Association of the OPRM1 Variant rs1799971 (A118G) with Non-Specific Liability to Substance Dependence in a Collaborative de novo Meta-Analysis of European-Ancestry Cohorts

Tae Hwi Schwantes-An, Juan Zhang, Li Shiun Chen, Sarah M. Hartz, Robert C. Culverhouse, Xiangning Chen, Hilary Coon, Josef Frank, Helen M. Kamens, Bettina Konte, Leena Kovanen, Antti Latvala, Lisa N. Legrand, Brion S. Maher, Whitney E. Melroy, Elliot C. Nelson, Mark W. Reid, Jason D. Robinson, Pei Hong Shen, Bao Zhu YangJudy A. Andrews, Paul Aveyard, Olga Beltcheva, Sandra A. Brown, Dale S. Cannon, Sven Cichon, Robin P. Corley, Norbert Dahmen, Louisa Degenhardt, Tatiana Foroud, Wolfgang Gaebel, Ina Giegling, Stephen J. Glatt, Richard A. Grucza, Jill Hardin, Annette M. Hartmann, Andrew C. Heath, Stefan Herms, Colin A. Hodgkinson, Per Hoffmann, Hyman Hops, David Huizinga, Marcus Ising, Eric O. Johnson, Elaine Johnstone, Radka P. Kaneva, Kenneth S. Kendler, Falk Kiefer, Henry R. Kranzler, Ken S. Krauter, Orna Levran, Susanne Lucae, Michael T. Lynskey, Wolfgang Maier, Karl Mann, Nicholas G. Martin, Manuel Mattheisen, Grant W. Montgomery, Bertram Müller-Myhsok, Michael F. Murphy, Michael C. Neale, Momchil A. Nikolov, Denise Nishita, Markus M. Nöthen, John Nurnberger, Timo Partonen, Michele L. Pergadia, Maureen Reynolds, Monika Ridinger, Richard J. Rose, Noora Rouvinen-Lagerström, Norbert Scherbaum, Christine Schmäl, Michael Soyka, Michael C. Stallings, Michael Steffens, Jens Treutlein, Ming Tsuang, Tamara L. Wall, Norbert Wodarz, Vadim Yuferov, Peter Zill, Andrew W. Bergen, Jingchun Chen, Paul M. Cinciripini, Howard J. Edenberg, Marissa A. Ehringer, Robert E. Ferrell, Joel Gelernter, David Goldman, John K. Hewitt, Christian J. Hopfer, William G. Iacono, Jaakko Kaprio, Mary Jeanne Kreek, Ivo M. Kremensky, Pamela A.F. Madden, Matt McGue, Marcus R. Munafò, Robert A. Philibert, Marcella Rietschel, Alec Roy, Dan Rujescu, Sirkku T. Saarikoski, Gary E. Swan, Alexandre A. Todorov, Michael M. Vanyukov, Robert B. Weiss, Laura J. Bierut, Nancy L. Saccone

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The mu1 opioid receptor gene, OPRM1, has long been a high-priority candidate for human genetic studies of addiction. Because of its potential functional significance, the non-synonymous variant rs1799971 (A118G, Asn40Asp) in OPRM1 has been extensively studied, yet its role in addiction has remained unclear, with conflicting association findings. To resolve the question of what effect, if any, rs1799971 has on substance dependence risk, we conducted collaborative meta-analyses of 25 datasets with over 28,000 European-ancestry subjects. We investigated non-specific risk for “general” substance dependence, comparing cases dependent on any substance to controls who were non-dependent on all assessed substances. We also examined five specific substance dependence diagnoses: DSM-IV alcohol, opioid, cannabis, and cocaine dependence, and nicotine dependence defined by the proxy of heavy/light smoking (cigarettes-per-day >20 vs. ≤10). The G allele showed a modest protective effect on general substance dependence (OR = 0.90, 95 % C.I. [0.83–0.97], p value = 0.0095, N = 16,908). We observed similar effects for each individual substance, although these were not statistically significant, likely because of reduced sample sizes. We conclude that rs1799971 contributes to mechanisms of addiction liability that are shared across different addictive substances. This project highlights the benefits of examining addictive behaviors collectively and the power of collaborative data sharing and meta-analyses.

Original languageEnglish
Pages (from-to)151-169
Number of pages19
JournalBehavior genetics
Issue number2
StatePublished - Mar 1 2016


  • Addiction
  • Genetic association
  • OPRM1
  • Opioid receptor
  • Single nucleotide polymorphism (SNP)
  • Substance dependence


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