title: Specific glial functions contribute to schizophrenia susceptibility.
abstract: Schizophrenia is a highly polygenic brain disorder. The main hypothesis for disease etiology in schizophrenia primarily focuses on the role of dysfunctional synaptic transmission. Previous studies have therefore directed their investigations toward the role of neuronal dysfunction. However, recent studies have shown that apart from neurons, glial cells also play a major role in synaptic transmission. Therefore, we investigated the potential causal involvement of the 3 principle glial cell lineages in risk to schizophrenia. We performed a functional gene set analysis to test for the combined effects of genetic variants in glial type-specific genes for association with schizophrenia. We used genome-wide association data from the largest schizophrenia sample to date, including 13 689 cases and 18 226 healthy controls. Our results show that astrocyte and oligodendrocyte gene sets, but not microglia gene sets, are associated with an increased risk for schizophrenia. The astrocyte and oligodendrocyte findings are related to astrocyte signaling at the synapse, myelin membrane integrity, glial development, and epigenetic control. Together, these results show that genetic alterations underlying specific glial cell type functions increase susceptibility to schizophrenia and provide evidence that the neuronal hypothesis of schizophrenia should be extended to include the role of glia.
authors: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, the Netherlands; danielle.posthuma@vu.nl.
authors: Andrea
authors: A
authors: Goudriaan
authors: Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, the Netherlands; Institute for Computing and Information Sciences, Radboud University, Nijmegen, the Netherlands;
authors: Christiaan
authors: C
authors: de Leeuw
authors: Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA;
authors: Stephan
authors: S
authors: Ripke
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden;
authors: Christina M
authors: CM
authors: Hultman
authors: Department of Psychiatry, Mount Sinai School of Medicine, New York, NY;
authors: Pamela
authors: P
authors: Sklar
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Center for Psychiatric Genomics, Department of Genetics, University of North Carolina, Chapel Hill, NC;
authors: Patrick F
authors: PF
authors: Sullivan
authors: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, the Netherlands;
authors: August B
authors: AB
authors: Smit
authors: Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, the Netherlands; danielle.posthuma@vu.nl.
authors: Danielle
authors: D
authors: Posthuma
authors: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, the Netherlands;
authors: Mark H G
authors: MH
authors: Verheijen
mesh_terms: D001253:Astrocytes / Q000378:metabolism*; D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D017628:Microglia / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism*; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism
keywords: GWAS; PGC; gene set analysis; genome-wide association; glia; psychiatric disease
references: Nature. 2010 Nov 11;468(7321):187-93
references: 21068826
references: Nat Neurosci. 2002 Apr;5(4):308-15
references: 11896398
references: Nat Rev Neurosci. 2005 Aug;6(8):626-40
references: 16025096
references: Acta Biochim Pol. 2008;55(4):619-28
references: 18985177
references: PLoS Biol. 2006 Oct;4(11):e343
references: 17048987
references: Cereb Cortex. 2013 Sep;23(9):2044-57
references: 22772651
references: Lancet. 1995 Aug 19;346(8973):477-81
references: 7637483
references: Trends Genet. 2012 Jul;28(7):323-32
references: 22480918
references: Adv Exp Med Biol. 2012;970:307-31
references: 22351062
references: J Neurosci. 2005 Jun 1;25(22):5376-81
references: 15930386
references: J Neurosci. 2003 Feb 1;23(3):915-26
references: 12574420
references: Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):675-9
