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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

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Abstract

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.

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Acknowledgments

For facilitating this collaboration to meta-analyze rs1799971, we thank Jonathan Pollock and the National Institute on Drug Abuse, which provided infrastructure support through conference calls and meetings. For this project we wish to acknowledge and thank the following people. For meta-analysis coordination at Washington University: Weimin Duan. For administrative support at Washington University: Sherri Fisher. We also thank Michael Bruchas, Washington University, for helpful discussions. For CADD: principal investigators John Hewitt, Institute for Behavioral Genetics, University of Colorado Boulder; Michael Stallings, Institute for Behavioral Genetics, University of Colorado Boulder; Christian Hopfer, University of Denver; Sandra Brown, University of California San Diego. For COGA: Principal Investigators B. Porjesz, V. Hesselbrock, H. Edenberg, L. Bierut; COGA includes ten different centers: University of Connecticut (V. Hesselbrock); Indiana University (H.J. Edenberg, J. Nurnberger Jr., T. Foroud); University of Iowa (S. Kuperman, J. Kramer); SUNY Downstate (B. Porjesz); Washington University in St. Louis (L. Bierut, A. Goate, J. Rice, K. Bucholz); University of California at San Diego (M. Schuckit); Rutgers University (J. Tischfield); Texas Biomedical Research Institute (L. Almasy), Howard University (R. Taylor) and Virginia Commonwealth University (D. Dick). Other COGA collaborators include: L. Bauer (University of Connecticut); D. Koller, S. O’Connor, L. Wetherill, X. Xuei (Indiana University); Grace Chan (University of Iowa); S. Kang, N. Manz, M. Rangaswamy (SUNY Downstate); J. Rohrbaugh, J-C Wang (Washington University in St. Louis); A. Brooks (Rutgers University); and F. Aliev (Virginia Commonwealth University). A. Parsian and M. Reilly are the NIAAA Staff Collaborators. We continue to be inspired by our memories of Henri Begleiter and Theodore Reich, founding PI and Co-PI of COGA, and also owe a debt of gratitude to other past organizers of COGA, including Ting-Kai Li, currently a consultant with COGA, P. Michael Conneally, Raymond Crowe, and Wendy Reich, for their critical contributions. The authors thank Kim Doheny and Elizabeth Pugh from CIDR and Justin Paschall from the NCBI dbGaP staff for valuable assistance with genotyping and quality control in developing the dataset available at dbGaP. For COGEND: COGEND is a collaborative research group and a part of the NIDA Genetics Consortium. Michael Brent, Alison Goate, Dorothy Hatsukami, Anthony Hinrichs, Heidi Kromrei, Tracey Richmond, Joe Henry Steinbach, Jerry Stitzel, Scott Saccone, Sharon Murphy; in memory of Theodore Reich, founding Principal Investigator of COGEND, we are indebted to his leadership in the establishment and nurturing of COGEND and acknowledge with great admiration his seminal scientific contributions to the field. For GADD: John Hewitt, Institute for Behavioral Genetics, University of Colorado Boulder; Michael Stallings, Institute for Behavioral Genetics, University of Colorado Boulder; Christian Hopfer, University of Denver; Sandra Brown, University of California San Diego. For Kreek: Matthew Randesi. For NAG: Yi-Ling Chou. For Yale-Penn: Genotyping services for a part of Yale-Penn were provided by the Center for Inherited Disease Research (CIDR) and Yale University (Center for Genome Analysis).

