Association of FKBP5 gene polymorphism with insomnia symptoms in the depressive episodes of stress-related bipolar disorder

PURPOSE: Stress-related bipolar disorder (BP) arises from complex genetic, environmental, and clinical interactions. While FKBP5(key stress response regulator) is linked to mood disorders, its role in insomnia during depressive episodes remains unclear. This study explores the association between FKBP5 polymorphisms and insomnia symptoms occurring during the depressive episodes of BP. MATERIALS AND METHODS: A total of 347 individuals with BP (42 ​% male, 58 ​% female; 78 ​% insomnia symptoms) were assessed using the SCID, OPCRIT, and TaqMan genotyping for eight FKBP5 polymorphisms. Participants were grouped based on the presence/absence of a stressor before the first episode. Statistical analyses (ANCOVA and Chi-square with pairwise post hoc tests) were performed using Statistica 13.3 and R. Functional annotation of significantly associated variants was conducted using Ensembl VEP, RegulomeDB, HaploReg, and SNPnexus. RESULTS: FKBP5 rs755658 polymorphism may be associated with insomnia symptoms in individuals with stressors, with CT/CC genotypes showing a higher likelihood of symptoms (p ​= ​0.03; BH-adjusted p ​= ​0.22, below the 0.25 threshold) compared to the TT. Seven polymorphisms were significantly associated with BP subtypes in those without stressors, suggesting genetic influence. The rs755658 variant is predicted to affect gene expression, transcription factor binding, and post-transcriptional regulation. CONCLUSIONS: These findings suggest that FKBP5 genetic variants may affect sleep disturbances with a stressor present, highlighting their role in stress regulation and insomnia during depressive episodes in BP. Given the study's exploratory nature, findings should be interpreted cautiously and validated in larger, independent samples. Future studies should investigate the underlying mechanisms and therapeutic implications.