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Glycobiology and schizophrenia: a biological hypothesis emerging from genomic research

Molecular Psychiatry volume 25, pages 3129–3139 (2020)Cite this article

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Abstract

Advances in genomics are opening new windows into the biology of schizophrenia. Though common variants individually have small effects on disease risk, GWAS provide a powerful opportunity to explore pathways and mechanisms contributing to pathophysiology. Here, we highlight an underappreciated biological theme emerging from GWAS: the role of glycosylation in schizophrenia. The strongest coding variant in schizophrenia GWAS is a missense mutation in the manganese transporter SLC39A8, which is associated with altered glycosylation patterns in humans. Furthermore, variants near several genes encoding glycosylation enzymes are unambiguously associated with schizophrenia: FUT9, MAN2A1, TMTC1, GALNT10, and B3GAT1. Here, we summarize the known biological functions, target substrates, and expression patterns of these enzymes as a primer for future studies. We also highlight a subset of schizophrenia-associated proteins critically modified by glycosylation including glutamate receptors, voltage-gated calcium channels, the dopamine D2 receptor, and complement glycoproteins. We hypothesize that common genetic variants alter brain glycosylation and play a fundamental role in the development of schizophrenia. Leveraging these findings will advance our mechanistic understanding of disease and may provide novel avenues for treatment development.

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Fig. 1: Glycosylation enzymes unambiguously associated with schizophrenia through GWAS.
Fig. 2: Select neuronal proteins critically modified through glycosylation and associated with schizophrenia through GWAS.

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References

  1. Moreno-Küstner B, Martín C, Pastor L. Prevalence of psychotic disorders and its association with methodological issues. A systematic review and meta-analyses. PLoS ONE. 2018;13:e0195687.

    PubMed  PubMed Central  Google Scholar 

  2. Owen MJ, Sawa A, Mortensen PB. Schizophrenia. Lancet. 2016;388:86–97.

    PubMed  PubMed Central  Google Scholar 

  3. American Psychiatric Association, DSM-5 Task Force. Diagnostic and statistical manual of mental disorders: DSM-5. American Psychiatric Association; Arlington, VA, USA; 2013.

  4. Kahn RS, Sommer IE, Murray RM, Meyer-Lindenberg A, Weinberger DR, Cannon TD, et al. Schizophrenia. Nat Rev Dis Prim. 2015;1:15067.

    PubMed  Google Scholar 

  5. Birnbaum R, Weinberger DR. Genetic insights into the neurodevelopmental origins of schizophrenia. Nat Rev Neurosci. 2017;18:727–40.

    CAS  PubMed  Google Scholar 

  6. Millan MJ, Andrieux A, Bartzokis G, Cadenhead K, Dazzan P, Fusar-Poli P, et al. Altering the course of schizophrenia: progress and perspectives. Nat Rev Drug Discov. 2016;15:485–515.

    CAS  PubMed  Google Scholar 

  7. Avramopoulos D. Recent advances in the genetics of schizophrenia. Mol Neuropsychiatry 2018;4:35–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421–7.

    PubMed Central  Google Scholar 

  9. Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N, et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016;530:177–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Lauc G, Pezer M, Rudan I, Campbell H. Mechanisms of disease: the human N-glycome. Biochim Biophys Acta. 2016;1860:1574–82.

    CAS  PubMed  Google Scholar 

  11. Varki A. Biological roles of glycans. Glycobiology. 2017;27:3–49.

    CAS  PubMed  Google Scholar 

  12. Varki A, Cummings RD, Esko JD, Stanley P, Hart GW, Aebi M, et al., editors. Essentials of Glycobiology. 3rd ed. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 2015.

  13. Williams SE, Mealer RG, Scolnick EM, Smoller JW, Cummings RD. Aberrant glycosylation in schizophrenia: A review of 25 years of post-mortem brain studies. Mol Psychiatry. https://doi.org/10.1038/s41380-020-0761-1. (In Press, 2020).

