Role of TNF-α -308G/A Polymorphism in Bipolar Disorder and its Relationship with Clinical and Demographic Variables

Gene-environment interactions might play a significant role in the development of bipolar disorder (BD). The objective of the current study was to investigate the association between tumor necrosis factor (TNF)-α -308 G/A polymorphism and BD and conduct a bioinformatics analysis of the protein-protein network of TNF-α. Gene-environment interactions and the relationship between stressful life events (SLEs) and substance abuse with TNF genotypes and other characteristics were analyzed.

The genomic deoxyribonucleic acid (DNA) of 400 patients with BD and 200 control subjects were extracted and genotyped for TNF-α -308 G/A polymorphism. SLEs and substance abuse were evaluated using the Life Event and Difficulty Schedule (LEDS) and a self-designed substance abuse questionnaire for the events six months prior to the onset of the disease, respectively. Gene-environment interactions were assessed by multiple statistical tools. Bioinformatics analysis of the TNF-α network and its interacting proteins was carried out using STRING and Cytoscape softwares.

Genotyping analysis revealed a significant association between TNF-α -308 G/A polymorphism and BD (p<0.009). Furthermore, analysis of gene-environment interaction revealed a significant association between TNF-α -308 G/A and SLEs (p=0.001) and TNF-α -308 G/A and substance abuse (p=0.001). Three distinct proteins, RELA, RIPK1, and BIRC3, were identified through hub analysis of the protein network.

TNF-α -308 G/A polymorphism is positively associated with BD. SLEs and substance abuse might trigger the early onset of BD. Proteins identified through bioinformatics analysis might contribute to the TNF-α mediated pathophysiology of BD and can be the potential therapeutic targets.