M115 - ASSOCIATION OF THE PLCB1 GENE WITH DRUG DEPENDENCE

Judit Cabana-Domínguez,Elena Martín-García,Carlos Roncero,Laura Pineda,R Felipe Palma-Álvarez,Elena Ros-Cucurull,Lara Grau-López,Abderaman Esojo,Miguel Casas,Concepció Arenas,Marta Ribases,Rafael Maldonado,Noèlia Fernàndez-Castillo,Bru Cormand

doi:10.1016/j.euroneuro.2017.08.422

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.

Highlights

Drug dependence is one of the major health problems worldwide
In this study we evaluated the contribution to drug dependence predisposition of single nucleotide polymorphisms (SNPs) located in the 3’UTR of genes expressed in the brain that are predicted to alter the binding of miRNA molecules
These associated SNPs were subsequently evaluated in an independent Spanish sample of 663 drug-dependent patients and 667 sex-matched controls and the association remained significant for rs1285 in the IDI1 gene (P = 0.034; odds ratio (OR) = 1.32, CI = [1.02–1.71]) and rs1047383 in the PLCB1 gene (P = 1.6e-03; OR = 1.37, CI = [1.13–1.67])

Summary

Introduction

Drug dependence is one of the major health problems worldwide. In Europe, about 25% of adults are estimated to have tried illicit drugs at some point in their lives[1]. Drug consumers use more than one drug at the same time: for example, within the group of European individuals who consumed a psychoactive substance in the last 12 months, 33% had consumed two different substances and 10% had used three[2]. This high prevalence of polydrug abuse is due to common and drug-specific genetic and environmental factors[3,4,5]. Recent studies have shown that some genes whose expression is altered by cocaine contribute to cocaine dependence susceptibility[11, 12]. MiRNAs have been shown to play an important role in different processes related to addiction such as reward, synaptic plasticity, learning, memory, withdrawal and relapse[28]

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Conclusion