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Gene Regulatory Network of Dorsolateral Prefrontal Cortex: a Master Regulator Analysis of Major Psychiatric Disorders

  • Giovana BristotEmail author
  • Marco Antônio De Bastiani
  • Bianca Pfaffenseller
  • Flávio Kapczinski
  • Márcia Kauer-Sant’Anna
Original Article
  • 67 Downloads

Abstract

Despite the strong genetic component of psychiatric disorders, traditional genetic studies have failed to find individual genes of large effect size. Thus, alternative methods, using bioinformatics, have been proposed to solve these biological puzzles. Of these, here we employ systems biology–based approaches to identify potential master regulators (MRs) of bipolar disorder (BD), schizophrenia (SZ), and major depressive disorder (MDD), their association with biological processes and their capacity to differentiate disorders’ phenotypes. High-throughput gene expression data was used to reconstruct standard human dorsolateral prefrontal cortex regulatory transcriptional network, which was then queried for regulatory units and MRs associated with the psychiatric disorders of interest. Furthermore, the activity status (active or repressed) of MR candidates was obtained and used in cluster analysis to characterize disease phenotypes. Finally, we explored the biological processes modulated by the MRs using functional enrichment analysis. Thirty-one, thirty-four, and fifteen MR candidates were identified in BD, SZ, and MDD, respectively. The activity state of these MRs grouped the illnesses in three clusters: MDD only, mostly BD, and a third one with BD and SZ. While BD and SZ share several biological processes related to ion transport and homeostasis, synapse, and immune function, SZ showed peculiar enrichment of processes related to cytoskeleton and neuronal structure. Meanwhile, MDD presented mostly processes related to glial development and fatty acid metabolism. Our findings suggest notable differences in functional enrichment between MDD and BD/SZ. Furthermore, similarities between BD and SZ may impose particular challenges in attempts to discriminate these pathologies based solely on their transcriptional profiles. Nevertheless, we believe that systems-oriented approaches are promising strategies to unravel the pathophysiology peculiarities underlying mental illnesses and reveal therapeutic targets.

Keywords

Major psychiatric disorders Bipolar disorder Schizophrenia Major depressive disorder Gene regulatory network, Master regulator analysis 

Notes

Acknowledgements

The authors are thankful for the support provided by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq-Brazil) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES-Brazil).

Author’s Contributions

GB conceived the study, carried out the selection of datasets and prepared the first draft. GB, BP, and MADB contributed to study design. MADB extracted data from Gene Expression Omnibus (GEO) and implemented the bioinformatics pipelines. MKS provided overall guidance and supervised the analysis. All authors interpreted the results and critically reviewed and approved the final version of the manuscript. GB and MADB contributed equally to this work.

Compliance with Ethical Standards

Conflict of Interest

MKS reports research grants from CNPq-INCT-TM, CNPq Universal, CNPq Produtividade em Pesquisa, SMRI, FIPE-HCPA and CAPES in the last 5 years. FK reports personal fees from Daiichi Sankyo, personal fees from Janssen-Cilag, grants from Stanley Medical Research Institute 07TGF/1148, grants from INCT-CNPq 465458/2014-9, grants from Canada Foundation for Innovation-CFI, outside the submitted work. All other authors declare no competing interests.

Supplementary material

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Authors and Affiliations

  1. 1.Laboratório de Psiquiatria Molecular–Centro de Pesquisa ExperimentalHospital de Clínicas de Porto AlegrePorto AlegreBrazil
  2. 2.Postgraduate Program in BiochemistryUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  3. 3.Laboratory of Cellular Biochemistry, Department of BiochemistryUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  4. 4.Department of Psychiatry and Behavioural NeurosciencesMcMaster UniversityHamiltonCanada
  5. 5.Department of PsychiatryUniversidade Federal do Rio Grande do SulPorto AlegreBrazil

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