A longitudinal study of gene expression in first-episode schizophrenia; exploring relapse mechanisms by co-expression analysis in peripheral blood.
Journal
Translational psychiatry
ISSN: 2158-3188
Titre abrégé: Transl Psychiatry
Pays: United States
ID NLM: 101562664
Informations de publication
Date de publication:
19 10 2021
19 10 2021
Historique:
received:
03
05
2021
accepted:
30
09
2021
revised:
22
09
2021
entrez:
20
10
2021
pubmed:
21
10
2021
medline:
6
11
2021
Statut:
epublish
Résumé
Little is known about the pathophysiological mechanisms of relapse in first-episode schizophrenia, which limits the study of potential biomarkers. To explore relapse mechanisms and identify potential biomarkers for relapse prediction, we analyzed gene expression in peripheral blood in a cohort of first-episode schizophrenia patients with less than 5 years of evolution who had been evaluated over a 3-year follow-up period. A total of 91 participants of the 2EPs project formed the sample for baseline gene expression analysis. Of these, 67 provided biological samples at follow-up (36 after 3 years and 31 at relapse). Gene expression was assessed using the Clariom S Human Array. Weighted gene co-expression network analysis was applied to identify modules of co-expressed genes and to analyze their preservation after 3 years of follow-up or at relapse. Among the 25 modules identified, one module was semi-conserved at relapse (DarkTurquoise) and was enriched with risk genes for schizophrenia, showing a dysregulation of the TCF4 gene network in the module. Two modules were semi-conserved both at relapse and after 3 years of follow-up (DarkRed and DarkGrey) and were found to be biologically associated with protein modification and protein location processes. Higher expression of DarkRed genes was associated with higher risk of suffering a relapse and early appearance of relapse (p = 0.045). Our findings suggest that a dysregulation of the TCF4 network could be an important step in the biological process that leads to relapse and suggest that genes related to the ubiquitin proteosome system could be potential biomarkers of relapse.
Identifiants
pubmed: 34667144
doi: 10.1038/s41398-021-01645-8
pii: 10.1038/s41398-021-01645-8
pmc: PMC8526619
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
539Investigateurs
M Bioque
(M)
S Amoretti
(S)
A Andreu-Bernabeu
(A)
X Gurriarán
(X)
A Alonso-Solís
(A)
E Grasa
(E)
P López
(P)
E Garcia
(E)
D Bergé
(D)
A Trabsa
(A)
L Sànchez-Pastor
(L)
O Jiménez-Rodríguez
(O)
E Pomarol-Clotet
(E)
I Feria-Raposo
(I)
A Butjosa
(A)
M Pardo
(M)
L Moreno-Izco
(L)
A M Sánchez-Torres
(AM)
J Saiz-Ruiz
(J)
L León-Quismondo
(L)
J Nacher
(J)
F Contreras
(F)
C De-la-Cámara
(C)
M Gutiérrez
(M)
P A Sáiz
(PA)
Informations de copyright
© 2021. The Author(s).
Références
Milev P, Ho BC, Arndt S, Andreasen NC. Predictive values of neurocognition and negative symptoms on functional outcome in schizophrenia: a longitudinal first-episode study with 7-year follow-up. Am J Psychiatry. 2005;162:495–506.
pubmed: 15741466
doi: 10.1176/appi.ajp.162.3.495
Kane JM. Treatment strategies to prevent relapse and encourage remission. J Clin Psychiatry. 2007;68:27–30.
pubmed: 18284275
Andreasen NC, Liu D, Ziebell S, Vora A, Ho BC. Relapse duration, treatment intensity, and brain tissue loss in schizophrenia: a prospective longitudinal MRI study. Am J Psychiatry. 2013;170:609–15.
pubmed: 23558429
doi: 10.1176/appi.ajp.2013.12050674
McCutcheon RA, Pillinger T, Mizuno Y, Montgomery A, Pandian H, Vano L, et al. The efficacy and heterogeneity of antipsychotic response in schizophrenia: a meta-analysis. Mol Psychiatry. 2021;26:1310–20.
pubmed: 31471576
doi: 10.1038/s41380-019-0502-5
Álvarez-Jiménez M, Gleeson JF, Henry LP, Harrigan SM, Harris MG, Killackey E, et al. Road to full recovery: longitudinal relationship between symptomatic remission and psychosocial recovery in first-episode psychosis over 7.5 years. Psychol Med. 2012;42:595–606.
pubmed: 21854682
doi: 10.1017/S0033291711001504
Bocchio-Chiavetto L, Zanardini R, Tosato S, Ventriglia M, Ferrari C, Bonetto C, et al. Immune and metabolic alterations in first episode psychosis (FEP) patients. Brain Behav Immun. 2018;70:315–24.
