Identifying key transcription factors for pharmacogenetic studies of antipsychotics induced extrapyramidal symptoms

Psychopharmacology - Tập 237 - Trang 2151-2159 - 2020
Daniel Boloc1, Natalia Rodríguez2, Teresa Torres3, Susana García-Cerro3, Mara Parellada4,5, Jeronimo Saiz-Ruiz5,6, Manuel J. Cuesta5,7, Miquel Bernardo1,5,8,9, Patricia Gassó3,9, Amalia Lafuente3,5,9, Sergi Mas3,5,9, Joan Albert Arnaiz3
1Department of Medicine, University of Barcelona, Barcelona, Spain
2Fundació Clínic per a la Recerca Biomèdica, Barcelona, Spain
3Dept. Clinical Foundations, Pharmacology Unit, University of Barcelona, Barcelona, Spain
4Child and Adolescent Psychiatry Department, Hospital General Universitario Gregorio Marañón School of Medicine, Universidad Complutense, IiSGM, Madrid, Spain
5Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Madrid, Spain
6Hospital Ramon y Cajal, Universidad de Alcala, IRYCIS, Madrid, Spain
7Department of Psychiatry, Complejo Hospitalario de Navarra. Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
8Barcelona Clínic Schizophrenia Unit, Hospital Clínic de Barcelona, Barcelona, Spain
9Spain The August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain

Tóm tắt

We explore the transcription factors involved in the molecular mechanism of antipsychotic (AP)-induced acute extrapyramidalsymptoms (EPS) in order to identify new candidate genes for pharmacogenetic studies. Protein-protein interaction (PPI) networks previously created from three pharmacogenomic models (in vitro, animal, and peripheral blood inhumans) were used to, by means of several bioinformatic tools; identify key transcription factors (TFs) that regulate each network. Once the TFs wereidentified, SNPs disrupting the binding sites (TFBS) of these TFs in the genes of each network were selected for genotyping. Finally, SNP-basedassociations with EPS were analyzed in a sample of 356 psychiatric patients receiving AP. Our analysis identified 33 TFs expressed in the striatum, and 125 SNPs disrupting TFBS in 50 genes of our initial networks. Two SNPs (rs938112,rs2987902) in two genes (LSMAP and ABL1) were significantly associated with AP induced EPS (p < 0.001). These SNPs disrupt TFBS regulated byPOU2F1. Our results highlight the possible role of the disruption of TFBS by SNPs in the pharmacological response to AP.

Tài liệu tham khảo

Aberg K, Adkins DE, Bukszár J, Webb BT, Caroff SN, Miller DD et al (2010) Genome wide association study of movement-related adverse antipsychotic effects. Biol Psychiatry 67:279–282 Al Hadithy AF, Wilffert B, Bruggeman R, Stewart RE, Brouwers JR, Matroos GE et al (2009) Lack of association between antipsychotic-induced parkinsonism or its subsymptoms and rs4606 SNP of RGS2 gene in African-Caribbeans and the possible role of the medication: the Curacao extrapyramidal syndromes study X. Hum Psychopharmacol 24:123–128 Alkelai A, Greenbaum L, Rigbi A, Kanyas K, Lerer B (2009) Genome-wide association study of antipsychotic-induced parkinsonism severity among schizophrenia patients. Psychopharmacology 206:491–499 Ansari KI, Ogawa D, Rooj AK, Lawler SE, Krichevsky AM, Johnson MD, Chiocca EA, Bronisz A, Godlewski J (2015) Glucose-based regulation of miR-451/AMPK signaling depends on the OCT1 transcription factor. Cell Rep 11:902–909 Bernardo M, Bioque M, Parellada M, Saiz Ruiz J, Cuesta MJ, Llerena A, Sanjuán J, Castro-Fornieles J, Arango C, Cabrera B, PEPs Group (2013) Assessing clinical and functional outcomes in a gene-environment interaction study in first episode of psychosis (PEPs). Rev Psiquiatr Salud Ment 6:4–16 Bibb JA, Snyder GL, Nishi A, Yan Z, Meijer L, Fienberg AA, Tsai LH, Kwon YT, Girault JA, Czernik AJ, Huganir RL, Hemmings HC Jr, Nairn AC, Greengard P (1999) Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons. Nature 402:669–671 Bindea G, Mlecnik B, Hackl H, Charoentong P, Tosolini M, Kirilovsky A, Fridman WH, Pagès F, Trajanoski Z, Galon J (2009) ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics 25:1091–1093 Blake JA, Eppig JT, Kadin JA, Richardson JE, Smith CL, Bult CJ (2017) the Mouse Genome Database Group,. Mouse Genome Database (MGD)-2017: community knowledge resource for the laboratory mouse. Nucleic Acids Res 45:D723–D729 Crowley JJ, Kim Y, Szatkiewicz JP, Pratt AL, Quackenbush CR, Adkins DE, van den Oord E, Bogue MA, Yang H, Wang W, Threadgill DW, de Villena FPM, McLeod HL, Sullivan PF (2012) Genome-wide association mapping of loci for antipsychotic-induced extrapyramidal symptoms in mice. Mamm Genome 23:322–335 Dalvai M, Schubart K, Besson A, Matthias P (2010) Oct1 is required for mTOR-induced G1 cell cycle arrest via the control of p27(Kip1) expression. Cell Cycle 99:3933–3944 Divac N, Prostran M, Jakovcevski I, Cerovac N (2014) Second-generation antipsychotics and extrapyramidal adverse effects. Biomed Res Int 656370 Dolzan V, Plesnicar BK, Serreti A, Mandelli L, Zalar B, Koprivsek J et al (2007) Polymorphisms in dopamine receptor DRD1 and DRD2 genes and psychopathological and extrapyramidal symptoms in patients on long-term antipsychotic treatment. Am J Med Genet B Neuropsychiatr Genet 144B:809–815 Drago A, Crisafulli C, Serretti A (2011) The genetics of antipsychotic induced tremors: a genome-wide pathway analysis on the STEP-BD SCP sample. Am J Med Genet B Neuropsychiatr Genet 156B:975–986 Drago A, Giegling I, Schäfer M, Hartmann AM, Möller HJ, De Ronchi D et al (2012) No association of a set of candidate genes on haloperidol side effects. PLoS One 7:e44853 Drago A, Giegling I, Schäfer M, Hartmann AM, Friedl M, Konte B, Möller HJ, de Ronchi D, Stassen HH, Serretti A, Rujescu D (2013) AKAP13, CACNA1, GRIK4 and GRIA1 genetic variations may be associated with haloperidol efficacy during acute treatment. Eur Neuropsychopharmacol 23:887–894 Gassó P, Mas S, Bernardo M, Alvarez S, Parellada E, Lafuente A (2009) A common variant in DRD3 gene is associated with risperidone-induced extrapyramidal symptoms. Pharm J 9:404–410 Giegling I, Drago A, Dolzan V, Plesnicar BK, Schafer M, Hartmann AM et al (2011) Glutamatergic gene variants impact the clinical profile of efficacy and side effects of haloperidol. Pharmacogenet Genomics 21:206–216 González JR, Armengol L, Solé X, Guinó E, Mercader JM, Estivill X, Moreno V (2007) SNPassoc: an R package to perform whole genome association studies. Bioinformatics 23:644–645 Greenbaum L, Strous RD, Kanyas K, Merbl Y, Horowitz A, Karni O, Katz E, Kotler M, Olender T, Deshpande SN, Lancet D, Ben-Asher E, Lerer B (2007) Association of the RGS2 gene with extrapyramidal symptoms induced by treatment with antipsychotic medication. Pharmacogenet Genomics 17:519–528 Gunes A, Scordo MG, Jaanson P, Dahl ML (2007) Serotonin and dopamine receptor gene polymorphisms and the risk of extrapyramidal side effects in perphenazine-treated schizophrenic patients. Psychopharmacology (Berlin) 190:479–484 Gunes A, Dahl ML, Spina E, Scordo MG (2008) Further evidence for the association between 5-HT2C receptor gene polymorphisms and extrapyramidal side effects in male schizophrenic patients. Eur J Clin Pharmacol 64:477–482 Güzey C, Scordo MG, Spina E, Landsem VM, Spigset O (2007) Antipsychotic-induced extrapyramidal symptoms in patients with schizophrenia: associations with dopamine and serotonin receptor and transporter polymorphisms. Eur J Clin Pharmacol 63:233–241 Hawrylycz MJ, Lein ES, Guillozet-Bongaarts AL, Shen EH, Ng L, Miller JA, van de Lagemaat LN, Smith KA, Ebbert A, Riley ZL, Abajian C, Beckmann CF, Bernard A, Bertagnolli D, Boe AF, Cartagena PM, Chakravarty MM, Chapin M, Chong J, Dalley RA, Daly BD, Dang C, Datta S, Dee N, Dolbeare TA, Faber V, Feng D, Fowler DR, Goldy J, Gregor BW, Haradon Z, Haynor DR, Hohmann JG, Horvath S, Howard RE, Jeromin A, Jochim JM, Kinnunen M, Lau C, Lazarz ET, Lee C, Lemon TA, Li L, Li Y, Morris JA, Overly CC, Parker PD, Parry SE, Reding M, Royall JJ, Schulkin J, Sequeira PA, Slaughterbeck CR, Smith