title: Transcriptome study of differential expression in schizophrenia.
abstract: Schizophrenia genome-wide association studies (GWAS) have identified common SNPs, rare copy number variants (CNVs) and a large polygenic contribution to illness risk, but biological mechanisms remain unclear. Bioinformatic analyses of significantly associated genetic variants point to a large role for regulatory variants. To identify gene expression abnormalities in schizophrenia, we generated whole-genome gene expression profiles using microarrays on lymphoblastoid cell lines (LCLs) from 413 cases and 446 controls. Regression analysis identified 95 transcripts differentially expressed by affection status at a genome-wide false discovery rate (FDR) of 0.05, while simultaneously controlling for confounding effects. These transcripts represented 89 genes with functions such as neurotransmission, gene regulation, cell cycle progression, differentiation, apoptosis, microRNA (miRNA) processing and immunity. This functional diversity is consistent with schizophrenia's likely significant pathophysiological heterogeneity. The overall enrichment of immune-related genes among those differentially expressed by affection status is consistent with hypothesized immune contributions to schizophrenia risk. The observed differential expression of extended major histocompatibility complex (xMHC) region histones (HIST1H2BD, HIST1H2BC, HIST1H2BH, HIST1H2BG and HIST1H4K) converges with the genetic evidence from GWAS, which find the xMHC to be the most significant susceptibility locus. Among the differentially expressed immune-related genes, B3GNT2 is implicated in autoimmune disorders previously tied to schizophrenia risk (rheumatoid arthritis and Graves' disease), and DICER1 is pivotal in miRNA processing potentially linking to miRNA alterations in schizophrenia (e.g. MIR137, the second strongest GWAS finding). Our analysis provides novel candidate genes for further study to assess their potential contribution to schizophrenia.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem, Evanston, IL 60201, USA.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Sanders
authors.forename: Harald H H
authors.initials: HH
authors.lastname: Göring
authors.forename: Jubao
authors.initials: J
authors.lastname: Duan
authors.forename: Eugene I
authors.initials: EI
authors.lastname: Drigalenko
authors.forename: Winton
authors.initials: W
authors.lastname: Moy
authors.forename: Jessica
authors.initials: J
authors.lastname: Freda
authors.forename: Deli
authors.initials: D
authors.lastname: He
authors.forename: Jianxin
authors.initials: J
authors.lastname: Shi
authors.forename: Pablo V
authors.initials: PV
authors.lastname: Gejman
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D002460:Cell Line; D005260:Female; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D058977:Molecular Sequence Annotation; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D059467:Transcriptome
references.citation: Hum Mutat. 2012 Dec;33(12):1639-46
references.pmid: 23065719
references.citation: PLoS Genet. 2012;8(3):e1002548
references.pmid: 22438815
references.citation: Nature. 2008 Mar 27;452(7186):423-8
references.pmid: 18344981
references.citation: Am J Med Genet. 2000 Spring;97(1):12-7
references.pmid: 10813800
references.citation: Nat Rev Genet. 2008 Jul;9(7):516-26
references.pmid: 18542080
references.citation: Proc Natl Acad Sci U S A. 1990 Mar;87(5):1663-7
references.pmid: 1689846