pubmed: 29548996
doi: 10.1016/j.bbi.2018.03.013
Kane JM. Improving patient outcomes in schizophrenia: achieving remission, preventing relapse, and measuring success. J Clin Psychiatry. 2013;74:e18.
pubmed: 24107769
doi: 10.4088/JCP.12117tx1c
García S, et al. Adherence to antipsychotic medication in bipolar disorder and schizophrenic patients: a systematic review. J Clin Psychopharmacol. 2016;36:355–71.
pubmed: 27307187
pmcid: 4932152
doi: 10.1097/JCP.0000000000000523
Rubio JM, Schoretsanitis G, John M, Tiihonen J, Taipale H, Guinart D, et al. Psychosis relapse during treatment with long-acting injectable antipsychotics in individuals with schizophrenia-spectrum disorders: an individual participant data meta-analysis. Lancet Psychiatry. 2020;7:749–61.
pubmed: 32828165
doi: 10.1016/S2215-0366(20)30264-9
Rubio JM, Taipale H, Correll CU, Tanskanen A, Kane JM, Tiihonen J. Psychosis breakthrough on antipsychotic maintenance: results from a nationwide study. Psychol Med. 2020;50:1356–67.
pubmed: 31190660
doi: 10.1017/S0033291719001296
Rubio JM, Malhotra AK, Kane JM. Towards a framework to develop neuroimaging biomarkers of relapse in schizophrenia. Behav Brain Res. 2021;402:113099.
pubmed: 33417996
doi: 10.1016/j.bbr.2020.113099
Remington G, Foussias G, Agid O, Fervaha G, Takeuchi H, Hahn M. The neurobiology of relapse in schizophrenia. Schizophr Res. 2014;152:381–90.
pubmed: 24206930
doi: 10.1016/j.schres.2013.10.009
Muller P, Seeman P. Dopaminergic supersensitivity after neuroleptics: time-course and specificity. Psychopharmacol (Berl). 1978;60:1–11.
doi: 10.1007/BF00429171
Chouinard G, Jones BD. Neuroleptic-induced supersensitivity psychosis: clinical and pharmacologic characteristics. Am J Psychiatry. 1980;137:16–21.
pubmed: 6101522
doi: 10.1176/ajp.137.1.16
Leucht S, Davis JM. Do antipsychotic drugs lose their efficacy for relapse prevention over time? Br J Psychiatry. 2017;211:127–9.
pubmed: 28864750
doi: 10.1192/bjp.bp.117.201103
Moncrieff J, Steingard S. A critical analysis of recent data on the long-term outcome of antipsychotic treatment. Psychol Med. 2019;49:750–3. https://doi.org/10.1017/S0033291718003811 .
Myin-Germeys I, Delespaul P, van Os J. Behavioural sensitization to daily life stress in psychosis. Psychol Med. 2005;35:733–41.
pubmed: 15918350
doi: 10.1017/S0033291704004179
Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry. 2011;70:663–71.
pubmed: 21641581
pmcid: 4071300
doi: 10.1016/j.biopsych.2011.04.013
Miller BJ, Gassama B, Sebastian D, Buckley P, Mellor A. Meta-analysis of lymphocytes in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry. 2013;73:993–9.
pubmed: 23062357
doi: 10.1016/j.biopsych.2012.09.007
Buckley PF, Mahadik S, Pillai A, Terry A Jr. Neurotrophins and schizophrenia. Schizophr Res. 2007;94:1–11.
pubmed: 17524622
doi: 10.1016/j.schres.2007.01.025
Pillai A, Schooler NR, Peter D, Looney SW, Goff DC, Kopelowicz A, et al. Predicting relapse in schizophrenia: is BDNF a plausible biological marker? Schizophr Res. 2018;193:263–8.
pubmed: 28734907
doi: 10.1016/j.schres.2017.06.059
Martinez-Cengotitabengoa M, MacDowell KS, Alberich S, Diaz FJ, Garcia-Bueno B, Rodriguez-Jimenez R, et al. BDNF and NGF signalling in early phases of psychosis: relationship with inflammation and response to antipsychotics after 1 year. Schizophr Bull. 2016;42:142–51.
pubmed: 26130821
Bernardo M, Amoretti S, Cuesta MJ, Parellada M, Mezquida G, 2EPs Group. The prevention of relapses in first episodes of schizophrenia: the 2EPs Project, background, rationale and study design. Rev Psiquiatr Salud Ment. 2021;14:164–76. https://doi.org/10.1016/j.rpsm.2020.07.004 .
American Psychiatric Association. DSM-IV: Diagnostic and Statistical Manual of Mental Disorders. Washington: American Psychiatric Association; 1994.