  14. de Vries T, Knegtel RM, Holmes EH, Macher BA. Fucosyltransferases: structure/function studies. Glycobiology. 2001;11:119R–28R.

    PubMed  Google Scholar 

  15. Schneider M, Al-Shareffi E, Haltiwanger RS. Biological functions of fucose in mammals. Glycobiology. 2017;27:601–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Kudo T, Ikehara Y, Togayachi A, Kaneko M, Hiraga T, Sasaki K, et al. Expression cloning and characterization of a novel murine alpha1, 3-fucosyltransferase, mFuc-TIX, that synthesizes the Lewis x (CD15) epitope in brain and kidney. J Biol Chem. 1998;273:26729–38.

    CAS  PubMed  Google Scholar 

  17. Cailleau-Thomas A, Coullin P, Candelier JJ, Balanzino L, Mennesson B, Oriol R, et al. FUT4 and FUT9 genes are expressed early in human embryogenesis. Glycobiology. 2000;10:789–802.

    CAS  PubMed  Google Scholar 

  18. Mai JK, Andressen C, Ashwell KW. Demarcation of prosencephalic regions by CD15-positive radial glia. Eur J Neurosci. 1998;10:746–51.

    CAS  PubMed  Google Scholar 

  19. Mai JK, Krajewski S, Reifenberger G, Genderski B, Lensing-Höhn S, Ashwell KW. Spatiotemporal expression gradients of the carbohydrate antigen (CD15) (Lewis X) during development of the human basal ganglia. Neuroscience. 1999;88:847–58.

    CAS  PubMed  Google Scholar 

  20. Gotz M, Wizenmann A, Reinhardt S, Lumsden A, Price J. Selective adhesion of cells from different telencephalic regions. Neuron. 1996;16:551–64.

    CAS  PubMed  Google Scholar 

  21. Sajdel-Sulkowska EM. Immunofluorescent detection of CD15-fucosylated glycoconjugates in primary cerebellar cultures and their function in glial-neuronal adhesion in the central nervous system. Acta Biochim Pol. 1998;45:781–90.

    CAS  PubMed  Google Scholar 

  22. Pruszak J, Ludwig W, Blak A, Alavian K, Isacson O. CD15, CD24, and CD29 define a surface biomarker code for neural lineage differentiation of stem cells. Stem Cells. 2009;27:2928–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Fagerberg L, Hallström BM, Oksvold P, Kampf C, Djureinovic D, Odeberg J, et al. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteom. 2014;13:397–406.

    CAS  Google Scholar 

  24. Kaneko M, Kudo T, Iwasaki H, Ikehara Y, Nishihara S, Nakagawa S, et al. Alpha1,3-fucosyltransferase IX (Fuc-TIX) is very highly conserved between human and mouse; molecular cloning, characterization and tissue distribution of human Fuc-TIX. FEBS Lett. 1999;452:237–42.

    CAS  PubMed  Google Scholar 

  25. Nishihara S, Iwasaki H, Nakajima K, Togayachi A, Ikehara Y, Kudo T, et al. Alpha1,3-fucosyltransferase IX (Fut9) determines Lewis X expression in brain. Glycobiology. 2003;13:445–55.

    CAS  PubMed  Google Scholar 

  26. Gouveia R, Schaffer L, Papp S, Grammel N, Kandzia S, Head SR, et al. Expression of glycogenes in differentiating human NT2N neurons. Downregulation of fucosyltransferase 9 leads to decreased Lewis(x) levels and impaired neurite outgrowth. Biochim Biophys Acta. 2012;1820:2007–19.

    CAS  PubMed  Google Scholar 

  27. Kudo T, Fujii T, Ikegami S, Inokuchi K, Takayama Y, Ikehara Y, et al. Mice lacking alpha1,3-fucosyltransferase IX demonstrate disappearance of Lewis x structure in brain and increased anxiety-like behaviors. Glycobiology. 2007;17:1–9.

