Stress-related bipolar disorder (BP) is shaped by intricate interactions among genetic, environmental, and clinical factors. Although the FKBP5 gene functions as a central modulator of the stress response and has been linked to several mood disorders, its potential involvement in insomnia during depressive episodes of BP remains insufficiently explored. This study aimed to examine the association between FKBP5 gene variants and insomnia symptoms emerging during depressive episodes in BP. The study enrolled 347 individuals diagnosed with BP (42% male, 58% female), of whom 78% experienced insomnia symptoms. Diagnostic assessments were conducted using the SCID and OPCRIT instruments, while eight FKBP5 single nucleotide polymorphisms (SNPs) were genotyped through the TaqMan method. Participants were divided according to the presence or absence of a significant stressor preceding their first mood episode. Statistical analyses, including ANCOVA and Chi-square tests with pairwise post hoc comparisons, were performed using Statistica 13.3 and R software. Functional characterization of variants with significant associations was carried out via Ensembl VEP, RegulomeDB, HaploReg, and SNPnexus. The FKBP5 rs755658 variant showed a potential link with insomnia symptoms among participants with prior stress exposure, where CT/CC genotypes were more frequently associated with insomnia (p = 0.03; BH-adjusted p = 0.22, below the 0.25 threshold) compared to the TT genotype. Additionally, seven other FKBP5 polymorphisms displayed significant associations with BP subtypes in participants without identifiable stressors, suggesting a genetic component independent of environmental triggers. Functional prediction analysis indicated that rs755658 may influence transcriptional activity, transcription factor binding, and post-transcriptional gene regulation. The results suggest that FKBP5 genetic variants could modulate vulnerability to insomnia in stress-affected individuals during depressive episodes of BP, underscoring their potential contribution to stress regulation pathways. Given the exploratory scope of this research, replication in larger, independent samples is necessary. Future investigations should focus on the molecular mechanisms and potential clinical implications for personalized treatment approaches.
