A complex network approach reveals a pivotal substructure of genes linked to schizophrenia

PLoS One. 2018 Jan 5;13(1):e0190110. doi: 10.1371/journal.pone.0190110. eCollection 2018.

Abstract

Research on brain disorders with a strong genetic component and complex heritability, such as schizophrenia, has led to the development of brain transcriptomics. This field seeks to gain a deeper understanding of gene expression, a key factor in exploring further research issues. Our study focused on how genes are associated amongst each other. In this perspective, we have developed a novel data-driven strategy for characterizing genetic modules, i.e., clusters of strongly interacting genes. The aim was to uncover a pivotal community of genes linked to a target gene for schizophrenia. Our approach combined network topological properties with information theory to highlight the presence of a pivotal community, for a specific gene, and to simultaneously assess the information content of partitions with the Shannon's entropy based on betweenness. We analyzed the publicly available BrainCloud dataset containing post-mortem gene expression data and focused on the Dopamine D2 receptor, encoded by the DRD2 gene. We used four different community detection algorithms to evaluate the consistence of our approach. A pivotal DRD2 community emerged for all the procedures applied, with a considerable reduction in size, compared to the initial network. The stability of the results was confirmed by a Dice index ≥80% within a range of tested parameters. The detected community was also the most informative, as it represented an optimization of the Shannon entropy. Lastly, we verified the strength of connection of the DRD2 community, which was stronger than any other randomly selected community and even more so than the Weighted Gene Co-expression Network Analysis module, commonly considered the standard approach for such studies. This finding substantiates the conclusion that the detected community represents a more connected and informative cluster of genes for the DRD2 community, and therefore better elucidates the behavior of this module of strongly related DRD2 genes. Because this gene plays a relevant role in Schizophrenia, this finding of a more specific DRD2 community will improve the understanding of the genetic factors related with this disorder.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Genetic Predisposition to Disease*
  • Humans
  • Receptors, Dopamine D2 / genetics*
  • Schizophrenia / genetics*

Substances

  • DRD2 protein, human
  • Receptors, Dopamine D2

Grants and funding

This research has been partly funded by the "Capitale Umano ad Alta Qualificazione" grant awarded by Fondazione Con Il Sud (2011-PDR-06) to Alessandro Bertolino, and by a Hoffmann-La Roche collaboration grant titled "Gene co-expression networks as roadmap for genotype to phenotype mapping in schizophrenia" awarded to Giulio Pergola. This project has received funding from the European Union Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 602450. This paper reflects only the author’s views and the European Union is not liable for any use that may be made of the information contained therein.