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

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Abstract

Introduction

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.

Methods

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.

Results

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.

Conclusion

Our results highlight the possible role of the disruption of TFBS by SNPs in the pharmacological response to AP.

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Acknowledgments

We thank the Language Advisory Service of the University of Barcelona, Spain, for manuscript revision. The authors also thank all subjects and their families for the time and effort spent on this study.

Funding

This study was supported by the Spanish Ministry of Health, Instituto de Salud Carlos III (FIS, Fondo de Investigacion Sanitaria PI10/02430, PI13/00812, PI16/0122) and the Catalan Innovation, Universities and Enterprise Authority (Grants DURSI 2014SGR436 and 2014SGR441). DB is supported by a FPU fellowship (FPU14/06834) from the “Ministerio de Educación, Cultura y Deporte.”

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Authors and Affiliations

  1. Department of Medicine, University of Barcelona, Barcelona, Spain

    Daniel Boloc & Miquel Bernardo

  2. Fundació Clínic per a la Recerca Biomèdica, Barcelona, Spain

    Natalia Rodríguez

  3. Dept. Clinical Foundations, Pharmacology Unit, University of Barcelona, Barcelona, Spain

    Teresa Torres, Susana García-Cerro, Patricia Gassó, Amalia Lafuente, Sergi Mas & Joan Albert Arnaiz

  4. Child and Adolescent Psychiatry Department, Hospital General Universitario Gregorio Marañón, School of Medicine, Universidad Complutense, IiSGM, Madrid, Spain

    Mara Parellada

  5. Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Madrid, Spain

    Mara Parellada, Jeronimo Saiz-Ruiz, Manuel J. Cuesta, Miquel Bernardo, Amalia Lafuente & Sergi Mas

  6. Hospital Ramon y Cajal, Universidad de Alcala, IRYCIS, Madrid, Spain

    Jeronimo Saiz-Ruiz

  7. Department of Psychiatry, Complejo Hospitalario de Navarra. Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain

    Manuel J. Cuesta

  8. Barcelona Clínic Schizophrenia Unit, Hospital Clínic de Barcelona, Barcelona, Spain

    Miquel Bernardo

  9. Spain The August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain

    Miquel Bernardo, Patricia Gassó, Amalia Lafuente & Sergi Mas

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  1. Daniel Boloc
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  2. Natalia Rodríguez
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Correspondence to Sergi Mas or Joan Albert Arnaiz.

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Conflict of interest

J. Saiz-Ruiz has been a speaker for and on the advisory boards of Lilly, GlaxoSmithKline, Lundbeck, Janssen, Servier, and Pfizer and has received grant/honoraria from Lilly and Astra-Zeneca.

M. Bernardo has been a consultant for, received grant/research support and honoraria from, and been on the speakers/advisory board of ABBiotics, Adamed, Almirall, AMGEN, Boehringer, Eli Lilly, Ferrer, Forum Pharmaceuticals, Gedeon, Hersill, Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Roche, and Servier.

The other authors declare no conflict of interests.

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Boloc, D., Rodríguez, N., Torres, T. et al. Identifying key transcription factors for pharmacogenetic studies of antipsychotics induced extrapyramidal symptoms. Psychopharmacology 237, 2151–2159 (2020). https://doi.org/10.1007/s00213-020-05526-8

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