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A COMT gene haplotype associated with methamphetamine abuse.

Sarah K Jugurnauth1, Chih-Ken Chen, Michael R Barnes

  • 1SGDP, Institute of Psychiatry, King's College, London, UK.

Pharmacogenetics and Genomics
|September 22, 2011
PubMed
Summary

Genetic variations in the COMT gene, specifically rs4680 and rs165599, are linked to methamphetamine addiction susceptibility. A particular haplotype (A/G) of these polymorphisms was underrepresented in methamphetamine users, suggesting a protective effect.

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Area of Science:

  • Neuroscience
  • Genetics
  • Psychiatry

Background:

  • Methamphetamine (MAMP) dependence is frequently comorbid with psychiatric disorders, affecting 12-13% of users with psychotic symptoms.
  • The mesolimbic pathway and dopaminergic systems are implicated in substance abuse, making dopaminergic genes like COMT (catechol-O-methyltransferase) key candidates for addiction research.
  • Previous studies indicated an association between the COMT val158met polymorphism (rs4680) and MAMP addiction.

Purpose of the Study:

  • To investigate the association of the COMT rs165599 polymorphism with methamphetamine addiction in a Taiwanese sample.
  • To explore the potential functional impact of rs165599 on COMT gene regulation.
  • To analyze haplotype effects combining rs4680 and rs165599 in relation to MAMP dependence.

Main Methods:

  • Genotyping of the COMT rs165599 polymorphism in 423 MAMP-dependent cases and 502 controls.
  • In-silico analysis of rs165599 for potential effects on microRNA binding and UTR stability.
  • Review of COMT 3'UTR transcript sequences for regulatory interactions.

Main Results:

  • No significant differences in allele or genotype frequencies for rs165599 were found between MAMP users and controls.
  • Haplotype analysis combining rs4680 and rs165599 revealed a significant association (global P=0.0044) with MAMP addiction.
  • A specific haplotype (A/G for rs4680/rs165599) was found to be underrepresented in MAMP users (haplotype P=0.001), suggesting a protective role.
  • Evidence suggests potential antisense interference with COMT expression from the neighboring Armadillo repeat gene deleted in velocardiofacial syndrome (ARVCF) gene in the COMT 3'UTR.

Conclusions:

  • While rs165599 alone did not show an association, the combined haplotype analysis with rs4680 provides significant insight into MAMP addiction susceptibility.
  • The underrepresentation of the A/G haplotype (rs4680/rs165599) suggests a potential protective genetic mechanism against MAMP dependence.
  • The COMT 3'UTR may be a regulatory region influenced by interactions with neighboring genes, impacting susceptibility to methamphetamine addiction.