    CAS  PubMed  Google Scholar 

  28. Misago M, Liao YF, Kudo S, Eto S, Mattei MG, Moremen KW, et al. Molecular cloning and expression of cDNAs encoding human alpha-mannosidase II and a previously unrecognized alpha-mannosidase IIx isozyme. Proc Natl Acad Sci USA. 1995;92:11766–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Moremen KW, Robbins PW. Isolation, characterization, and expression of cDNAs encoding murine alpha-mannosidase II, a Golgi enzyme that controls conversion of high mannose to complex N-glycans. J Cell Biol. 1991;115:1521–34.

    CAS  PubMed  Google Scholar 

  30. Chui D, Oh-Eda M, Liao YF, Panneerselvam K, Lal A, Marek KW, et al. Alpha-mannosidase-II deficiency results in dyserythropoiesis and unveils an alternate pathway in oligosaccharide biosynthesis. Cell. 1997;90:157–67.

    CAS  PubMed  Google Scholar 

  31. Chui D, Sellakumar G, Green R, Sutton-Smith M, McQuistan T, Marek K, et al. Genetic remodeling of protein glycosylation in vivo induces autoimmune disease. Proc Natl Acad Sci USA. 2001;98:1142–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Akama TO, Nakagawa H, Sugihara K, Narisawa S, Ohyama C, Nishimura S-I, et al. Germ cell survival through carbohydrate-mediated interaction with Sertoli cells. Science. 2002;295:124–7.

    PubMed  Google Scholar 

  33. Akama TO, Nakagawa H, Wong NK, Sutton-Smith M, Dell A, Morris HR, et al. Essential and mutually compensatory roles of {alpha}-mannosidase II and {alpha}-mannosidase IIx in N-glycan processing in vivo in mice. Proc Natl Acad Sci USA. 2006;103:8983–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Hill WD, Marioni RE, Maghzian O, Ritchie SJ, Hagenaars SP, McIntosh AM, et al. A combined analysis of genetically correlated traits identifies 187 loci and a role for neurogenesis and myelination in intelligence. Mol Psychiatry. 2018. https://doi.org/10.1038/s41380-017-0001-5.

  35. Savage JE, Jansen PR, Stringer S, Watanabe K, Bryois J, de Leeuw CA, et al. Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence. Nat Genet. 2018;50:912–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Thyme SB, Pieper LM, Li EH, Pandey S, Wang Y, Morris NS, et al. Phenotypic landscape of schizophrenia-associated genes defines candidates and their shared functions. Cell. 2019. https://doi.org/10.1016/j.cell.2019.01.048.

  37. Sunryd JC, Cheon B, Graham JB, Giorda KM, Fissore RA, Hebert DN. TMTC1 and TMTC2 are novel endoplasmic reticulum tetratricopeptide repeat-containing adapter proteins involved in calcium homeostasis. J Biol Chem. 2014;289:16085–99.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Larsen ISB, Narimatsu Y, Joshi HJ, Siukstaite L, Harrison OJ, Brasch J, et al. Discovery of an O-mannosylation pathway selectively serving cadherins and protocadherins. Proc Natl Acad Sci USA. 2017;114:11163–8.

    PubMed  PubMed Central  Google Scholar 

  39. Vester-Christensen MB, Halim A, Joshi HJ, Steentoft C, Bennett EP, Levery SB, et al. Mining the O-mannose glycoproteome reveals cadherins as major O-mannosylated glycoproteins. Proc Natl Acad Sci USA. 2013;110:21018–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Larsen ISB, Narimatsu Y, Joshi HJ, Yang Z, Harrison OJ, Brasch J, et al. Mammalian O-mannosylation of cadherins and plexins is independent of protein O-mannosyltransferases 1 and 2. J Biol Chem. 2017;292:11586–98.

    PubMed  PubMed Central  Google Scholar 

  41. Shao Z, Noh H, Bin Kim W, Ni P, Nguyen C, Cote SE, et al. Dysregulated protocadherin-pathway activity as an intrinsic defect in induced pluripotent stem cell-derived cortical interneurons from subjects with schizophrenia. Nat Neurosci. 2019;22:229–42.

