Bipolar affective disorder (BD) is a severe psychiatric disorder characterized by periodic changes in mood from depression to mania. Disruptions of biological rhythms increase risk of mood disorders. Because clinical representation of disease is heterogeneous, homogenous sets of patients are suggested to use in the association analyses. In our study, we aimed to apply previously computed structure of bipolar disorder symptom dimension for analyses of genetic association. We based quantitative trait on: main depression, sleep disturbances, appetite disturbances, excitement and psychotic dimensions consisted of OPCRIT checklist items. We genotyped 42 polymorphisms from circadian clock genes: PER3, ARNTL, CLOCK and TIMELSSS from 511 patients BD (n = 292 women and n = 219 men). As quantitative trait we used clinical dimensions, described above. Genetic associations between alleles and quantitative trait were performed using applied regression models applied in PLINK. In addition, we used the Kruskal–Wallis test to look for associations between genotypes and quantitative trait. During second stage of our analyses, we used multidimensional scaling (multifactor dimensionality reduction) for quantitative trait to compute pairwise epistatic interactions between circadian gene variants. We found association between ARNTL variant rs11022778 main depression (p = 0.00047) and appetite disturbances (p = 0.004). In epistatic interaction analyses, we observed two locus interactions between sleep disturbances (p = 0.007; rs11824092 of ARNTL and rs11932595 of CLOCK) as well as interactions of subdimension in main depression and ARNTL variants (p = 0.0011; rs3789327, rs10766075) and appetite disturbances in depression and ARNTL polymorphism (p = 7 × 10⁻⁴; rs11022778, rs156243).

Background: Individual functions of members of the bromodomain (BRD) and extra-terminal (BET) protein family underlying the anti-inflammatory effects of BET inhibitors in rheumatoid arthritis (RA) are incompletely understood. Here, we aimed to analyze the regulatory functions of BRD3, an understudied member of the BET protein family, in RA synovial fibroblasts (FLS). Methods: BRD3 was silenced in FLS prior to stimulation with TNF. Alternatively, FLS were treated with I-BET. Transcriptomes were analyzed by RNA sequencing (RNAseq), followed by pathway enrichment analysis. We confirmed results for selective target genes by real-time PCR, ELISA, and Western blotting. Results: BRD3 regulates the expression of several cytokines and chemokines in FLS, and positively correlates with inflammatory scores in the RA synovium. In addition, RNAseq pointed to a profound role of BRD3 in regulating FLS proliferation, metabolic adaption, and response to stress, including oxidative stress, and autophagy. Conclusions: BRD3 acts as an upstream regulatory factor that integrates the response to inflammatory stimuli and stress conditions in FLS and executes many functions of BET proteins that have previously been identified using pan-BET inhibitors.