Dna methylation, gene expression, and response to lithium in bipolar disorder: a study from ips cells derived into neurons

Bipolar Disorder (BD) is a psychiatric disorder characterized by mood instability from manic or hypomanic phases to depressive states. This condition affects 1 to 4 % of the worldwide population with no gender or ethnic variation. Three categories of medication are mostly used: mood stabilizers, atypical antipsychotics and sometimes, antidepressants. Lithium is the most studied mood stabilizer. While it is still in use after 70 years, the mechanisms driving its action are not totally understood. Whereas it is highly effective for a fraction of the BD patients, some others poorly respond to it. Our overarching aim is to understand the differential response to lithium in order to predict response to treatment and to develop personalized medical approaches. To conduct this study we used IPS cells derived into neurons from three groups of individuals: control, responders to lithium (R) and non-responders (NR) to lithium. DNA from this sample was analyzed for methylation using Whole genome bisulfite sequencing and expression by RNA seq. we then analyzed these data with bio-informatics tools (R packages) and enrichment analyses software. By contrasting BD-R and BD-NR, we identified significant differences in DNA methylation and gene expression in the WNT pathway. For instance, Frizzled 9 (FZD9), an interactor of WNT, and DKK2, an antagonist of the WNT-FZD9 complex, were differentially methylated and expressed between the two groups. Lithium has been reported as an activator of the WNT pathway by the direct inhibition of one of its components: GSK3 beta. The epigenetic differences between BD-R and BD-NR shed light on the mechanisms behind the response to lithium, opening the way to the identification of biomarkers, to the understanding of therapeutic mechanisms and ultimately to the development of personalized medicine. In future studies, we will compare our results with DNA methylation data obtained from blood samples of BD-R and BD-NR patients.