NIA. The Genetic Consortium for Late Onset Alzheimer’s Disease includes a genome-wide association study funded as part of the Division of Neuroscience, NIA. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the Genetic Consortium for Late Onset Alzheimer’s Disease. In addition, JG would like to thank Wayne C. Birchfield for directing his attention to the role of ammonia metabolism in cognitive functioning.
Funding
This study was funded by East Tennessee State University.
Author information
Authors and Affiliations
Contributions
JG and KW performed the research, and JG wrote the first draft of the manuscript. PB, KW, and YL contributed to the content of the manuscript. All authors have approved the final version of this article.
Corresponding author
Ethics declarations
Conflicts of Interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Griffin, J.W.D., Liu, Y., Bradshaw, P.C. et al. In Silico Preliminary Association of Ammonia Metabolism Genes GLS, CPS1, and GLUL with Risk of Alzheimer’s Disease, Major Depressive Disorder, and Type 2 Diabetes. J Mol Neurosci 64, 385–396 (2018). https://doi.org/10.1007/s12031-018-1035-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-018-1035-0