Funding

R01 DA026911 from The National Institute on Drug Abuse (NIDA) supported this project and the coordinating team at Washington University. BG/ROMA are supported by R01 DA018823 (Todorov) from NIDA. CADD/GADD/NYS are supported by R01 DA021905 (Brown, Wall), R01 AA017889 (Ehringer), P60 DA011015 (Hewitt), R01 DA012845 (Hewitt), T32 DA017637 (Hewitt), R01 DA021913 (Hopfer), K24 DA032555 (Hopfer), K01 AA019447 (Kamens), and R01 DA035804 (Wall, Hopfer, Stallings) from NIDA and NIAAA. CATS is supported by R01 DA017305 (Nelson) from NIDA. Dr. Degenhardt is supported by an Australian National Health and Medical Research Council (NHMRC) principal research fellowship (#1041472). The National Drug and Alcohol Research Centre at UNSW Australia is supported by funding from the Australian Government under the Substance Misuse Prevention and Service Improvements Grant Fund. CEDAR-SADS is supported by R01 DA019157 (Vanyukov) from NIDA. CEDAR is supported by P50 DA005605 (Tarter) from NIDA. SADS is supported by R01 DA011922 (Vanyukov) from NIDA. The following studies made up the Cinciripini study: CASSI is supported by R01 DA11822 (Cinciripini), PEERS EMA is supported by K07 CA92209 (Carter), PEERS NS is supported by R21 CA81649 (Cinciripini) and PEERS WS, PEERS NS and SCOPE are supported by P50 CA070907 (Cinciripini) from NIDA and NCI. COGA is supported by U10 AA008401 (Bierut, Nurnberger, Edenberg, Hesselbrock, Porjesz) from NIAAA and genotyping was supported by U01 HG004438 (Valle) from The Genes and Environment Initiative (GEI) and HHSN268200782096C from the National Institutes of Health (NIH). Contributions from COGEND are supported by R01 DA019963 (Bierut), R01 DA013423 (Bierut), P01 CA089392 (Bierut), K08 DA030398 (L.-S. Chen), K08 DA032680 (Hartz), R01 DA019963 (Bierut), R01 DA038076 (L.-S. Chen), R21 DA038241 (Culverhouse), R01 DA026911 (Saccone) and R01 DA036583 (Bierut) from NIDA and the National Cancer Institute (NCI). Funding for COGEND genotyping was provided by 1 X01 HG005274-01 and performed at Center for Inherited Disease Research (CIDR) which is funded through a federal contract from NIH to JHU (HHSN268200782096C). Finnish Health 2000 is supported by Finnish National Institute for Health and Welfare institutional funding. FSCD is supported by R01 DA013423 (Bierut) from NIDA. Gene Environment Association Studies (GENEVA) Coordinating Center assisted with genotype cleaning as well as general study coordination, for FSCD; GENEVA is supported by U01 HG004446. FTC/FT12 is supported by K02 AA018755 (Rose), R01 AA-09203 (Rose), R37 AA-12502 (Rose), 141054 (Kaprio) and 263278 (Kaprio) from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and Academy of Finland. FTC/NAG-FIN is funded by GRAND (Kaprio) from Pfizer Inc., 213506 (Kaprio) and 129680 (Kaprio) from Academy of Finland, Health-F4-2007-201413 (Kaprio) from European Union Seventh Framework Programme, ENGAGE project, DA12854 (Madden) from NIDA, Wellcome Trust Sanger Institute, Sigrid Juselius Foundation and Jenny & Antti Wihuri Foundation. GESGA is supported by 01EB0410 (Mann), 01GS0852 (Kiefer), and  BMBF 01ZX1311A (Kiefer, Rietschel) (e:Med program) from the German Federal Ministry of Education and Research (BMBF), FZK 01GS08152 (Nöthen, Rietschel) from National Genome Research Network (NGFN Plus). Drs. Cichon and Nöthen are supported by Alfried Krupp von Bohlen und Halbach-Stiftung. IAS is supported by R01 DA015789 (Philibert) from NIDA. Kreek is supported by P50 DA05130 (Kreek) from NIDA and The Adelson Medical Research Foundation (Kreek). MCTFR is supported by R01 DA005147 (Iacono), R01 DA036216 (Iacono) and R01 U01 DA024417 (Iacono) from NIDA, R01 AA009367 (McGue) and R01 AA0011886 (McGue) from NIAAA and R01 MH066140 (McGue) from the National Institute of Mental Health (NIMH). MGHD is supported by R01 DA012846 (Tsuang) from NIDA and grants from NARSAD: The Brain and Behavior Research Foundation (Tsuang, Glatt), the Sidney R. Baer, Jr. Foundation (Tsuang), and the Gerber Foundation (Glatt). OYSUP is supported by RC2 DA028793 (Andrews) from NIDA. OZALC-NAG is supported by R01 AA075356 (Heath), R01 AA07728 (Heath), R01 AA13220 (Martin), R01 AA13321 (Heath), R01 AA13322 (Heath), R01 AA11998 (Heath) and R01 AA17688 (Heath) from NIAAA, R01 DA12854 (Madden) and K08 DA019951 (Pergadia) from NIDA and grants from the Australian National Health and Medical Research Council. Patch II/PiP are supported by C53/A6281 (Aveyard) from Cancer Research UK. Marcus Munafò and Paul Aveyard are members of the United Kingdom Centre for Tobacco and Alcohol Studies, a UKCRC Public Health Research: Centre of Excellence. Funding from British Heart Foundation, Cancer Research UK, Economic and Social Research Council, Medical Research Council, and the National Institute for Health Research, under the auspices of the UK Clinical Research Collaboration, is gratefully acknowledged. SMOFAM is supported by R01 DA003706 (Hops), U01 DA020830 (Lerman) from NIDA and 7PT2000-2004 (Swan) from University of California Tobacco-Related Disease Research Program. Utah is supported by P01 HL72903 (Hoidal) from NIDA and NHLBI. VA-Twin is supported by DA019498 (X. Chen) from NIDA; support was also provided by R01 DA18673 (Neale) from NIDA. Yale-Penn is supported by RC2 DA028909 (Gelernter), R01 DA12690 (Gelernter), R01 DA12849 (Gelernter), R01 DA18432 (Kranzler) and K01 DA24758 (Yang) from NIDA, R01 AA017535 (Gelernter) and R01 AA11330 (Gelernter) from NIAAA and Dr. Yang is supported by a Young Investigator Award from NARSAD: the Brain and Behavior Research Fund. Dr. Schwantes-An is also supported by the Division of Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. Funding sources had no further role in the study design; in the collection, analysis and interpretation of data; in the writing; or in the decision to submit the paper for publication.

