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Association of the κ-opioid system with alcohol dependence

Molecular Psychiatry volume 11, pages 1016–1024 (2006)Cite this article

Abstract

Opioid receptors and their endogenous peptide ligands play important roles in the reward and reinforcement of drugs such as heroin, cocaine, and alcohol. The binding of dynorphins to the κ-opioid receptor has been shown to produce aversive states, which may prevent the development of reinforcement. We genotyped SNPs throughout OPRK1, encoding the κ-opioid receptor, and PDYN, which encodes its ligand prodynorphin, in a group of 1860 European American individuals from 219 multiplex alcohol dependent families. Family-based analyses demonstrated associations between alcohol dependence and multiple SNPs in the promoter and 3′ end of PDYN, and in intron 2 of OPRK1. Haplotype analyses further supported the association of PDYN. Thus, variations in the genes encoding both the κ-opioid receptor and its ligand, OPRK1 and PDYN, are associated with the risk for alcohol dependence; this makes biological sense as variations in either should affect signaling through the κ-opioid system.

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Acknowledgements

We thank Jinghua Zhao, Gayathri Rajan, Christopher Rush, Jun Wang and Robert George for technical assistance with genotyping, sequencing and data organization. Genotyping facilities were provided by the Center for Medical Genomics at Indiana University School of Medicine, supported in part by the Indiana 21st Century Research and Technology Fund and the Indiana Genomics Initiative at Indiana University (INGEN, supported in part by the Lilly Endowment, Inc.). The Collaborative Study on the Genetics of Alcoholism (COGA), Co-Principal Investigators B Porjesz, V Hesselbrock, H Edenberg, L Bierut, includes nine different centers where data collection, analysis, and storage take place. The nine sites and Principal Investigators and Co-Investigators are: University of Connecticut (V Hesselbrock); Indiana University (HJ Edenberg, J Nurnberger Jr, PM Conneally, T Foroud); University of Iowa (S Kuperman, R Crowe); SUNY Downstate (B Porjesz); Washington University in St Louis (L Bierut, A Goate, J Rice); University of California at San Diego (M Schuckit); Howard University (R Taylor); Rutgers University (J Tischfield); Southwest Foundation (L Almasy). Zhaoxia Ren serves as the NIAAA Staff Collaborator. This national collaborative study is supported by the NIH Grant U10AA008401 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA). In memory of Henri Begleiter and Theodore Reich, Principal and Co-Principal Investigators of COGA since its inception; we are indebted to their leadership in the establishment and nurturing of COGA, and acknowledge with great admiration their seminal scientific contributions to the field.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA

    X Xuei, H-J Tian & H J Edenberg

  2. Department of Psychiatry, Washington University, St Louis, MO, USA

    D Dick, A Agrawal, L Bierut, A Goate & K Bucholz

  3. Department of Psychology, Washington University, St Louis, MO, USA

    D Dick

  4. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

    L Flury-Wetherill, T Foroud & H J Edenberg

  5. Department of Psychiatry, University of California-San Diego, San Diego, CA, USA

    M Schuckit

  6. Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN, USA

    J Nurnberger Jr

  7. Department of Genetics, Rutgers University, Piscataway, NJ, USA

    J Tischfield

  8. Division of Child Psychiatry, University of Iowa Hospitals, Iowa City, IA, USA

    S Kuperman

  9. Department of Psychiatry, SUNY Downstate Medical Center, Brooklyn, NY, USA

    B Porjesz & H Begleiter

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Correspondence to X Xuei.

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Xuei, X., Dick, D., Flury-Wetherill, L. et al. Association of the κ-opioid system with alcohol dependence. Mol Psychiatry 11, 1016–1024 (2006). https://doi.org/10.1038/sj.mp.4001882

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Keywords

  • alcoholism
  • opioids
  • κ-opioid receptor
  • dynorphin
  • genetics
  • single nucleotide polymorphism

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