references: 12525699
references: J Lipid Res. 2011 Mar;52(3):419-34
references: 21062955
references: Mol Psychiatry. 2011 Mar;16(3):286-92
references: 20157312
references: Nature. 2011 Oct 26;478(7370):483-9
references: 22031440
references: Glia. 2012 Apr;60(4):594-604
references: 22279005
references: Ann N Y Acad Sci. 2005 Dec;1064:134-48
references: 16394153
references: Schizophr Res. 2009 Mar;108(1-3):134-42
references: 19150222
references: Neuron. 2004 Feb 5;41(3):405-15
references: 14766179
references: Nat Protoc. 2009;4(1):44-57
references: 19131956
references: Nat Neurosci. 2008 Nov;11(11):1271-82
references: 18849986
references: Nat Med. 2012 Jul;18(7):1130-5
references: 22706386
references: Trends Neurosci. 2008 Jul;31(7):361-70
references: 18538868
references: Biol Psychiatry. 2008 Nov 1;64(9):820-2
references: 18534557
references: Mol Psychiatry. 2012 Oct;17(10):996-1006
references: 21931320
references: Nat Genet. 2011 Sep 18;43(10):969-76
references: 21926974
references: Neurosci Lett. 2012 Aug 1;522(2):151-5
references: 22728822
references: BMC Bioinformatics. 2006 Oct 24;7:470
references: 17062145
references: Cell Mol Life Sci. 2008 Sep;65(18):2801-13
references: 18726178
references: Nat Neurosci. 2009 Jan;12(1):15-20
references: 19029886
references: Prog Neurobiol. 2011 Jan;93(1):13-24
references: 20950668
references: Genomics. 2008 Nov;92(5):265-72
references: 18722519
references: J Neurosci. 2008 Jan 2;28(1):264-78
references: 18171944
references: J Neurosci Res. 2005 Aug 1;81(3):327-41
references: 15948185
references: Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W741-8
references: 15980575
references: Science. 2010 Nov 5;330(6005):783-8
references: 21051630
references: Nat Neurosci. 2011 Mar;14(3):285-93
references: 21346746
references: Brain Res Bull. 2010 Sep 30;83(3-4):140-6
references: 20433911
references: BMJ. 2005 Jan 22;330(7484):158-9
references: 15661762
references: Proc Natl Acad Sci U S A. 2009 Dec 15;106(50):21383-8
references: 19948958
references: Nucleic Acids Res. 2007 Jan;35(Database issue):D766-70
references: 17182626
references: Mol Psychiatry. 2010 May;15(5):463-72
references: 18936756
references: Am J Hum Genet. 2010 Feb 12;86(2):113-25
references: 20060087
references: Neurosci Biobehav Rev. 2011 Jan;35(3):878-93
references: 20974172
references: J Immunol. 2002 Sep 1;169(5):2264-73
references: 12193691
references: Eur J Neurosci. 2004 Feb;19(4):1005-15
references: 15009148
references: Genes Dev. 2003 Oct 1;17(19):2450-64
references: 14522948
references: Nat Genet. 2008 May;40(5):489-90
references: 18443579
references: J Biol Chem. 2000 Mar 17;275(11):7764-70
references: 10713089
references: PLoS One. 2010 Dec 21;5(12):e15500
references: 21203536
references: Psychol Med. 2006 Oct;36(10):1417-25
references: 16863597
references: J Neurochem. 2007 Aug;102(3):627-45
references: 17442053
references: Proc Natl Acad Sci U S A. 1975 Nov;72(11):4376-80
references: 1060115
references: Nature. 2009 Aug 6;460(7256):748-52
references: 19571811
references: Nat Genet. 2007 Jul;39(7):813-5
references: 17597768
references: Nature. 2010 Oct 14;467(7317):832-8
references: 20881960
references: Am J Hum Genet. 2007 Sep;81(3):559-75
references: 17701901
references: Neuron. 2008 Nov 6;60(3):398-9
references: 18995807
references: J Neurosci. 2006 Oct 11;26(41):10387-96
references: 17035523
references: Am J Hum Genet. 2009 Jul;85(1):13-24
references: 19539887
references: Brain Pathol. 2004 Oct;14(4):406-14
references: 15605988
references: Nature. 2008 Nov 6;456(7218):18-21
references: 18987709
references: Nature. 2010 Nov 11;468(7321):223-31
references: 21068831
references: Lancet. 2003 Sep 6;362(9386):758
references: 13678867
references: Glia. 2003 Dec;44(3):219-31
references: 14603463
references: Neurobiol Dis. 2013 May;53:49-60
references: 23146995
references: Nucleic Acids Res. 2011 Oct;39(18):7974-91
references: 21729871