Transcriptomic and genetic studies identify NFAT5 as a candidate gene for cocaine dependence.
Cocaine reward and reinforcing effects are mediated mainly by dopaminergic neurotransmission. In this study, we aimed at evaluating gene expression changes induced by acute cocaine exposure on SH-SY5Y-differentiated cells, which have been widely used as a dopaminergic neuronal model. Expression changes and a concomitant increase in neuronal activity were observed after a 5 μM cocaine exposure, whereas no changes in gene expression or in neuronal activity took place at 1 μM cocaine. Changes in gene expression were identified in a total of 756 genes, mainly related to regulation of transcription and gene expression, cell cycle, adhesion and cell projection, as well as mitogen-activeated protein kinase (MAPK), CREB, neurotrophin and neuregulin signaling pathways. Some genes displaying altered expression were subsequently targeted with predicted functional single-nucleotide polymorphisms (SNPs) in a case-control association study in a sample of 806 cocaine-dependent patients and 817 controls. This study highlighted associations between cocaine dependence and five SNPs predicted to alter microRNA binding at the 3'-untranslated region of the NFAT5 gene. The association of SNP rs1437134 with cocaine dependence survived the Bonferroni correction for multiple testing. A functional effect was confirmed for this variant by a luciferase reporter assay, with lower expression observed for the rs1437134G allele, which was more pronounced in the presence of hsa-miR-509. However, brain volumes in regions of relevance to addiction, as assessed with magnetic resonance imaging, did not correlate with NFAT5 variation. These results suggest that the NFAT5 gene, which is upregulated a few hours after cocaine exposure, may be involved in the genetic predisposition to cocaine dependence.
Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, Barcelona, Catalonia, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.|Institut de Biomedicina de la Universitat de Barcelona, Barcelona, Catalonia, Spain.
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Fernàndez-Castillo
Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, Barcelona, Catalonia, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.
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Cabana-Domínguez
Departament d'Estructura i Constituents de la Matèria, Universitat de Barcelona, Barcelona, Spain.
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Soriano
Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.|Psychiatric Genetics Unit, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.|Biomedical Network Research Center on Mental Health (CIBERSAM), Barcelona, Spain.
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Sànchez-Mora
Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.|Biomedical Network Research Center on Mental Health (CIBERSAM), Barcelona, Spain.|Addiction and Dual Diagnosis Unit, Psychiatric Service, Hospital Universitari Vall d'Hebron, Agència de Salut Pública, Barcelona, Spain.|Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
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Roncero
Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.|Biomedical Network Research Center on Mental Health (CIBERSAM), Barcelona, Spain.|Addiction and Dual Diagnosis Unit, Psychiatric Service, Hospital Universitari Vall d'Hebron, Agència de Salut Pública, Barcelona, Spain.|Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
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Grau-López
Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.|Addiction and Dual Diagnosis Unit, Psychiatric Service, Hospital Universitari Vall d'Hebron, Agència de Salut Pública, Barcelona, Spain.|Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
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Ros-Cucurull
Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.|Biomedical Network Research Center on Mental Health (CIBERSAM), Barcelona, Spain.|Addiction and Dual Diagnosis Unit, Psychiatric Service, Hospital Universitari Vall d'Hebron, Agència de Salut Pública, Barcelona, Spain.|Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
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Daigre
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.|Donders Institute for Brain, Cognition and Behaviour, Raboud University, Nijmegen, The Netherlands.
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van Donkelaar
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.|Donders Institute for Brain, Cognition and Behaviour, Raboud University, Nijmegen, The Netherlands.|Department of Psychiatry, Radboud University Medical Center, Nijmegen, The Netherlands.
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Franke
Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.|Biomedical Network Research Center on Mental Health (CIBERSAM), Barcelona, Spain.|Addiction and Dual Diagnosis Unit, Psychiatric Service, Hospital Universitari Vall d'Hebron, Agència de Salut Pública, Barcelona, Spain.|Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
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Casas
Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.|Psychiatric Genetics Unit, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.|Biomedical Network Research Center on Mental Health (CIBERSAM), Barcelona, Spain.
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Ribasés
Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, Barcelona, Catalonia, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.|Institut de Biomedicina de la Universitat de Barcelona, Barcelona, Catalonia, Spain.
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Cormand
D016022:Case-Control Studies; D018929:Cell Culture Techniques; D019970:Cocaine-Related Disorders / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D046228:Microarray Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics*
C118125:NFAT5 protein, human; D014157:Transcription Factors