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

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.

New alcohol-related genes suggest shared genetic mechanisms with neuropsychiatric disorders

“…Both genes (along with PPP1R1P) are centrally involved in rewardmediating mesocortico-limbic pathways and both are implicated in the development of schizophrenia. For example, there is a robust GWAS association between schizophrenia and SNP rs4938021 in DRD2 (in perfect LD with our novel alcohol intake-related variant rs7121986) and DRD2 appears to be pivotal in network analyses of genes involved in schizophrenia 52 . Taken together, our results suggest that there are shared genetic mechanisms between the regulation of alcohol intake and susceptibility to schizophrenia, as well as other neuropsychiatric disorders.…”

Genome-wide association and functional studies identify 46 novel loci for alcohol consumption and suggest common genetic mechanisms with neuropsychiatric disorders

“…Both genes (along with PPP1R1P ) are centrally involved in reward-mediating mesocortico-limbic pathways and both are implicated in the development of schizophrenia. For example, there is a robust GWAS association between schizophrenia and SNP rs4938021 in DRD2 (in perfect LD with our novel alcohol intake-related variant rs7121986) and DRD2 appears to be pivotal in network analyses of genes involved in schizophrenia 52 . Taken together, our results suggest that there are shared genetic mechanisms between the regulation of alcohol intake and susceptibility to schizophrenia, as well as other neuropsychiatric disorders.…”

The Eminence of Co-Expressed Ties in Schizophrenia Network Communities

“…The research is innovative in discovering the impact of weak ties in schizophrenia gene networks. Previous studies have focused on network-based approaches for recognizing gene expressions from schizophrenia network [73,74]. However, these studies have not acknowledged the relevance of tie structures within schizophrenia gene networks.…”