RESUMO
Bipolar disorder (BD) is a severe mental illness with a strong genetic component. Despite its high degree of heritability, current genetic studies have failed to reveal individual loci of large effect size. In lieu of focusing on individual genes, we investigated regulatory units (regulons) in BD to identify candidate transcription factors (TFs) that regulate large groups of differentially expressed genes. Network-based approaches should elucidate the molecular pathways governing the pathophysiology of BD and reveal targets for potential therapeutic intervention. The data from a large-scale microarray study was used to reconstruct the transcriptional associations in the human prefrontal cortex, and results from two independent microarray data sets to obtain BD gene signatures. The regulatory network was derived by mapping the significant interactions between known TFs and all potential targets. Five regulons were identified in both transcriptional network models: early growth response 3 (EGR3), TSC22 domain family, member 4 (TSC22D4), interleukin enhancer-binding factor 2 (ILF2), Y-box binding protein 1 (YBX1) and MAP-kinase-activating death domain (MADD). With a high stringency threshold, the consensus across tests was achieved only for the EGR3 regulon. We identified EGR3 in the prefrontal cortex as a potential key target, robustly repressed in both BD signatures. Considering that EGR3 translates environmental stimuli into long-term changes in the brain, disruption in biological pathways involving EGR3 may induce an impaired response to stress and influence on risk for psychiatric disorders, particularly BD.
Assuntos
Transtorno Bipolar/genética , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/genética , Proteína 3 de Resposta de Crescimento Precoce/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Proteína do Fator Nuclear 45/genética , Córtex Pré-Frontal/metabolismo , Fatores de Transcrição/genética , Proteína 1 de Ligação a Y-Box/genética , Adolescente , Adulto , Estudos de Casos e Controles , Feminino , Redes Reguladoras de Genes , Humanos , Microdissecção e Captura a Laser , Masculino , Pessoa de Meia-Idade , Transcriptoma , Adulto JovemRESUMO
OBJECTIVE: Substance use disorders and birth-cohort have been associated with an earlier onset in bipolar disorder (BD). This study aimed at evaluating the inter-relations of these factors in age-at-onset in bipolar illness. METHOD: Two-hundred and thirty patients with bipolar I disorder were cross-sectionally evaluated. Patients were categorized into four age groups for analysis. Lifetime comorbidity and age-at-onset were derived from the Structured Clinical Interview for DSM-IV. RESULTS: There was a strong linear association between age group and age-at-onset. Lifetime alcohol and drug use disorders were also associated with age-at-onset. Illicit drug and alcohol use disorders and age group remained significant in the multivariate model. No interactions appeared. CONCLUSION: Both age group and dual diagnoses had strong and independent impacts on age-at-onset in out-patients with BD. Substance abuse may be partly accountable for earlier symptom onset, but other features of BD in younger generations are still in need to be accounted for.