SC, Sodt AJ, Sunkin SM, Swanson BE, Vawter MP, Williams D, Wohnoutka P, Zielke HR, Geschwind DH, Hof PR, Smith SM, Koch C, Grant SGN, Jones AR (2012) An anatomically comprehensive atlas of the adult human transcriptome. Nature 489:391–399 Heinla I, Leidmaa E, Kongi K, Pennert A, Innos J, Nurk K et al (2015) Gene expression patterns and environmental enrichment-induced effects in the hippocampi of mice suggest importance of Lsamp in plasticity. Front Neurosci 9:205 Kang J, Shakya A, Tantin D (2009) Stem cells, stress, metabolism and cancer: a drama in two Octs. Trends Biochem Sci 34:491–499 Kapur S, Remington G (2001) Dopamine D(2) receptors and their role in atypical antipsychotic action: still necessary and may even be sufficient. Biol Psychiatry 50:873–883 Karolchik D, Hinrichs AS, Furey TS, Roskin KM, Sugnet CW, Haussler D, Kent WJ (2004) The UCSC Table browser data retrieval tool. Nucleic Acids Res 32:D493–D496 Koido K, Traks T, Balõtšev R, Eller T, Must A, Koks S, Maron E, Tõru I, Shlik J, Vasar V, Vasar E (2012) Associations between LSAMP gene polymorphisms and major depressive disorder and panic disorder. Transl Psychiatry 2:e152 Koido K, Janno S, Traks T, Parksepp M, Ljubajev Ü, Veiksaar P, Must A, Shlik J, Vasar V, Vasar E (2014) Associations between polymorphisms of LSAMP gene and schizophrenia. Psychiatry Res 215:797–798 Lafuente A, Bernardo M, Mas S, Crescenti A, Aparici M, Gassó P et al (2007) Dopamine transporter (DAT) genotype (VNTR) and phenotype in extrapyramidal symptoms induced by antipsychotics. Schizophr Res 90:115–122 Lafuente A, Bernardo M, Mas S, Crescenti A, Aparici M, Gassó P et al (2008) Polymorphism of dopamine D2 receptor (TaqIA, TaqIB, and-141C Ins/Del) and dopamine degradation enzyme (COMT G158A, A-278G) genes and extrapyramidal symptoms in patients with schizophrenia and bipolar disorders. Psychiatry Res 161:131–141 Langfelder P, Horvath S (2008) WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics 9:559 Lawford BR, Barnes M, Swagell CD, Connor JP, Burton SC, Heslop K, Voisey J, Morris CP, Nyst P, Noble EP, Young RM (2013) DRD2/ANKK1 Taq1A (rs 1800497 C>T) genotypes are associated with susceptibility to second generation antipsychotic-induced akathisia. J Psychopharmacol 27:343–348 Mas S, Gassó P, Alvarez S, Parellada E, Bernardo M, Lafuente A (2012) Intuitive pharmacogenetics: spontaneous risperidone dosage is related to CYP2D6, CYP3A5 and ABCB1 genotypes. Pharm J 12:255–259 Mas S, Gassó P, Bernardo M, Lafuente A (2013) Functional analysis of gene expression in risperidone treated cells provide new insights in molecular mechanism and new candidate genes for pharmacogenetic studies. Eur Neuropsychopharmacol 23:329–337 Mas S, Gassó P, Parellada E, Bernardo M, Lafuente A (2015a) Network analysis of gene expression in peripheral blood identifies mTOR and NF-κB pathways involved in antipsychotic-induced extrapyramidal symptoms. Pharm J 15:452–460 Mas S, Gassó P, Lafuente A (2015b) Applicability of gene expression and systems biology to develop pharmacogenetic predictors; antipsychotic-induced extrapyramidal symptoms as an example. Pharmacogenomics 16:1975–1988 Mas S, Gassó P, Ritter MA, Malagelada C, Bernardo M, Lafuente A (2015c) Pharmacogenetic predictor of extrapyramidal symptoms induced by antipsychotics: multilocus interaction in the mTOR pathway. Eur Neuropsychopharmacol 25:51–59 Mas S, Gassó P, Boloc D, Rodriguez N, Mármol F, Sánchez J, Bernardo M, Lafuente A (2016a) Network analysis of gene expression in mice provides new evidence of involvement of the mTOR pathway in antipsychotic-induced extrapyramidal symptoms. Pharm J 16:293–300 Mas S, Gassó P, Lafuente A, Bioque M, Lobo A, Gonzàlez-Pinto A et al (2016b) Pharmacogenetic study of antipsychotic induced acute extrapyramidal symptoms in a first episode psychosis cohort: role of dopamine, serotonin and glutamate candidate genes. Pharm J 16:439–445 McClay JL, Adkins DE, Aberg K, Stroup S, Perkins DO, Vladimirov