references.citation: Psychiatr Clin North Am. 2007 Sep;30(3):323-38
references.pmid: 17720026
references.citation: Genomics. 1997 Jul 1;43(1):1-8
references.pmid: 9226366
references.citation: Arch Gen Psychiatry. 2000 Jul;57(7):685-91
references.pmid: 10891039
references.citation: Neuroscience. 2012 Dec 6;225:35-43
references.pmid: 22960622
references.citation: J Interferon Cytokine Res. 2011 Jan;31(1):89-97
references.pmid: 21142871
references.citation: Nature. 2009 Aug 6;460(7256):744-7
references.pmid: 19571808
references.citation: Peptides. 2011 Oct;32(10):2003-9
references.pmid: 21930170
references.citation: J Neurosci. 2008 Apr 23;28(17):4322-30
references.pmid: 18434510
references.citation: Nat Genet. 2012 Oct;44(10):1084-9
references.pmid: 22941192
references.citation: Br J Psychiatry. 2011 Sep;199(3):245-6
references.pmid: 21881099
references.citation: J Am Acad Child Adolesc Psychiatry. 2010 Sep;49(9):884-97
references.pmid: 20732625
references.citation: Mol Cell Biol. 1983 Apr;3(4):539-50
references.pmid: 6406835
references.citation: Am J Hum Genet. 2003 Jul;73(1):34-48
references.pmid: 12802786
references.citation: Mol Psychiatry. 2007 Sep;12(9):842-53
references.pmid: 17505468
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2006 Jan 5;141B(1):71-5
references.pmid: 16342282
references.citation: Cell Mol Life Sci. 2011 Feb;68(4):721-33
references.pmid: 20711648
references.citation: Nat Genet. 2011 Sep 18;43(10):977-83
references.pmid: 21926972
references.citation: J Biol Chem. 2008 Nov 7;283(45):30689-98
references.pmid: 18779328
references.citation: Lancet. 2011 Feb 19;377(9766):641-9
references.pmid: 21292315
references.citation: Psychiatry Clin Neurosci. 2006 Oct;60(5):633-5
references.pmid: 16958950
references.citation: Am J Psychiatry. 2010 Jul;167(7):854-65
references.pmid: 20516154
references.citation: Mol Neurobiol. 2012 Feb;45(1):99-108
references.pmid: 22167484
references.citation: BJOG. 2011 Jan;118(2):145-53
references.pmid: 21054766
references.citation: Nat Protoc. 2009;4(1):44-57
references.pmid: 19131956
references.citation: Epidemiol Rev. 2008;30:67-76
references.pmid: 18480098
references.citation: Bipolar Disord. 2010 Sep;12(6):638-46
references.pmid: 20868462
references.citation: Biol Psychiatry. 2007 Oct 1;62(7):711-21
references.pmid: 17568569
references.citation: Alcohol Clin Exp Res. 2005 Mar;29(3):303-9
references.pmid: 15770103
references.citation: Diagn Mol Pathol. 2000 Sep;9(3):121-31
references.pmid: 10976718
references.citation: Science. 2012 Feb 24;335(6071):930-1
references.pmid: 22362999
references.citation: Nat Genet. 2011 Jun 19;43(7):699-705
references.pmid: 21685912
references.citation: Neuropharmacology. 2013 May;68:184-94
references.pmid: 22564440
references.citation: Schizophr Res. 1996 Mar;19(1):33-40
references.pmid: 9147494
references.citation: Nat Genet. 2003 Oct;35(2):131-8
references.pmid: 14517540
references.citation: Hum Mol Genet. 2011 Apr 15;20(8):1643-52
references.pmid: 21289059
references.citation: Infect Disord Drug Targets. 2008 Sep;8(3):195-205
references.pmid: 18782037
references.citation: Biol Psychiatry. 2012 Jan 15;71(2):129-35
references.pmid: 22074612
references.citation: Trends Neurosci. 2012 May;35(5):325-34
references.pmid: 22436491
references.citation: Psychiatry Clin Neurosci. 2004 Aug;58(4):438-40
references.pmid: 15298659
references.citation: Curr Opin Pharmacol. 2007 Feb;7(1):27-32
references.pmid: 17085073