Andreasen NC, Carpenter WT Jr, Kane JM, Lasser RA, Marder SR, Weinberger DR. Remission in schizophrenia: proposed criteria and rationale for consensus. Am J Psychiatry. 2005;162:441–9.
pubmed: 15741458
doi: 10.1176/appi.ajp.162.3.441
Williams JB, Gibbon M, First MB, Spitzer RL, Davies M, Borus J, et al. The Structured Clinical Interview for DSM-III-R (SCID). II. Multisite test-retest reliability. Arch Gen Psychiatry. 1992;49:630–6.
pubmed: 1637253
doi: 10.1001/archpsyc.1992.01820080038006
Kaufman J, Birmaher B, Brent D, Rao U, Flynn C, Moreci P, et al. Schedule for affective disorders and schizophrenia for school-age children-present and lifetime version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry. 1997;36:980–8.
pubmed: 9204677
doi: 10.1097/00004583-199707000-00021
Peralta V, Cuesta MJ. Validación de la escala de los síndromes positivo y negativo (PANSS) en una muestra de esquizofrénicos españoles. Actas Luso Esp Neurol Psiquiatr. 1994;22:171–7.
Unni EJ, Farris KB. Development of a new scale to measure self-reported medication nonadherence. Res Soc Adm Pharm. 2015;11:e133–143.
doi: 10.1016/j.sapharm.2009.06.005
Carvalho BS, Irizarry RA. A framework for oligonucleotide microarray preprocessing. Bioinformatics. 2010;26:2363–7.
pubmed: 20688976
pmcid: 2944196
doi: 10.1093/bioinformatics/btq431
Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinforma. 2008;9:559.
doi: 10.1186/1471-2105-9-559
Langfelder P, Luo R, Oldham MC, Horvath S. Is my network module preserved and reproducible? PLoS Comput Biol. 2011;7:e1001057.
pubmed: 21283776
pmcid: 3024255
doi: 10.1371/journal.pcbi.1001057
Reimand J, Arak T, Adler P, Kolberg L, Reisberg S, Peterson H, et al. Profiler—a web server for functional interpretation of gene lists (2016 update). Nucleic Acids Res. 2016;44:W83–89.
pubmed: 27098042
pmcid: 4987867
doi: 10.1093/nar/gkw199
Gandal MJ, Haney JR, Parikshak NN, Leppa V, Ramaswami G, Hartl C, et al. Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. Science. 2018;359:693–7.
pubmed: 29439242
pmcid: 5898828
doi: 10.1126/science.aad6469
Fromer M, Roussos P, Sieberts SK, Johnson JS, Kavanagh DH, Perumal TM, et al. Gene expression elucidates functional impact of polygenic risk for schizophrenia. Nat Neurosci. 2016;19:1442–53.
pubmed: 27668389
pmcid: 5083142
doi: 10.1038/nn.4399
Huckins LM, Dobbyn A, Ruderfer DM, Hoffman G, Wang W, Pardiñas AF, et al. Gene expression imputation across multiple brain regions provides insights into schizophrenia risk. Nat Genet. 2019;51:659–74.
pubmed: 30911161
pmcid: 7034316
doi: 10.1038/s41588-019-0364-4
Pardiñas AF, Holmans P, Pocklington AJ, Escott-Price V, Ripke S, Carrera N, et al. Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Nat Genet. 2018;50:381–9.
pubmed: 29483656
pmcid: 5918692
doi: 10.1038/s41588-018-0059-2
Shen L, Sinai ISoMaM. GeneOverlap: test and visualize gene overlaps. R package version 1.26.0. 2020. http://shenlab-sinai.github.io/shenlab-sinai/ .
Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43:e47.
pubmed: 25605792
pmcid: 4402510
doi: 10.1093/nar/gkv007
Luza S, Opazo CM, Bousman CA, Pantelis C, Bush AI, Everall IP. The ubiquitin proteasome system and schizophrenia. Lancet Psychiatry. 2020;7:528–37.
pubmed: 32061320
doi: 10.1016/S2215-0366(19)30520-6
Middleton FA, Mirnics K, Pierri JN, Lewis DA, Levitt P. Gene expression profiling reveals alterations of specific metabolic pathways in schizophrenia. J Neurosci. 2002;22:2718–29.
pubmed: 11923437
pmcid: 6758309
doi: 10.1523/JNEUROSCI.22-07-02718.2002
Altar CA, Jurata LW, Charles V, Lemire A, Liu P, Bukhman Y, et al. Deficient hippocampal neuron expression of proteasome, ubiquitin, and mitochondrial genes in multiple schizophrenia cohorts. Biol Psychiatry. 2005;58:85–96.
pubmed: 16038679
doi: 10.1016/j.biopsych.2005.03.031
Bousman CA, Chana G, Glatt SJ, Chandler SD, May T, Lohr J, et al. Positive symptoms of psychosis correlate with expression of ubiquitin proteasome genes in peripheral blood. Am J Med Genet B Neuropsychiatr Genet. 2010;153B:1336–41.
