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A functional haplotype implicated in vulnerability to develop cocaine dependence is associated with reduced PDYN
Vadim Yuferov1, Fei Ji, David A Nielsen
1Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY 10065, USA. yuferov@rockefeller.edu
Summary
Genetic variations in the prodynorphin gene (PDYN) are linked to cocaine and alcohol addiction vulnerability. A specific PDYN haplotype shows lower gene expression, potentially influencing addiction risk.
Area of Science:
- Neuroscience
- Genetics
- Addiction Research
Background:
- Dynorphin peptides and kappa-opioid receptors play a role in the rewarding effects of substances like cocaine, heroin, and alcohol.
- Genetic variations within the prodynorphin gene (PDYN) may influence susceptibility to substance dependence.
Purpose of the Study:
- To investigate the association between prodynorphin gene (PDYN) polymorphisms and cocaine dependence, as well as cocaine/alcohol codependence.
- To explore the impact of identified genetic variations on PDYN gene expression in human brain tissue.
Main Methods:
- Genotyping of six single nucleotide polymorphisms (SNPs) in the PDYN gene in Caucasian and African American individuals with and without substance dependence.
- Haplotype analysis to identify combinations of SNPs associated with dependence.
- Allele-specific gene expression analysis using postmortem human brain samples from heterozygous individuals.
Main Results:
- Significant associations were found between 3'UTR SNPs in the PDYN gene and cocaine dependence/cocaine-alcohol codependence in Caucasians.
- A specific haplotype (CCT) was significantly associated with cocaine dependence and combined cocaine/alcohol codependence.
- Lower expression of the PDYN gene (preprodynorphin mRNA) was observed in postmortem brains of individuals carrying the risk CCT haplotype.
Conclusions:
- A 3'UTR PDYN haplotype is implicated in vulnerability to cocaine addiction and/or cocaine/alcohol codependence.
- This risk haplotype is associated with reduced PDYN gene mRNA expression in the human dorsal and ventral striatum.
- These findings suggest a genetic mechanism involving PDYN expression that contributes to substance addiction.
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