references.citation: Am J Psychiatry. 2011 Mar;168(3):302-16
references.pmid: 21285140
references.citation: PLoS Genet. 2006 Oct 20;2(10):e172
references.pmid: 17054398
references.citation: Neurobiol Aging. 2012 Apr;33(4):836.e1-3
references.pmid: 21794955
references.citation: J Clin Psychiatry. 2010 May;71(5):520-7
references.pmid: 20492850
references.citation: Bioinformatics. 2010 Jan 15;26(2):259-62
references.pmid: 19933162
references.citation: J Psychiatr Res. 2011 Apr;45(4):435-41
references.pmid: 20863517
references.citation: J Psychiatr Res. 2008 Jan;42(1):35-40
references.pmid: 17097106
references.citation: Nat Genet. 2011 Sep 18;43(10):969-76
references.pmid: 21926974
references.citation: Mol Psychiatry. 2010 Dec;15(12):1176-89
references.pmid: 19721432
references.citation: Acta Psychiatr Scand. 2007 Nov;116(5):317-33
references.pmid: 17919153
references.citation: Front Genet. 2013 Apr 26;4:58
references.pmid: 23637704
references.citation: Am J Psychiatry. 2006 Mar;163(3):521-8
references.pmid: 16513876
references.citation: J Neurosci. 2000 Jan 15;20(2):617-25
references.pmid: 10632591
references.citation: Genes Immun. 2008 Jun;9(4):334-7
references.pmid: 18401352
references.citation: RNA. 2011 Apr;17(4):761-72
references.pmid: 21343387
references.citation: PLoS Genet. 2013 Apr;9(4):e1003449
references.pmid: 23637621
references.citation: Alzheimer Dis Assoc Disord. 2012 Jul-Sep;26(3):277-81
references.pmid: 21946017
references.citation: BMC Med. 2008 Jun 24;6:14
references.pmid: 18577219
references.citation: Nat Genet. 2008 Jul;40(7):880-5
references.pmid: 18511947
references.citation: Proc Natl Acad Sci U S A. 1967 Jul;58(1):199-205
references.pmid: 5231600
references.citation: Curr Top Behav Neurosci. 2010;4:611-28
references.pmid: 21312415
references.citation: J Cell Physiol. 2009 Sep;220(3):672-9
references.pmid: 19441079
references.citation: PLoS Genet. 2011 Jan 13;7(1):e1001273
references.pmid: 21249183
references.citation: Science. 2002 Aug 16;297(5584):1143
references.pmid: 12183620
references.citation: Biochem Biophys Res Commun. 2004 Jul 2;319(3):866-70
references.pmid: 15184063
references.citation: Science. 2006 Jan 6;311(5757):77-80
references.pmid: 16400147
references.citation: Nat Genet. 2008 Mar;40(3):322-8
references.pmid: 18278044
references.citation: J Psychiatr Res. 2011 Nov;45(11):1426-31
references.pmid: 21722919
references.citation: Mol Psychiatry. 2012 Apr;17(4):433-44
references.pmid: 21423239
references.citation: Schizophr Bull. 2010 Jan;36(1):14-23
references.pmid: 19996148
references.citation: Mol Neurobiol. 2010 Aug;42(1):4-9
references.pmid: 20552413
references.citation: Nat Genet. 2012 Mar 25;44(5):511-6
references.pmid: 22446963
references.citation: J Physiol. 2010 Sep 15;588(Pt 18):3349-54
references.pmid: 20530112
references.citation: Exp Cell Res. 2008 Feb 1;314(3):463-77
references.pmid: 18096156
references.citation: Stem Cells. 2010 Jun;28(6):1060-70
references.pmid: 20506192
references.citation: PLoS Genet. 2009 Nov;5(11):e1000718
references.pmid: 19911041
references.citation: J Cell Biol. 2010 Apr 5;189(1):127-41
references.pmid: 20368621
references.citation: Hum Mol Genet. 2009 Oct 15;18(R2):R211-5
references.pmid: 19808798
references.citation: J Immunol. 2002 Mar 1;168(5):2356-64
references.pmid: 11859126
references.citation: Nature. 2011 May 25;474(7351):380-4
references.pmid: 21614001
references.citation: Nat Genet. 2010 May;42(5):441-7
references.pmid: 20418890
references.citation: Nat Genet. 2008 May;40(5):492-3