    PubMed  PubMed Central  Google Scholar 

  42. de Wit J, Ghosh A. Specification of synaptic connectivity by cell surface interactions. Nat Rev Neurosci. 2016;17:22–35.

    PubMed  Google Scholar 

  43. Basu R, Duan X, Taylor MR, Martin EA, Muralidhar S, Wang Y, et al. Heterophilic type II cadherins are required for high-magnitude synaptic potentiation in the hippocampus. Neuron. 2017;96:160–76.e8.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Chen WV, Nwakeze CL, Denny CA, O’Keeffe S, Rieger MA, Mountoufaris G, et al. Pcdhαc2 is required for axonal tiling and assembly of serotonergic circuitries in mice. Science. 2017;356:406–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Mountoufaris G, Chen WV, Hirabayashi Y, O’Keeffe S, Chevee M, Nwakeze CL, et al. Multicluster Pcdh diversity is required for mouse olfactory neural circuit assembly. Science. 2017;356:411–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Yun EJ, Vu TH. mSmile is necessary for bronchial smooth muscle and alveolar myofibroblast development. Anat Rec. 2012;295:167–76.

    CAS  Google Scholar 

  47. Jerber J, Zaki MS, Al-Aama JY, Rosti RO, Ben-Omran T, Dikoglu E, et al. Biallelic mutations in TMTC3, encoding a transmembrane and TPR-containing protein, lead to cobblestone lissencephaly. Am J Hum Genet. 2016;99:1181–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Farhan SMK, Nixon KCJ, Everest M, Edwards TN, Long S, Segal D, et al. Identification of a novel synaptic protein, TMTC3, involved in periventricular nodular heterotopia with intellectual disability and epilepsy. Hum Mol Genet. 2017;26:4278–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Steentoft C, Vakhrushev SY, Joshi HJ, Kong Y, Vester-Christensen MB, Schjoldager KT-BG, et al. Precision mapping of the human O-GalNAc glycoproteome through SimpleCell technology. EMBO J. 2013;32:1478–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Ju T, Cummings RD. Protein glycosylation: chaperone mutation in Tn syndrome. Nature. 2005;437:1252.

    CAS  PubMed  Google Scholar 

  51. Ju T, Otto VI, Cummings RD. The Tn antigen-structural simplicity and biological complexity. Angew Chem Int Ed Engl. 2011;50:1770–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Bennett EP, Mandel U, Clausen H, Gerken TA, Fritz TA, Tabak LA. Control of mucin-type O-glycosylation: a classification of the polypeptide GalNAc-transferase gene family. Glycobiology. 2012;22:736–56.

    CAS  PubMed  Google Scholar 

  53. Bult CJ, Blake JA, Smith CL, Kadin JA, Richardson JE, the Mouse Genome Database Group. et al. Mouse genome database (MGD) 2019. Nucleic Acids Res. 2019;47:D801–6.

    CAS  PubMed  Google Scholar 

  54. Goes FS, McGrath J, Avramopoulos D, Wolyniec P, Pirooznia M, Ruczinski I, et al. Genome-wide association study of schizophrenia in Ashkenazi Jews. Am J Med Genet Part B Neuropsychiatr Genet. 2015;168:649–59.

    CAS  Google Scholar 

  55. Morise J, Takematsu H, Oka S. The role of human natural killer-1 (HNK-1) carbohydrate in neuronal plasticity and disease. Biochim Biophys Acta Gen Subj. 2017;1861:2455–61.

    CAS  PubMed  Google Scholar 

  56. Bakker H, Friedmann I, Oka S, Kawasaki T, Nifant’ev N, Schachner M, et al. Expression cloning of a cDNA encoding a sulfotransferase involved in the biosynthesis of the HNK-1 carbohydrate epitope. J Biol Chem. 1997;272:29942–6.

    CAS  PubMed  Google Scholar 

  57. Abo T, Balch CM. A differentiation antigen of human NK and K cells identified by a monoclonal antibody (HNK-1). J Immunol. 1950;1981:1024–9.

