Disturbo bipolare e cefalea a grappolo: identificazione di geni e pathway molecolari e loro potenziale coinvolgimento nella risposta alla terapia con sali di litio tramite analisi dei profili di espressione genome‑wide

Cluster headache (CH) and bipolar disorder (BD) are pathological conditions affecting 1% and 1.5% of the general population, respectively. Albeit the pathogenesis has not yet been completely elucidated, family and twin studies have suggested a genetic basis for both disorders, with an estimated heritability of 80% for BD and up to 60% for CH. Though BD and CH are very different diseases, they show important clinical similarities, such as a temporal pattern of disturbances, dysregulation of the wake-­‐sleep cycle, neuroendocrine derangements, and more important positive clinical response to lithium and valproate treatments in a significant proportion of treated patients. In the present study, we sought to explore whether BD and CH patients responders to lithium share common molecular pathways potentially involved in predisposing to positively respond to prophylactic lithium treatment. To this aim, we carried out a transcriptome study in lymphoblastoid cell lines from 10 BD type I patients, responders to lithium, 8 CH patients responders to lithium treatment and 10 healthy subjects (CO). Expression profiles were measured by Affymetrix GeneChip Human Gene ST 1.0 covering 36,079 transcripts. Expression levels of BD and CH patients were compared with CO using a t-­‐test, in order to identify commonly dysregulated genes. Pathway analysis was performed based on the hypergeometric test for over representation of specific Kyoto Encyclopedia of Genes and Genomes (KEGG). A total of 544 and 1172 genes were differentially expressed in BD versus CO and CH versus CO respectively. Filtering criteria were based on corrected p value < 0.05 and a Fold Change (FC) ≥ |1.3|. Among these genes, 314 were commonly altered both in CH and BD compared to CO. The most significant dysregulated gene in BD and CH was RNA binding motif (RNP1, RRM) protein 3 (RBM3), a gene implicated in sleep regulation and in the temperature entrained circadian gene expression (corrected p value of 6,30x 10-­‐09 in BD vs CO and 1,88x 10-­‐09 in CH vs CO). Pathway analysis showed that Protein processing in endoplasmic reticulum pathway was one of the most significantly enriched in BD and CH when compared to CO. In conclusion, data from this pilot microarray study may provide useful and relevant information for a better understanding of the molecular underpinnings of lithium response and on the neurobiology of BD and CH.