Convergent functional genomics of cocaine misuse in humans and animal models

ABSTRACT

Background: Data from the Global Burden of Disease Study 2016 recently estimated that after opioid and cannabis use disorders, cocaine use disorders were among the most common, with around 5.8 million cases around the world. Several genome-wide expression studies (GWES) for cocaine misuse have been carried out in brain tissues from patients and controls and in mouse and rat models.

Objectives: In the current work, we used a convergent functional genomics approach to identify novel candidate genes and pathways for cocaine misuse.

Methods: We carried out meta-analyses for available GWES for cocaine misuse in humans and mouse and rat models (three, four, and two GWES, respectively). Multiple lines of evidence (GWES, genome-wide association and epigenomic data) were integrated to prioritize top candidate genes, and a functional enrichment analysis was carried out.

Results: Several top candidate genes supported by multiple lines of genomic evidence, and with known roles in brain plasticity, were identified: APP, GRIN2A, GRIN2B, KCNA2, MAP4, PCDH10, PPP3CA, SNCB, and SV2C. An enrichment of genes regulated by the AP1 transcription factor was found.

Conclusion: This is the first meta-analysis of GWES for cocaine misuse in humans and mouse and rat models. The analysis of convergence of multiple lines of genome-wide evidence identified novel candidate genes and pathways for cocaine misuse, which are of basic and clinical importance.

KEYWORDS:

• Addiction
• brain expression
• cocaine misuse
• microarrays
• RNA-seq

Acknowledgments

YG-G is supported by a PhD fellowship from Centro de Estudios Interdisciplinarios Básicos y Aplicados CEIBA (Rodolfo Llinás Program). DAF is supported by research grants from Colciencias and VCTI. Authors thank researchers who contributed with additional data from primary studies that were not available in the original articles. In addition, authors thank Prof. Stephen Glatt, PhD, for his suggestions and comments about this manuscript.

Disclosure of interest

The authors report no conflict of interest.

Additional information

Funding

This work was supported by the VCTI-UAN (Vicerrectoría de Ciencia, Tecnología e Innovación, Universidad Antonio Nariño).