    Google Scholar 

  58. Chou DK, Ilyas AA, Evans JE, Costello C, Quarles RH, Jungalwala FB. Structure of sulfated glucuronyl glycolipids in the nervous system reacting with HNK-1 antibody and some IgM paraproteins in neuropathy. J Biol Chem. 1986;261:11717–25.

    CAS  PubMed  Google Scholar 

  59. Yamamoto S, Oka S, Inoue M, Shimuta M, Manabe T, Takahashi H, et al. Mice deficient in nervous system-specific carbohydrate epitope HNK-1 exhibit impaired synaptic plasticity and spatial learning. J Biol Chem. 2002;277:27227–31.

    CAS  PubMed  Google Scholar 

  60. Morita I, Kakuda S, Takeuchi Y, Kawasaki T, Oka S. HNK-1 (human natural killer-1) glyco-epitope is essential for normal spine morphogenesis in developing hippocampal neurons. Neuroscience. 2009;164:1685–94.

    CAS  PubMed  Google Scholar 

  61. Nobile-Orazio E, Manfredini E, Carpo M, Meucci N, Monaco S, Ferrari S, et al. Frequency and clinical correlates of anti-neural IgM antibodies in neuropathy associated with IgM monoclonal gammopathy. Ann Neurol. 1994;36:416–24.

    CAS  PubMed  Google Scholar 

  62. García-Ayllón M-S, Botella-López A, Cuchillo-Ibañez I, Rábano A, Andreasen N, Blennow K, et al. HNK-1 carrier glycoproteins are decreased in the Alzheimer’s disease brain. Mol Neurobiol. 2017;54:188–99.

    PubMed  Google Scholar 

  63. Jeffries AR, Mungall AJ, Dawson E, Halls K, Langford CF, Murray RM, et al. Beta-1,3-Glucuronyltransferase-1 gene implicated as a candidate for a schizophrenia-like psychosis through molecular analysis of a balanced translocation. Mol Psychiatry. 2003;8:654–63.

    CAS  PubMed  Google Scholar 

  64. Kähler AK, Djurovic S, Rimol LM, Brown AA, Athanasiu L, Jönsson EG, et al. Candidate gene analysis of the human natural killer-1 carbohydrate pathway and perineuronal nets in schizophrenia: B3GAT2 is associated with disease risk and cortical surface area. Biol Psychiatry. 2011;69:90–6.

    PubMed  Google Scholar 

  65. Ramakrishnan B, Ramasamy V, Qasba PK. Structural snapshots of β-1,4-galactosyltransferase-I along the kinetic pathway. J Mol Biol. 2006;357:1619–33.

    CAS  PubMed  Google Scholar 

  66. Breton C, Šnajdrová L, Jeanneau C, Koča J, Imberty A. Structures and mechanisms of glycosyltransferases. Glycobiology. 2006;16:29R–37R.

    CAS  PubMed  Google Scholar 

  67. Chang A, Singh S, Phillips GN, Thorson JS. Glycosyltransferase structural biology and its role in the design of catalysts for glycosylation. Curr Opin Biotechnol. 2011;22:800–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Park JH, Hogrebe M, Grüneberg M, DuChesne I, von der Heiden AL, Reunert J, et al. SLC39A8 deficiency: a disorder of manganese transport and glycosylation. Am J Hum Genet. 2015;97:894–903.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Boycott KM, Beaulieu CL, Kernohan KD, Gebril OH, Mhanni A, Chudley AE, et al. Autosomal-recessive intellectual disability with cerebellar atrophy syndrome caused by mutation of the manganese and zinc transporter gene SLC39A8. Am J Hum Genet. 2015;97:886–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Mealer RG, Jenkins BG, Chen C-Y, Daly MJ, Ge T, Lehoux S, et al. A schizophrenia risk locus alters brain metal transport and plasma glycosylation. 2019. https://doi.org/10.1101/757088.

  71. Lin W, Vann DR, Doulias P-T, Wang T, Landesberg G, Li X, et al. Hepatic metal ion transporter ZIP8 regulates manganese homeostasis and manganese-dependent enzyme activity. J Clin Investig. 2017;127:2407–17.