Author information

Authors and Affiliations

  1. Department of Genetics, Washington University School of Medicine, 4523 Clayton Avenue, Campus Box 8232, St. Louis, MO, 63110, USA

    Tae-Hwi Schwantes-An, Juan Zhang & Nancy L. Saccone

  2. Genometrics Section, Computational and Statistical Genomics Branch, Division of Intramural Research, National Human Genome Research Institute, US National Institutes of Health (NIH), Baltimore, MD, 21224, USA

    Tae-Hwi Schwantes-An

  3. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA

    Li-Shiun Chen, Sarah M. Hartz, Elliot C. Nelson, Richard A. Grucza, Andrew C. Heath, Momchil A. Nikolov, Michele L. Pergadia, Pamela A.F. Madden, Alexandre A. Todorov & Laura J. Bierut

  4. Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA

    Robert C. Culverhouse

  5. Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, 23298, USA

    Xiangning Chen, Kenneth S. Kendler, Michael C. Neale & Jingchun Chen

  6. Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT, 84108, USA

    Hilary Coon & Dale S. Cannon

  7. Department of Genetic Epidemiology in Psychiatry, Medical Faculty Mannheim, Central Institute of Mental Health, Heidelberg University, 68159, Mannheim, Germany

    Josef Frank, Jens Treutlein & Marcella Rietschel

  8. Institute for Behavioral Genetics, University of Colorado, Boulder, CO, 80309, USA

    Helen M. Kamens, Whitney E. Melroy, Robin P. Corley, Ken S. Krauter, Michael C. Stallings, Marissa A. Ehringer & John K. Hewitt

  9. Department of Integrative Physiology, University of Colorado, Boulder, CO, 80309, USA

    Helen M. Kamens, Whitney E. Melroy & Marissa A. Ehringer

  10. Department of Biobehavioral Health, The Pennsylvania State University, University Park, PA, 16802, USA

    Helen M. Kamens

  11. Department of Psychiatry, Universitätsklinikum Halle (Saale), 06112, Halle (Saale), Germany

    Bettina Konte, Ina Giegling, Annette M. Hartmann & Dan Rujescu

  12. Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, 00271, Finland

    Leena Kovanen, Timo Partonen, Noora Rouvinen-Lagerström, Jaakko Kaprio & Sirkku T. Saarikoski

  13. Department of Public Health, University of Helsinki, Helsinki, 00014, Finland

    Antti Latvala & Jaakko Kaprio

  14. Department of Psychology, University of Minnesota, Minneapolis, MN, 55455, USA

    Lisa N. Legrand, William G. Iacono & Matt McGue

  15. Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, 21205, USA

    Brion S. Maher

  16. Oregon Research Institute, Eugene, OR, 97403, USA

    Mark W. Reid, Judy A. Andrews & Hyman Hops

  17. Department of Behavioral Science, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Jason D. Robinson & Paul M. Cinciripini