pubmed: 20552680
doi: 10.1002/ajmg.b.31106
Arion D, Corradi JP, Tang S, Datta D, Boothe F, He A, et al. Distinctive transcriptome alterations of prefrontal pyramidal neurons in schizophrenia and schizoaffective disorder. Mol Psychiatry. 2015;20:1397–405.
pubmed: 25560755
pmcid: 4492919
doi: 10.1038/mp.2014.171
Hertzberg L, Maggio N, Muler I, Yitzhaky A, Majer M, Haroutunian V, et al. Comprehensive gene expression analysis detects global reduction of proteasome subunits in schizophrenia. Schizophr Bull. 2021;47:785–95. https://doi.org/10.1093/schbul/sbaa160.
Seabra G, de Almeida V, Reis-de-Oliveira G, Crunfli F, Antunes ASLM, Martins-de-Souza D. Ubiquitin-proteasome system, lipid metabolism and DNA damage repair are triggered by antipsychotic medication in human oligodendrocytes: implications in schizophrenia. Sci Rep. 2020;10:12655.
pubmed: 32724114
pmcid: 7387551
doi: 10.1038/s41598-020-69543-5
Teixeira JR, Szeto RA, Carvalho VMA, Muotri AR, Papes F. Transcription factor 4 and its association with psychiatric disorders. Transl Psychiatry. 2021;11:19.
pubmed: 33414364
pmcid: 7791034
doi: 10.1038/s41398-020-01138-0
Jung M, Häberle BM, Tschaikowsky T, Wittmann MT, Balta EA, Stadler VC, et al. Analysis of the expression pattern of the schizophrenia-risk and intellectual disability gene TCF4 in the developing and adult brain suggests a role in development and plasticity of cortical and hippocampal neurons. Mol Autism. 2018;9:20.
pubmed: 29588831
pmcid: 5863811
doi: 10.1186/s13229-018-0200-1
Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium. Genome-wide association study identifies five new schizophrenia loci. Nat Genet. 2011;43:969–76.
doi: 10.1038/ng.940
Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421–7.
pmcid: 4112379
doi: 10.1038/nature13595
Wray NR, Ripke S, Mattheisen M, Trzaskowski M, Byrne EM, Abdellaoui A, et al. Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nat Genet. 2018;50:668–81.
pubmed: 29700475
pmcid: 5934326
doi: 10.1038/s41588-018-0090-3
Cross-Disorder Group of the Psychiatric Genomics Consortium. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet. 2013;381:1371–9.
pmcid: 3714010
doi: 10.1016/S0140-6736(12)62129-1
Gelernter J, Sun N, Polimanti R, Pietrzak R, Levey DF, Bryois J, et al. Genome-wide association study of post-traumatic stress disorder reexperiencing symptoms in >165,000 US veterans. Nat Neurosci. 2019;22:1394–401.
pubmed: 31358989
pmcid: 6953633
doi: 10.1038/s41593-019-0447-7
Baratz KH, Tosakulwong N, Ryu E, Brown WL, Branham K, Chen W, et al. E2-2 protein and Fuchs’s corneal dystrophy. N Engl J Med. 2010;363:1016–24.
doi: 10.1056/NEJMoa1007064
pubmed: 20825314
Wieben ED, Aleff RA, Tosakulwong N, Butz ML, Highsmith WE, Edwards AO, et al. A common trinucleotide repeat expansion within the transcription factor 4 (TCF4, E2-2) gene predicts Fuchs corneal dystrophy. PLoS One. 2012;7:e49083.
pubmed: 23185296
pmcid: 3504061
doi: 10.1371/journal.pone.0049083
Ellinghaus D, Folseraas T, Holm K, Ellinghaus E, Melum E, Balschun T, et al. Genome-wide association analysis in primary sclerosing cholangitis and ulcerative colitis identifies risk loci at GPR35 and TCF4. Hepatology. 2013;58:1074–83.
pubmed: 22821403
doi: 10.1002/hep.25977
Chen J, Cao H, Kaufmann T, Westlye LT, Tost H, Meyer-Lindenberg A, et al. Identification of reproducible BCL11A alterations in schizophrenia through individual-level prediction of coexpression. Schizophr Bull. 2020;46:1165–71.
pmcid: 7505190
doi: 10.1093/schbul/sbaa047
Hannon E, Dempster E, Viana J, Burrage J, Smith AR, Macdonald R, et al. An integrated genetic-epigenetic analysis of schizophrenia: evidence for co-localization of genetic associations and differential DNA methylation. Genome Biol. 2016;17:176.
pubmed: 27572077
pmcid: 5004279
doi: 10.1186/s13059-016-1041-x