    PubMed  PubMed Central  Google Scholar 

  72. Li M, Wu D-D, Yao Y-G, Huo Y-X, Liu J-W, Su B, et al. Recent positive selection drives the expansion of a schizophrenia risk nonsynonymous variant at SLC39A8 in Europeans. Schizophr Bull. 2016;42:178–90.

    PubMed  Google Scholar 

  73. Costas J. The highly pleiotropic gene SLC39A8 as an opportunity to gain insight into the molecular pathogenesis of schizophrenia. Am J Med Genet B Neuropsychiatr Genet. 2018;177:274–83.

    CAS  PubMed  Google Scholar 

  74. Fujishiro H, Himeno S. New insights into the roles of ZIP8, a cadmium and manganese transporter, and its relation to human diseases. Biol Pharm Bull. 2019;42:1076–82.

    CAS  PubMed  Google Scholar 

  75. Zang Z-S, Xu Y-M, Lau ATY. Molecular and pathophysiological aspects of metal ion uptake by the zinc transporter ZIP8 (SLC39A8). Toxicol Res. 2016;5:987–1002.

    CAS  Google Scholar 

  76. Nebert DW, Liu Z. SLC39A8 gene encoding a metal ion transporter: discovery and bench to bedside. Hum Genom. 2019;13:51.

    Google Scholar 

  77. Howes O, McCutcheon R, Stone J. Glutamate and dopamine in schizophrenia: an update for the 21st century. J Psychopharmacol. 2015;29:97–115.

    PubMed  PubMed Central  Google Scholar 

  78. The UniProt Consortium. UniProt: a worldwide hub of protein knowledge. Nucleic Acids Res. 2019;47:D506–15.

    Google Scholar 

  79. Kandel MB, Yamamoto S, Midorikawa R, Morise J, Wakazono Y, Oka S, et al. N-glycosylation of the AMPA-type glutamate receptor regulates cell surface expression and tetramer formation affecting channel function. J Neurochem. 2018;147:730–47.

    CAS  PubMed  Google Scholar 

  80. Storey GP, Opitz-Araya X, Barria A. Molecular determinants controlling NMDA receptor synaptic incorporation. J Neurosci J Soc Neurosci. 2011;31:6311–6.

    CAS  Google Scholar 

  81. Sinitskiy AV, Stanley NH, Hackos DH, Hanson JE, Sellers BD, Pande VS. Computationally discovered potentiating role of glycans on NMDA receptors. Sci Rep. 2017;7:44578.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Lichnerova K, Kaniakova M, Park SP, Skrenkova K, Wang Y-X, Petralia RS, et al. Two N-glycosylation sites in the GluN1 subunit are essential for releasing N-methyl-d-aspartate (NMDA) receptors from the endoplasmic reticulum. J Biol Chem. 2015;290:18379–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Skrenkova K, Lee S, Lichnerova K, Kaniakova M, Hansikova H, Zapotocky M, et al. N-glycosylation regulates the trafficking and surface mobility of GluN3A-containing NMDA receptors. Front Mol Neurosci. 2018;11:188.

    PubMed  PubMed Central  Google Scholar 

  84. Min C, Zheng M, Zhang X, Guo S, Kwon K-J, Shin CY, et al. N-linked glycosylation on the N-terminus of the dopamine D2 and D3 receptors determines receptor association with specific microdomains in the plasma membrane. Biochim Biophys Acta. 2015;1853:41–51.

    CAS  PubMed  Google Scholar 

  85. Lazniewska J, Weiss N. Glycosylation of voltage-gated calcium channels in health and disease. Biochim Biophys Acta Biomembr. 2017;1859:662–8.

    CAS  PubMed  Google Scholar 

  86. Park H-J, Min S-H, Won Y-J, Lee J-H. Asn-linked glycosylation contributes to surface expression and voltage-dependent gating of Cav1.2 Ca2+ channel. J Microbiol Biotechnol. 2015;25:1371–9.