  18. Section of Human Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, 20892, USA

    Pei-Hong Shen, Colin A. Hodgkinson & David Goldman

  19. Department of Psychiatry, Yale University, New Haven, CT, 06516, USA

    Bao-Zhu Yang & Joel Gelernter

  20. Department of Primary Care Health Sciences, University of Oxford, Oxford, OX2 6GG, United Kingdom

    Paul Aveyard

  21. Department of Medical Chemistry and Biochemistry, Molecular Medicine Center, Medical University-Sofia, 1431, Sofia, Bulgaria

    Olga Beltcheva, Radka P. Kaneva, Momchil A. Nikolov & Ivo M. Kremensky

  22. Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093, USA

    Sandra A. Brown, Ming Tsuang & Tamara L. Wall

  23. Department. of Genomics, Life and Brain Center, Institute of Human Genetics, University of Bonn, Bonn, 53127, Germany

    Sven Cichon, Stefan Herms, Per Hoffmann, Manuel Mattheisen & Markus M. Nöthen

  24. Division of Medical Genetics, Department of Biomedicine, University Hospital Basel, University of Basel, Basel, 4003, Switzerland

    Sven Cichon, Stefan Herms & Per Hoffmann

  25. Ökumenisches Hainich-Klinikum, Mühlhausen/Thüringen, Germany

    Norbert Dahmen

  26. National Drug and Alcohol Research Centre, University of New South Wales, Randwick, NSW, 2031, Australia

    Louisa Degenhardt

  27. School of Population and Global Health, University of Melbourne, Melbourne, 3010, Australia

    Louisa Degenhardt

  28. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Tatiana Foroud

  29. University of Düsseldorf, 40225, Düsseldorf, Germany

    Wolfgang Gaebel

  30. Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, 13210, USA

    Stephen J. Glatt

  31. Center for Health Sciences, Biosciences Division, SRI International, Menlo Park, CA, 94025, USA

    Jill Hardin, Denise Nishita & Andrew W. Bergen

  32. University of Bonn, 53113, Bonn, Germany

    Wolfgang Maier

  33. Institute of Behavioral Science, University of Colorado, Boulder, CO, 80309, USA

    David Huizinga

  34. Max-Planck-Institute of Psychiatry, 80804, Munich, Germany

    Marcus Ising, Susanne Lucae & Bertram Müller-Myhsok

  35. Behavioral Health Research Division, Research Triangle Institute International, Durham, NC, 27709, USA

    Eric O. Johnson

  36. Department of Oncology, University of Oxford, Oxford, OX3 7DQ, United Kingdom

    Elaine Johnstone

  37. Department of Addictive Behavior and Addiction Medicine, Medical Faculty Mannheim, Central Institute of Mental Health, Heidelberg University, 68159, Mannheim, Germany

    Falk Kiefer

  38. Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Henry R. Kranzler

  39. Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO, 80309, USA

    Ken S. Krauter

  40. Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, 10065, USA

    Orna Levran, Vadim Yuferov & Mary Jeanne Kreek

  41. Addictions Department, Institute of Psychiatry, King’s College London, London, SE5 8BB, UK

    Michael T. Lynskey

  42. Medical Faculty Mannheim, Central Institute of Mental Health, Heidelberg University, 68159, Mannheim, Germany

    Karl Mann & Christine Schmäl

  43. Department of Genetic Epidemiology, Queensland Institute of Medical Research, Brisbane, QLD, 4029, Australia

    Nicholas G. Martin & Grant W. Montgomery

  44. Harvard School of Public Health, Boston, MA, 02115, USA

    Manuel Mattheisen

  45. Aarhus University, Aarhus, 8000, Denmark

    Manuel Mattheisen

  46. Childhood Cancer Research Group, University of Oxford, Oxford, OX3 7LG, UK

    Michael F. Murphy

  47. Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    John Nurnberger

  48. Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, 15213, USA

    Maureen Reynolds & Michael M. Vanyukov

  49. Department of Psychiatry, University Medical Center Regensburg, University of Regensburg, 8548, Regensburg, Germany

    Monika Ridinger & Norbert Wodarz

  50. Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, 47405, USA

    Richard J. Rose

  51. Addiction Research Group at the Department of Psychiatry and Psychotherapy, LVR Hospital Essen, University of Duisburg-Essen, 45147, Essen, Germany

