Incorporating Information of microRNAs into Pathway Analysis in a Genome-Wide Association Study of Bipolar Disorder

Abstract

MicroRNAs (miRNAs) are known to be important post-transcriptional regulators that are involved in the etiology of complex psychiatric traits. The present study aimed to incorporate miRNAs information into pathway analysis using a genome-wide association dataset to identify relevant biological pathways for bipolar disorder (BPD). We selected psychiatric- and neurological-associated miRNAs (N = 157) from PhenomiR database. The miRNA target genes (miTG) predictions were obtained from . Canonical pathways (N = 4,051) were downloaded from the Molecule Signature Database. We employed a novel weighting scheme for miTGs in pathway analysis using methods of gene set enrichment analysis and sum-statistic. Under four statistical scenarios, 38 significantly enriched pathways (P-value < 0.01 after multiple testing correction) were identified for the risk of developing BPD, including pathways of ion channels associated (e.g., gated channel activity, ion transmembrane transporter activity, and ion channel activity) and nervous related biological processes (e.g., nervous system development, cytoskeleton, and neuroactive ligand receptor interaction). Among them, 19 were identified only when the weighting scheme was applied. Many miRNA-targeted genes were functionally related to ion channels, collagen, and axonal growth and guidance that have been suggested to be associated with BPD previously. Some of these genes are linked to the regulation of miRNA machinery in the literature. Our findings provide support for the potential involvement of miRNAs in the psychopathology of BPD. Further investigations to elucidate the functions and mechanisms of identified candidate pathways are needed.

Differentially methylated regions in bipolar disorder and suicide

“…One pathway exclusively found from the BD‐NC analysis was “axonal guidance signaling.” Neurons extend axons to reach target cells and form functional circuits during development, and dysregulation of axon guiding can result in deficits in neural circuit formation. This is consistent with other previous studies; a meta‐analysis studying potential cardiometabolic mood disorder genes (Amare, Schubert, Klingler‐Hoffmann, Cohen‐Woods, & Baune, ), a microRNA BD study (Shih, Kao, Chuang, & Kuo, ), a genetic family‐wide BD study (Xu et al, ), and a BD/schizophrenia methylation study (Xiao et al, ), which all found an association between BD and axonal guidance signaling. Furthermore, lithium, a common medication for BD, increases axonal spreading (Lucas, Goold, Gordon‐Weeks, & Salinas, ), and the Wnt signaling pathway, which is activated by lithium (Klein & Melton, ), also regulates axon guidance (Garcia, Udeh, Kalahasty, & Hackam, ).…”

Biomarkers for bipolar disorder: current insights

“…109 Some miRNAs have been described as important regulators of neurogenesis and formation of synaptic plasticity, [110][111][112] where a majority of their targeted genes are involved in regulation of ion channels and neuronal processes -both of which have been previously implicated in BD. 113 This supports the potential role of miRNAs in the regulation of brain function and thus, may be involved in the pathophysiology of BD. 113 Another important fact that must be discussed in this section is the effect of treating patients with BD with mood stabilizers.…”

“…113 This supports the potential role of miRNAs in the regulation of brain function and thus, may be involved in the pathophysiology of BD. 113 Another important fact that must be discussed in this section is the effect of treating patients with BD with mood stabilizers. A number of miRNAs have been found to be upregulated …”

Deficits in axon‐associated proteins in prefrontal white matter in bipolar disorder but not schizophrenia

“…Abnormal organization of microtubules has been described in neuronal precursor cells from subjects with BD . In addition, analysis of genomic, transcriptomic and protein interaction data has revealed enrichment of cytoskeletal networks in BD , suggestive of a general alteration in cytoskeleton dynamics in this disorder. DISC1 is a multifunctional protein that plays a role in regulating a large number of signaling pathways involved in brain development and function .…”