    CAS  PubMed  Google Scholar 

  87. Tétreault M-P, Bourdin B, Briot J, Segura E, Lesage S, Fiset C, et al. Identification of glycosylation sites essential for surface expression of the CaVα2δ1 subunit and modulation of the cardiac CaV1.2 channel activity. J Biol Chem. 2016;291:4826–43.

    PubMed  PubMed Central  Google Scholar 

  88. Andrade A, Sandoval A, González-Ramírez R, Lipscombe D, Campbell KP, Felix R. The alpha(2)delta subunit augments functional expression and modifies the pharmacology of Ca(V)1.3 L-type channels. Cell Calcium. 2009;46:282–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Andrade A, Hope J, Allen A, Yorgan V, Lipscombe D, Pan JQ. A rare schizophrenia risk variant of CACNA1I disrupts CaV3.3 channel activity. Sci Rep. 2016;6:34233.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Weiss N, Black SAG, Bladen C, Chen L, Zamponi GW. Surface expression and function of Cav3.2 T-type calcium channels are controlled by asparagine-linked glycosylation. Pflug Arch. 2013;465:1159–70.

    CAS  Google Scholar 

  91. Bunkenborg J, Pilch BJ, Podtelejnikov AV, Wiśniewski JR. Screening for N-glycosylated proteins by liquid chromatography mass spectrometry. Proteomics. 2004;4:454–65.

    CAS  PubMed  Google Scholar 

  92. Ramachandran P, Boontheung P, Xie Y, Sondej M, Wong DT, Loo JA. Identification of N-linked glycoproteins in human saliva by glycoprotein capture and mass spectrometry. J Proteome Res. 2006;5:1493–503.

    CAS  PubMed  Google Scholar 

  93. Zhang H, Li X-J, Martin DB, Aebersold R. Identification and quantification of N-linked glycoproteins using hydrazide chemistry, stable isotope labeling and mass spectrometry. Nat Biotechnol. 2003;21:660–6.

    CAS  PubMed  Google Scholar 

  94. Liu T, Qian W-J, Gritsenko MA, Camp DG, Monroe ME, Moore RJ, et al. Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry. J Proteome Res. 2005;4:2070–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Chen R, Jiang X, Sun D, Han G, Wang F, Ye M, et al. Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry. J Proteome Res. 2009;8:651–61.

    CAS  PubMed  Google Scholar 

  96. Halim A, Rüetschi U, Larson G, Nilsson J. LC-MS/MS characterization of O-glycosylation sites and glycan structures of human cerebrospinal fluid glycoproteins. J Proteome Res. 2013;12:573–84.

    CAS  PubMed  Google Scholar 

  97. Escudero-Esparza A, Kalchishkova N, Kurbasic E, Jiang WG, Blom AM. The novel complement inhibitor human CUB and Sushi multiple domains 1 (CSMD1) protein promotes factor I-mediated degradation of C4B and C3B and inhibits the membrane attack complex assembly. FASEB J. 2013;27:5083–93.

    CAS  PubMed  Google Scholar 

  98. Ritchie GE, Moffatt BE, Sim RB, Morgan BP, Dwek RA, Rudd PM. Glycosylation and the complement system. Chem Rev. 2002;102:305–20–19.

    CAS  PubMed  Google Scholar 

  99. Wang B. Sialic acid is an essential nutrient for brain development and cognition. Annu Rev Nutr. 2009;29:177–222.

    PubMed  Google Scholar 

  100. Schnaar RL, Gerardy-Schahn R, Hildebrandt H. Sialic acids in the brain: gangliosides and polysialic acid in nervous system development, stability, disease, and regeneration. Physiol Rev. 2014;94:461–518.

    PubMed  PubMed Central  Google Scholar 

  101. Abeln M, Albers I, Peters-Bernard U, Flächsig-Schulz K, Kats E, Kispert A, et al. Sialic acid is a critical fetal defense against maternal complement attack. J Clin Investig. 2019;129:422–36.