    Norbert Scherbaum

  52. Department of Psychiatry, University of Munich, 3860, Munich, Germany

    Michael Soyka

  53. Private Hospital Meiringen, Meiringen, Switzerland

    Michael Soyka

  54. Department of Psychology & Neuroscience, University of Colorado, Boulder, CO, 80309, USA

    Michael C. Stallings & John K. Hewitt

  55. Research Department, Federal Institute for Drugs and Medical Devices (BfArM), Kurt-Georg-Kiesinger-Allee 3, 53175, Bonn, Germany

    Michael Steffens

  56. University of Munich, Munich, Germany

    Peter Zill

  57. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Howard J. Edenberg

  58. Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, 15261, USA

    Robert E. Ferrell

  59. Department of Genetics, Yale University, New Haven, CT, 06516, USA

    Joel Gelernter

  60. Department of Neurobiology, Yale University, New Haven, CT, 06516, USA

    Joel Gelernter

  61. Department of Psychiatry, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA

    Christian J. Hopfer

  62. Institute for Molecular Medicine FIMM, University of Helsinki, 00014, Helsinki, Finland

    Jaakko Kaprio

  63. MRC Integrative Epidemiology Unit, UK Centre for Tobacco and Alcohol Studies, and School of Experimental Psychology, University of Bristol, Bristol, BS8 1TU, UK

    Marcus R. Munafò

  64. Department of Psychiatry, University of Iowa, Iowa City, IA, 52242, USA

    Robert A. Philibert

  65. Psychiatry Service, Department of Veteran Affairs, New Jersey VA Health Care System, East Orange, NJ, 07018, USA

    Alec Roy

  66. Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT, 84112, USA

    Robert B. Weiss

  67. Psychiatric Hospital, Konigsfelden, Windisch, Switzerland

    Monika Ridinger

  68. Department of Medicine, Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, CA, 94304, USA

    Gary E. Swan

  69. Key Laboratory of Brain Function and Disease, School of Life Sciences, Chinese Academy of Sciences, University of Science and Technology of China, Hefei, Anhui, 230026, China

    Juan Zhang

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Corresponding author

Correspondence to Nancy L. Saccone.

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Conflict of interest

Dr. Bierut is listed as an inventor on Issued U.S. Patent 8 080 371, “Markers for Addiction” covering the use of certain SNPs in determining the diagnosis, prognosis, and treatment of addiction, and served as a consultant for Pfizer in 2008. Dr. NL Saccone is the spouse of Dr. SF Saccone, who is also listed as an inventor on the above patent. Dr. Cinciripini served on the scientific advisory board of Pfizer, conducted educational talks sponsored by Pfizer on smoking cessation (2006–2008), and has received grant support from Pfizer. Dr. Degenhardt has no relevant disclosures for this specific project; however, for general pharmaceutical company disclosures, Dr. Degenhardt has received untied educational grants from Reckitt Benckiser to conduct post-marketing surveillance of the diversion and injection of opioid substitution therapy medications in Australia. Although these activities are unrelated to the current study, Dr. Kranzler has been a consultant or advisory board member for Alkermes, Lilly, Lundbeck, Otsuka and Pfizer; he is also a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which is supported by Ethypharm, Lilly, Lundbeck, AbbVie, and Pfizer. Dr. Ridinger is member of the advisory board of Lundbeck referring to Nalmefene. Prof. Dr. N. Scherbaum received honoraria for several activities (advisory boards, lectures, manuscripts and educational material) by the factories Sanofi-Aventis, Reckitt-Benckiser, Lundbeck, and Janssen-Cilag. During the last three years he participated in clinical trials financed by the pharmaceutical industry. The remaining authors declare no conflict of interest.

Informed Consent

The procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 and 2008. All participants provided informed consent.

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Edited by Irwin Waldman.

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Schwantes-An, TH., Zhang, J., Chen, LS. et al. 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. Behav Genet 46, 151–169 (2016). https://doi.org/10.1007/s10519-015-9737-3

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  • DOI: https://doi.org/10.1007/s10519-015-9737-3

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