In this study, we found 12 common genes between MS and OCD with a wide-ranging and targeted overview of available resources. Furthermore, network analysis showed that among the 12 common genes, three genes of BDNF, TNFα, and NRXN1, were the most central genes, in the order of centrality.
BDNF is a member of the neurotrophin family, which plays essential roles in many neural processes such as synaptic plasticity, neuronal development, and cell survival [50, 51]. This protein promotes ensheathing the neurites with myelin by maturating oligodendrocyte precursor cells to oligodendrocytes and increasing myelin synthesis via tropomyosin-related kinase B signaling in them [52]. It has been shown that the level of BDNF in patients with relapsing-remitting MS (RRMS) is reduced [53], and this decrease can contribute to the progression of axonal loss and demyelinating disease in MS patients [54]. It has also reported that Sequence Variants in the BDNF gene are related to OCD [40, 55]. Other studies have also shown that the Val66Met BDNF gene variant is associated with OCD development [56, 57].
TNFα is a cytokine released from various types of cells, such as macrophages, lymphocytes, neutrophils, and brain astrocytes [58]. This cytokine has many functions in immunity, inflammation, and cell death [59]. Various studies have shown that TNFα levels in the brain and cerebrospinal fluid of MS patients rise, and an increase in this pro-inflammatory cytokine is associated with the development of MS [60–62]. The presence of this gene in the regenerated gene network represents the involvement of the immune system and inflammatory processes in these disorders. Also, the role of TNFα and inflammatory reactions have been shown in the progression of OCD, and it has been shown that polymorphisms in the TNFα gene are related to OCD [63]. Besides, the plasma levels of this pro-inflammatory cytokine are related to the progress of OCD [64].
Neurexins are a family of proteins that are essential as cell adhesion molecules in the development and establishment of the nervous system synapses [65]. Reduced synaptic density in the hippocampus and cerebral cortex of MS patients and impaired function of the neural circuits in the OCD has already been documented [66–68]. Besides, the dysregulation of NRXN1 leads to neurodegeneration in MS patients [69]. Noh et al. study also showed that NRXN1 is a strongly linked gene with OCD [70]. Because BDNF/ TrkB signaling plays an important role in regulating synaptic strength and transmission [50], the involvement of BDNF and NRXN1 genes in MS and OCD can explain the synaptic disruption in these two disorders.
Among the new genes that entered the network, TNFRSF1A and MAP3K7 genes had the highest degree of centrality and degree of difference and importance. The Tumor Necrosis Factor Receptor superfamily member 1A (TNFRSF1A) gene encodes a variety of TNFα receptors (TNFR1), which results in many inflammatory processes, apoptosis, and cell survival [71]. Studies have shown that variation in the TNFRSF1A gene can contribute to the progression of MS [72]. Simsek et al. suggested that low levels of TNFα through the TNFRSF1A may cause OCD or worsen it [73]. Although further studies on the changes in this gene in OCD can be valuable.
Mitogen-activated protein kinase 7 is an upstream activator of Jun N-terminal kinases (JNKs), which is activated in response to various stimuli such as growth factors, pro-inflammatory cytokines, hormones, and environmental stress and plays an important role in the development of the nervous system [74]. MAP3K7 has been reported as a new autoantigen in MS patients [75]. Future studies on the possible role of the MAP3K7 gene in MS and OCD can be helpful.
The results of enrichment analysis on common genes between MS and OCD show the regulation of the inflammatory response to antigenic stimuli (CNR1, HLA-DRB1, TNF), response to external stimulus (BDNF, CNR1, EFNB1, HLA-DRB1, NRXN1, SLC1A2, TNF, UCP2) and axon development (BDNF, CNR1, EFNB1, NRXN1) are the most important processes affected by these two disorders. It is believed that cannabinoid receptor 1 (CNR1) exists on peripheral immune cells, and is strongly expressed in active T cells [76]. Class II major histocompatibility complex (MHC) genes are molecules expressed by various types of immune system cells, including B cells, activated T cells, macrophages, dendritic cells, and thymus epithelial cells. They play a central role in the immune system by presenting peptides derived from extracellular proteins [77]. BDNF is a factor that is essential for the growth and development of axons [78], and studies have shown that the expression of BDNF in the inflammation conditions is significantly reduced [79, 80]. Neurexins play a significant role in synaptogenesis, and neurotransmitter releases [65, 81]. The findings indicate that CNR1 is essential for the normal growth of axons [82], and the rate of expression of these receptors on peripheral blood mononuclear cells increases in inflammatory conditions by inflammatory cytokines [83]. It has also been shown that defect in EFNB1 gene leads to malformation of the corpus callosum [84]. The results also showed that estrogen receptor activity and estrogen response element-binding are other processes associated with MS and OCD common genes. It shows that estrogen may also play a role in the pathogenesis of these disorders. It has been shown that the use of the ER1 and ER2 ligands has protective effects in the animal model of MS, namely, experimental autoimmune encephalomyelitis (EAE) [85, 86].
Further analyses of MS and OCD common genes indicate that the integral component of the plasma membrane, membrane raft, and growth cone are the most important areas affected by the disorders. Membrane rafts play a significant role in the adhesion and motility of growth cone, and therefore their normal function is essential for axon guidance [87].
Tissue/cell specific expression analysis showed that five major brain regions and two cell lines are associated with MS and OCD. The relationship between dorsal striatum, prefrontal cortex, cingulate cortex, and cerebral cortex with MS in neuroimaging studies has been proven in patients [88, 89]. Astrocytes are the most important glial cells in the CNS. In the animal model of EAE, they have neuroprotective and anti-inflammatory effects by the expression of ER1 and the production of neurosteroids such as estrogen [90]. The reactive form of these cells is critical in the development of brain lesions and the production of scars in MS by producing pro-inflammatory cytokines and movement of innate immune cells (chemotaxis) into the brain tissue [91]. The role of CD19+ B-cell in the pathogenesis of MS has also been proven [92]. Besides, dysfunction of structures such as the striatum, cerebral cortex, prefrontal cortex, and cingulate cortex in OCD has also been reported [93]. At the cellular level, recent studies have also shown the involvement of brain astrocytes in repetitive and compulsive behaviors [94, 95].
MicroRNAs are small noncoding RNA molecule that are involved in the regulation of gene expression through silencing their target mRNAs and inhibit their translation [96]. Each miRNA can regulate the expression of a large number of target genes. Recent experiments have strongly focused on these molecules. For instance miR-410 has neuroprotective effects and can regulate neurogenesis [97, 98]. Also, miR-344-3p is crucial for development of nervous system and morphogenesis [99]. Interestingly, miR-221 could stimulate Schwann cell proliferation [100] and also, decrease inflammatory responses and cell death in neuronal cells [101].