    PubMed  Google Scholar 

  102. Ferreira VP, Pangburn MK, Cortés C. Complement control protein factor H: the good, the bad, and the inadequate. Mol Immunol. 2010;47:2187–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Nomura K, Vilalta A, Allendorf DH, Hornik TC, Brown GC. Activated microglia desialylate and phagocytose cells via neuraminidase, galectin-3, and mer tyrosine kinase. J Immunol. 2017;198:4792–801.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Linnartz B, Kopatz J, Tenner AJ, Neumann H. Sialic acid on the neuronal glycocalyx prevents complement C1 binding and complement receptor-3-mediated removal by microglia. J Neurosci J Soc Neurosci. 2012;32:946–52.

    CAS  Google Scholar 

  105. Linnartz-Gerlach B, Schuy C, Shahraz A, Tenner AJ, Neumann H. Sialylation of neurites inhibits complement-mediated macrophage removal in a human macrophage-neuron co-culture system. Glia. 2016;64:35–47.

    PubMed  Google Scholar 

  106. Lawrie SM, O’Donovan MC, Saks E, Burns T, Lieberman JA. Improving classification of psychoses. Lancet Psychiatry. 2016;3:367–74.

    PubMed  Google Scholar 

  107. Lawrie SM, O’Donovan MC, Saks E, Burns T, Lieberman JA. Towards diagnostic markers for the psychoses. Lancet Psychiatry. 2016;3:375–85.

    PubMed  Google Scholar 

  108. Ng E, Lind PM, Lindgren C, Ingelsson E, Mahajan A, Morris A, et al. Genome-wide association study of toxic metals and trace elements reveals novel associations. Hum Mol Genet. 2015;24:4739–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Arai M, Yamada K, Toyota T, Obata N, Haga S, Yoshida Y, et al. Association between polymorphisms in the promoter region of the sialyltransferase 8B (SIAT8B) gene and schizophrenia. Biol Psychiatry. 2006;59:652–9.

    CAS  PubMed  Google Scholar 

  110. Sato C, Hane M. Mental disorders and an acidic glycan-from the perspective of polysialic acid (PSA/polySia) and the synthesizing enzyme, ST8SIA2. Glycoconj J. 2018;35:353–73.

    CAS  PubMed  Google Scholar 

  111. Nelson MR, Tipney H, Painter JL, Shen J, Nicoletti P, Shen Y, et al. The support of human genetic evidence for approved drug indications. Nat Genet. 2015;47:856–60.

    CAS  PubMed  Google Scholar 

  112. Ng BG, Freeze HH. Perspectives on glycosylation and its congenital disorders. Trends Genet. 2018;34:466–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Verheijen J, Tahata S, Kozicz T, Witters P, Morava E. Therapeutic approaches in congenital disorders of glycosylation (CDG) involving N-linked glycosylation: an update. Genet Med. 2019. https://doi.org/10.1038/s41436-019-0647-2.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank Stephan Ripke of MGH and Broad Institute for allowing inclusion of the current estimate of schizophrenia GWAS associations and B3GAT1 as a personal communication. This work was supported by a foundation grant from the Stanley Center for Psychiatric Research at the Broad Institute of Harvard/MIT (awarded to RGM).

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  1. These authors contributed equally: Robert G. Mealer, Sarah E. Williams

Authors and Affiliations

  1. Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA

    Robert G. Mealer, Sarah E. Williams, Mark J. Daly, Edward M. Scolnick & Jordan W. Smoller

  2. The Stanley Center for Psychiatric Research at Broad Institute, Cambridge, MA, USA

    Robert G. Mealer, Mark J. Daly, Edward M. Scolnick & Jordan W. Smoller

  3. Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Robert G. Mealer, Sarah E. Williams & Richard D. Cummings

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  1. Robert G. Mealer
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Correspondence to Robert G. Mealer.

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Mealer, R.G., Williams, S.E., Daly, M.J. et al. Glycobiology and schizophrenia: a biological hypothesis emerging from genomic research. Mol Psychiatry 25, 3129–3139 (2020). https://doi.org/10.1038/s41380-020-0753-1

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