Background: Addiction susceptibility and treatment responsiveness are greatly influenced by genetic factors. Sequence variation in genes involved in the mechanisms of drug action have the potential to influence addiction risk and treatment outcome. The opioid receptor system is involved in mediating the rewarding effects of cocaine and opioids. The μ-opioid receptor (MOR) has traditionally been considered the primary target for opioid addiction. The MOR, however, interacts with and is regulated by many known MOR interacting proteins (MORIPs), including the δ-opioid receptor (DOR). Methods: The present study evaluated the contribution of OPRD1, the gene encoding the DOR, to the risk of addiction to opioids and cocaine. The association of OPRD1 polymorphisms with both opioid addiction (OA) and cocaine addiction (CA) was analyzed in African American (OA n= 336, CA n= 503) and European American (OA n= 1007, CA n= 336) populations. Results: The primary finding of this study is an association of rs678849 with cocaine addiction in African Americans (allelic p=0.0086). For replication purposes, this SNP was analyzed in a larger independent population of cocaine addicted African Americans and controls and the association was confirmed (allelic p=4.53×10-5; n=993). By performing a meta-analysis on the expanded populations, the statistical evidence for an association was substantially increased (allelic p=8.5×10-7) (p-values non-FDR corrected). Conclusion: The present study suggests that polymorphisms in OPRD1 are relevant for cocaine addiction in the African American population and provides additional support for a broad role for OPRD1 variants in drug dependence.
Bibliographical noteFunding Information:
We would like to acknowledge NIDA's Center for Genetic Studies in conjunction with Washington University and Rutgers University Cell & DNA Repository for providing DNA samples collected from the following studies and investigators: Opioid Samples: Addictions: Genotypes, Polymorphisms and Function, Mary Jeanne Kreek, M.D.; Genetics of Opioid Dependence, Joel Gelernter, M.D., Kathleen Brady, M.D., Ph.D., Henry Kranzler, M.D., Roger Weiss, M.D.; Opioid Dependence, Wade Berrettini, M.D., Ph.D. Cocaine Samples: An Introduction to the Family Study of Cocaine Dependence, Laura Bierut, M.D.; Genetics of Cocaine Induced Psychosis, Joseph F Cubells, M.D., Ph.D. We would also like to acknowledge the NIDA Clinical Trials Network (CTN) and the University of Pennsylvania CTN node (George Woody, M.D., grant: 2U10DA013043) for support and provision of additional DNA samples from opioid addicted individuals. The NIMH control subjects were collected by the NIMH Schizophrenia Genetics Initiative ‘Molecular Genetics of Schizophrenia II’ (MGS-2) collaboration. The investigators and co-investigators are: ENH/Northwestern University, Evanston, IL, MH059571, Pablo V. Gejman, M.D. (Collaboration Coordinator; PI), Alan R. Sanders, M.D.; Emory University School of Medicine, Atlanta, GA, MH59587, Farooq Amin, M.D. (PI); Louisiana State University Health Sciences Center; New Orleans, Louisiana, MH067257, Nancy Buccola APRN, BC, MSN (PI); University of California-Irvine, Irvine, CA, MH60870, William Byerley, M.D. (PI); Washington University, St. Louis, MO, U01,MH060879, C. Robert Cloninger, M.D. (PI); University of Iowa, Iowa, IA, MH59566, Raymond Crowe, M.D. (PI), Donald Black, M.D.; University of Colorado, Denver, CO, MH059565, Robert Freedman, M.D. (PI); University of Pennsylvania, Philadelphia, PA, MH061675, Douglas Levinson M.D. (PI); University of Queensland, Queensland, Australia, MH059588, Bryan Mowry, M.D. (PI); Mt. Sinai School of Medicine, New York, NY, MH59586, Jeremy Silverman, Ph.D. (PI).
This work was supported by the Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania , Training Program in Neuropsychopharmacology ( T32MH014654 , P.I.: I. Lucki) and a NIDA Distinguished International Scientist Award (MV). Financial support is gratefully acknowledged from NIDA grant P20DA025995 (P.I.: W. Berrettini), the Veterans Administration Mental Illness Research Education and Clinical Center MIRECC) at the Philadelphia VAMC (David Oslin, MD, PI) and NIDA grants P60DA05186 (P.I.: Charles O’Brien) and P50DA012756 (P.I.: H. Pettinati). NIDA had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication
- Association study
- Delta-opioid receptor