M115: ASSOCIATION OF THE PLCB1 GENE WITH DRUG DEPENDENCE

Abstract

Background Drug dependence is a complex neuropsychiatric disorder that results from the interaction of genetic and environmental factors. MicroRNAs (miRNAs) are very abundant in the central nervous system and seem to play key roles in the drug-induced plasticity of the brain that likely drives the emergence of addiction. Some studies suggest that SNPs located in both miRNAs and miRNA target sites may alter the miRNA-mediated regulation of gene expression that underlies disease and non-pathological phenotypes. Here we aimed at exploring the role of miRNAs in drug addiction by performing a two stage case-control association study. Methods We genotyped SNPs located in regions of miRNA binding in a Spanish sample of 735 cases and 739 controls and replicated the results in an independent follow-up sample of 663 cases and 667 controls. The possible functional impact of associated SNPs on the binding of different miRNAs was performed with a luciferase reporter assay. Finally, we evaluated alterations of gene expression under cocaine in a gene harboring associated variants using different in vivo and in vitro models. Results We identified an association between rs1047383 in the 3’UTR of the PLCB1 gene and drug dependence, particularly with cocaine addiction, that was replicated. Then we tested the effect of this SNP and rs1047381-rs708910 (in LD with it) on the binding of 10 miRNAs. Hsa-miR-582 was found to downregulate gene expression, without showing differences between the two alleles at rs708910. Finally, we explored the possibility that PLCB1 expression is altered by cocaine. We observed a significant upregulation of PLCB1 in the nucleus accumbens of cocaine abusers and in human dopaminergic-like neurons after cocaine treatment. In order to confirm the contribution of PLCB1 to cocaine dependence we are currently assessing cocaine-seeking behavior in heterozygous Plcb1 knockout mice. Discussion To our knowledge, this is the first study assessing the effect of SNPs in miRNA binding sites in drug dependence, and we provide additional evidence for the participation of the PLCB1 gene in the vulnerability to susceptibility to drug dependence.