references.pmid: 18443581
references.citation: Am J Hum Genet. 2004 Oct;75(4):624-38
references.pmid: 15329799
references.citation: Am J Med Genet. 1999 Aug 20;88(4):337-43
references.pmid: 10402499
references.citation: J Mol Neurosci. 2013 Mar;49(3):594-9
references.pmid: 23015298
references.citation: Hum Mol Genet. 2007 Jan 1;16(1):24-35
references.pmid: 17158188
references.citation: Biochem Soc Trans. 2003 Dec;31(Pt 6):1343-8
references.pmid: 14641060
references.citation: PLoS One. 2011;6(11):e26726
references.pmid: 22096494
references.citation: CNS Neurosci Ther. 2011 Dec;17(6):620-8
references.pmid: 22070192
references.citation: Alcohol Clin Exp Res. 2010 May;34(5):840-52
references.pmid: 20201924
references.citation: Proc Natl Acad Sci U S A. 2008 Apr 8;105(14):5614-9
references.pmid: 18385371
references.citation: Oncogene. 2008 Dec;27 Suppl 1:S20-9
references.pmid: 19641504
references.citation: Lancet. 2007 Sep 8;370(9590):859-77
references.pmid: 17804063
references.citation: Schizophr Bull. 2014 Mar;40(2):399-409
references.pmid: 23378013
references.citation: J Immunol. 2011 Dec 15;187(12):6456-62
references.pmid: 22095711
references.citation: Neuron. 2000 May;26(2):457-64
references.pmid: 10839363
references.citation: Neurobiol Dis. 2012 May;46(2):291-301
references.pmid: 22406400
references.citation: Gene. 1998 Sep 18;218(1-2):111-20
references.pmid: 9751809
references.citation: J Neurosci Res. 2006 Nov 1;84(6):1187-96
references.pmid: 16941650
references.citation: J Virol. 1999 Nov;73(11):9690-1
references.pmid: 10577062
references.citation: Biol Psychiatry. 2011 Mar 1;69(5):472-8
references.pmid: 20832056
references.citation: Mol Psychiatry. 2009 Feb;14(2):143-55
references.pmid: 18301395
references.citation: Cell Stem Cell. 2009 Sep 4;5(3):320-31
references.pmid: 19733543
references.citation: Nucleic Acids Res. 2001 May 1;29(9):e45
references.pmid: 11328886
references.citation: Arthritis Rheum. 2012 Mar;64(3):647-54
references.pmid: 21976003
references.citation: J Mol Cell Biol. 2010 Jun;2(3):152-63
references.pmid: 20457670
references.citation: Trends Genet. 2008 Aug;24(8):408-15
references.pmid: 18597885
references.citation: Proc Natl Acad Sci U S A. 2011 Oct 11;108(41):17141-6
references.pmid: 21969577
references.citation: Nat Rev Immunol. 2009 Oct;9(10):692-703
references.pmid: 19859064
references.citation: Nat Genet. 2007 Oct;39(10):1202-7
references.pmid: 17873877
references.citation: Physiol Genomics. 2000 Nov 09;4(1):83-91
references.pmid: 11074017
references.citation: Arch Gen Psychiatry. 1982 Aug;39(8):879-83
references.pmid: 7103676
references.citation: Neuropharmacology. 2011 Jun;60(7-8):1007-16
references.pmid: 21074545
references.citation: Nature. 2009 Aug 6;460(7256):748-52
references.pmid: 19571811
references.citation: J Neurochem. 2002 Sep;82(5):1262-71
references.pmid: 12358773
references.citation: Neurology. 2012 Aug 14;79(7):659-67
references.pmid: 22786590
references.citation: J Clin Psychiatry. 2005 Sep;66(9):1122-9
references.pmid: 16187769
references.citation: DNA Res. 2003 Dec 31;10(6):287-9
references.pmid: 15029959
references.citation: Nature. 2009 Aug 6;460(7256):753-7
references.pmid: 19571809
references.citation: Nat Genet. 2007 Oct;39(10):1208-16
references.pmid: 17873875
references.citation: Genes Cells. 2013 Mar;18(3):176-94
references.pmid: 23294285
references.citation: Nat Genet. 2010 May;42(5):448-53
references.pmid: 20418888