VI et al (2011) Genome-wide pharmacogenomic analysis of response to treatment with antipsychotics. Mol Psychiatry 16:76–85 Minguez P, Götz S, Montaner D, Al-Shahrour F, Dopazo J (2009) SNOW, a web-based tool for the statistical analysis of protein-protein interaction networks. Nucleic Acids Res 37:W109–W114 Nishi A, Bibb JA, Snyder GL, Higashi H, Nairn AC, Greengard P (2000) Amplification of dopaminergic signaling by a positive feedback loop. Proc Natl Acad Sci U S A 97:12840–12845 Nurnberger JI Jr, Koller DL, Jung J, Edenberg HJ, Foroud T, Guella I (2014) Identification of pathways for bipolar disorder: a meta-analysis. JAMA Psychiatry 71(6):657–664 Pance A (2016) Oct-1, to go or not to go? That is the PolII question. Biochim Biophys Acta 1859:820–824 Philips MA, Lilleväli K, Heinla I, Luuk H, Hundahl CA, Kongi K, Vanaveski T, Tekko T, Innos J, Vasar E (2015) Lsamp is implicated in the regulation of emotional and social behavior by use of alternative promoters in the brain. Brain Struct Funct 220:1381–1393 Roussos P, Mitchell AC, Voloudakis G, Fullard JF, Pothula VM, Tsang J, Stahl EA, Georgakopoulos A, Ruderfer DM, Charney A, Okada Y, Siminovitch KA, Worthington J, Padyukov L, Klareskog L, Gregersen PK, Plenge RM, Raychaudhuri S, Fromer M, Purcell SM, Brennand KJ, Robakis NK, Schadt EE, Akbarian S, Sklar P (2014) A role for noncoding variation in schizophrenia. Cell Rep 9:1417–1429 Schork AJ, Thompson WK, Pham P, Torkamani A, Roddey JC, Sullivan PF, Kelsoe JR, O'Donovan MC, Furberg H, The Tobacco and Genetics Consortium, The Bipolar Disorder Psychiatric Genomics Consortium, The Schizophrenia Psychiatric Genomics Consortium, Schork NJ, Andreassen OA, Dale AM (2013) All SNPs are not created equal: genome-wide association studies reveal a consistent pattern of enrichment among functionally annotated SNPs. PLoS Genet 9:e1003449 Simpson GM, Angus JW (1970) A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl 212:11–19 Sokolowski M, Wasserman J, Wasserman D (2016) Polygenic associations of neurodevelopmental genes in suicide attempt. Mol Psychiatry 21:1381–1390 Strand AD, Baquet ZC, Aragaki AK, Holamans P, Yang L, Cleren C et al (2007) Expression profiling of Huntington’s disease models suggests that brain-derived neurotrophic factor depletion plays a major role in striatal degeneration. J Neurosci 27:11758–11768 Sullivan PF, Fan C, Perou CM (2006) Evaluating the comparability of gene expression in blood and brain. Am J Med Genet B Neuropsychiatr Genet 141B:261–268 The 1000 Genomes Project Consortium (2015) A global reference for human genetic variation. Nature 526:68–74 Tybura P, Trześniowska-Drukała B, Bienkowski P, Beszlej A, Frydecka D, Mierzejewski P, Samochowiec A, Grzywacz A, Samochowiec J (2014) Pharmacogenetics of adverse events in schizophrenia treatment: comparison study of ziprasidone, olanzapine and perazine. Psychiatry Res 219:261–267 Vanaveski T, Singh K, Narvik J, Eskla KL, Visnapuu T, Heinla I et al (2017) Promoter-specific expression and genomic structure of IgLON family genes in mouse. Front Neurosci 11:38 Weiden PJ (2007) Switching antipsychotics as a treatment strategy for antipsychotic-induced weight gain and dyslipidemia. J Clin Psychiatry 68:34–39 Wilffert B, Al Hadithy AF, Sing VJ, Matroos G, Hoeck HW, van Os J et al (2009) The role of dopamine D3, 5-HT2A and 5-HT2C receptor variants as pharmacogenetic determinants in tardive dyskinesia in African-Caribbean patients under chronic antipsychotic treatment: Curacao extrapyramidal syndromes study IX. J Psychopharmacol 23:652–659 Zhou ZH, Wu YF, Wang XM, Han YZ (2017) The c-Abl inhibitor in Parkinson disease. Neurol Sci 38:547–552 Zivković M, Mihaljevic-Peles A, Bozina N, Sagud M, Nikolac-Perkovic M, Vuksan-Cusa B et al (2013) The association study of polymorphisms in DAT, DRD2, and COMT genes and acute extrapyramidal adverse effects in male schizophrenic patients treated with haloperidol. J Clin Psychopharmacol 33:593–599