Determining the role of SLC6A4 polymorphisms on the anti-depressant response: from causality to identification of molecular signatures and robust biomarkers – PolyDep

Major depressive disorder (MDD) is a complex multifactorial disorder. More than half of the patients show no clinical improvement in response to first-line antidepressants (ADs). Understanding of these individual differences in ADs responses is a first step to personalized medicine. For that purpose, researchers need to combine several experimental paradigms (in silico, in vitro and in vivo) to model key aspects of the disease.
To develop a more adapted approach for research in biological psychiatry, we propose to combine human studies together with the common marmoset, Challitrix jacchus. Primates represent the best model reproducing existing networks in the human brain and most neuronal populations present in humans are conserved in marmosets. Genetic variants associated to psychiatric disorders have also been found in marmosets. Accumulating evidences indicate that the primate expanded repertoire of non-coding RNAs, (such as microRNAs) that exert fine regulatory functions on gene expression are involved in psychiatric disorders pathogenesis.
In this proposal, we will address three major issues: 1) Do precise genetic polymorphisms contribute to the lack of ADs response observed in patients? 2) What are the molecular mechanisms underlying responsiveness to different ADs? 3) Can we integrate genetic-molecular data to identify robust biomarkers of ADs responses? For that, we are focusing on the serotonin transporter gene (SLC6A4) as previous work in humans and marmosets have associated genetic variants to differential outcome to ADs treatment. To establish causal links, this consortium has already made significant efforts to set up molecular tools (i.e. Cas9 tools editing tools), cellular models (i.e. generation of marmoset induced pluripotent stem cells) and large characterized human cohorts of depressed patients to implement this research program. Results to be obtained in this project will pave the way to a more efficient therapeutic approach.