references.citation: Virulence. 2010 Sep-Oct;1(5):440-64
references.pmid: 21178486
references.citation: Nat Rev Genet. 2008 Nov;9(11):843-54
references.pmid: 18927579
references.citation: Hum Mol Genet. 2010 Oct 15;19(20):4072-82
references.pmid: 20663923
references.citation: Am J Psychiatry. 2011 Dec;168(12):1303-10
references.pmid: 22193673
references.citation: J Biol Chem. 2010 Feb 19;285(8):5878-87
references.pmid: 20022952
references.citation: J Neurosci. 2010 Aug 25;30(34):11317-25
references.pmid: 20739552
references.citation: Nat Rev Genet. 2004 Dec;5(12):889-99
references.pmid: 15573121
references.citation: Schizophr Bull. 2007 Nov;33(6):1343-53
references.pmid: 17329232
references.citation: Schizophr Res. 2004 Jan 1;66(1):21-9
references.pmid: 14693349
references.citation: N Engl J Med. 2007 Aug 30;357(9):851-62
references.pmid: 17660530
references.citation: PLoS Genet. 2009 Oct;5(10):e1000692
references.pmid: 19834560
references.citation: Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):5082-7
references.pmid: 20202923
references.citation: Nat Genet. 2006 Aug;38(8):904-9
references.pmid: 16862161
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2007 Apr 5;144B(3):332-40
references.pmid: 17192956
references.citation: Nat Genet. 2012 Feb 19;44(3):247-50
references.pmid: 22344220
references.citation: Am J Hum Genet. 2002 Aug;71(2):337-48
references.pmid: 12098102
references.citation: BMC Psychiatry. 2007 Sep 06;7:46
references.pmid: 17822540
references.citation: PLoS Genet. 2008 Nov;4(11):e1000287
references.pmid: 19043577
references.citation: Nature. 2003 Mar 20;422(6929):297-302
references.pmid: 12646919
references.citation: Neurobiol Aging. 2013 Jun;34(6):1708.e7-13
references.pmid: 23153929
references.citation: Eur J Hum Genet. 2012 Sep;20(9):1004-8
references.pmid: 22433715
references.citation: Arch Gen Psychiatry. 1994 Mar;51(3):199-214
references.pmid: 8122957
references.citation: Biochem J. 2012 Jun 15;444(3):375-82
references.pmid: 22642576
references.citation: Prog Neurobiol. 2011 Jan;93(1):23-58
references.pmid: 20955757
references.citation: Neural Dev. 2012 Jul 04;7:17
references.pmid: 22559903
references.citation: Science. 2005 May 6;308(5723):833-8
references.pmid: 15774722
references.citation: Am J Psychiatry. 2010 Mar;167(3):261-80
references.pmid: 20123911
references.citation: Nat Genet. 2003 Mar;33(3):422-5
references.pmid: 12567189
references.citation: Nature. 2011 May 12;473(7346):221-5
references.pmid: 21490598
references.citation: Am J Hum Genet. 2006 Feb;78(2):315-33
references.pmid: 16400611
references.citation: Bioinformatics. 2008 Jul 1;24(13):1547-8
references.pmid: 18467348
references.citation: Nat Struct Biol. 2003 Nov;10(11):882-91
references.pmid: 14583738
references.citation: Acta Psychiatr Scand Suppl. 2000;401:3-38
references.pmid: 10887978
references.citation: Gene Expr. 2010;15(1):13-25
references.pmid: 21061914
references.citation: Biol Psychiatry. 2011 Jan 15;69(2):180-7
references.pmid: 21111402
references.citation: BMC Res Notes. 2009 Sep 25;2:195
references.pmid: 19781058
references.citation: PLoS Genet. 2010 Apr 01;6(4):e1000888
references.pmid: 20369019
references.citation: Autism Res. 2011 Aug;4(4):262-70
references.pmid: 21491613
references.citation: Adv Genet. 2008;60:571-601
references.pmid: 18358333
references.citation: Br J Psychiatry. 2012 May;200(5):374-80
references.pmid: 22442099
references.citation: Am J Psychiatry. 2008 Apr;165(4):497-506
references.pmid: 18198266