Immune, RNA, and Neurocognitive Genetic Networks in Bipolar Disorder Subtypes: A Transcriptomic Meta-Analysis.

Background: Little is known about the pathogenesis of Bipolar Disorder, and even less is known about the genetic differences between its subtypes. Bipolar Disorder is classified into different subtypes, which present different symptoms and lifetime courses. While genetic studies have been conducted in Bipolar Disorder, most examined the gene expression of only Bipolar Disorder Type 1. Studies that include Bipolar Disorder Type 1 and Bipolar Disorder Type 2 often fail to differentiate them into separate conditions. Few large transcriptomic meta-analyses in Bipolar Disorder have been conducted to identify genetic pathways. Thus, using publicly available data sets we aim here to uncover significant differential gene expression that allows distinguishing Type 1 and Type 2 Bipolar Disorders, as well as find patterns in Bipolar Disorder as a whole.

Methods: We analyze 17 different gene expression data sets from different tissue in Bipolar Disorder using GEO2R and manual analysis, of which 15 contained significant differential gene expression results. We use STRING and Cytoscape to examine Gene Ontology to find significantly affected genetic pathways. We identify hub genes using cytoHubba, a plugin in Cytoscape. We find genes common to data sets of the same material or subtype.

Results: 12 out of 15 data sets are enriched for immune system and RNA related pathways. 9 out of 15 data sets are enriched for neurocognitive and metal ion related GO terms. Analysis of Bipolar Disorder Type 1 vs Bipolar Disorder Type 2 revealed most differentially expressed genes were related to immune function, especially cytokines. Terms related to synaptic signaling and neurotransmitter secretion were found in down-regulated GO terms while terms related to neuron apoptosis and death were up-regulated. We identify the gene SNCA as a potential biomarker for overall Bipolar Disorder diagnosis due to its prevalence in our data sets.

Conclusions: The immune system and RNA related pathways are significantly enriched across the Bipolar Disorder data sets. The role of these pathways is likely more critically important to the function of Bipolar Disorder than currently understood. Further studies should clearly label the subtype of Bipolar Disorder used in their research and more effort needs to be undertaken to collect samples from Cyclothymic Disorder and Bipolar Disorder Type 2.