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Behav Genet. 2016 Mar;46(2):151-69. doi: 10.1007/s10519-015-9737-3. Epub 2015 Sep 21.

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.

Schwantes-An TH1,2, Zhang J1,3, Chen LS4, Hartz SM4, Culverhouse RC5, Chen X6, Coon H7, Frank J8, Kamens HM9,10,11, Konte B12, Kovanen L13, Latvala A14, Legrand LN15, Maher BS16, Melroy WE9,10, Nelson EC4, Reid MW17, Robinson JD18, Shen PH19, Yang BZ20, Andrews JA17, Aveyard P21, Beltcheva O22, Brown SA23, Cannon DS7, Cichon S24,25, Corley RP9, Dahmen N26, Degenhardt L27,28, Foroud T29, Gaebel W30, Giegling I12, Glatt SJ31, Grucza RA4, Hardin J32, Hartmann AM12, Heath AC4, Herms S24,25, Hodgkinson CA19, Hoffmann P24,25, Hops H17, Huizinga D33, Ising M34, Johnson EO35, Johnstone E36, Kaneva RP22, Kendler KS6, Kiefer F37, Kranzler HR38, Krauter KS9,39, Levran O40, Lucae S34, Lynskey MT41, Maier W42, Mann K43, Martin NG44, Mattheisen M24,45,46, Montgomery GW44, Müller-Myhsok B34, Murphy MF47, Neale MC6, Nikolov MA4,22, Nishita D32, Nöthen MM24, Nurnberger J48, Partonen T13, Pergadia ML4, Reynolds M49, Ridinger M50,51, Rose RJ52, Rouvinen-Lagerström N13, Scherbaum N53, Schmäl C43, Soyka M54,55, Stallings MC9,56, Steffens M57, Treutlein J8, Tsuang M23, Wall TL23, Wodarz N50, Yuferov V40, Zill P58, Bergen AW32, Chen J6, Cinciripini PM18, Edenberg HJ59, Ehringer MA9,10, Ferrell RE60, Gelernter J20,61,62, Goldman D19, Hewitt JK9,56, Hopfer CJ63, Iacono WG15, Kaprio J13,14,64, Kreek MJ40, Kremensky IM22, Madden PA4, McGue M15, Munafò MR65, Philibert RA66, Rietschel M8, Roy A67, Rujescu D12, Saarikoski ST13, Swan GE68, Todorov AA4, Vanyukov MM49, Weiss RB69, Bierut LJ4, Saccone NL70.

Author information

1
Department of Genetics, Washington University School of Medicine, 4523 Clayton Avenue, Campus Box 8232, St. Louis, MO, 63110, USA.
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.
3
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.
4
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA.
5
Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.
6
Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, 23298, USA.
7
Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT, 84108, USA.
8
Department of Genetic Epidemiology in Psychiatry, Medical Faculty Mannheim, Central Institute of Mental Health, Heidelberg University, 68159, Mannheim, Germany.
9
Institute for Behavioral Genetics, University of Colorado, Boulder, CO, 80309, USA.
10
Department of Integrative Physiology, University of Colorado, Boulder, CO, 80309, USA.
11
Department of Biobehavioral Health, The Pennsylvania State University, University Park, PA, 16802, USA.
12
Department of Psychiatry, Universitätsklinikum Halle (Saale), 06112, Halle (Saale), Germany.
13
Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, 00271, Finland.
14
Department of Public Health, University of Helsinki, Helsinki, 00014, Finland.
15
Department of Psychology, University of Minnesota, Minneapolis, MN, 55455, USA.
16
Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, 21205, USA.
17
Oregon Research Institute, Eugene, OR, 97403, USA.
18
Department of Behavioral Science, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
19
Section of Human Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, 20892, USA.
20
Department of Psychiatry, Yale University, New Haven, CT, 06516, USA.
21
Department of Primary Care Health Sciences, University of Oxford, Oxford, OX2 6GG, United Kingdom.
22
Department of Medical Chemistry and Biochemistry, Molecular Medicine Center, Medical University-Sofia, 1431, Sofia, Bulgaria.
23
Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093, USA.
24
Department. of Genomics, Life and Brain Center, Institute of Human Genetics, University of Bonn, Bonn, 53127, Germany.
25
Division of Medical Genetics, Department of Biomedicine, University Hospital Basel, University of Basel, Basel, 4003, Switzerland.
26
Ökumenisches Hainich-Klinikum, Mühlhausen/Thüringen, Germany.
27
National Drug and Alcohol Research Centre, University of New South Wales, Randwick, NSW, 2031, Australia.
28
School of Population and Global Health, University of Melbourne, Melbourne, 3010, Australia.
29
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
30
University of Düsseldorf, 40225, Düsseldorf, Germany.
31
Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, 13210, USA.
32
Center for Health Sciences, Biosciences Division, SRI International, Menlo Park, CA, 94025, USA.
33
Institute of Behavioral Science, University of Colorado, Boulder, CO, 80309, USA.
34
Max-Planck-Institute of Psychiatry, 80804, Munich, Germany.
35
Behavioral Health Research Division, Research Triangle Institute International, Durham, NC, 27709, USA.
36
Department of Oncology, University of Oxford, Oxford, OX3 7DQ, United Kingdom.
37
Department of Addictive Behavior and Addiction Medicine, Medical Faculty Mannheim, Central Institute of Mental Health, Heidelberg University, 68159, Mannheim, Germany.
38
Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
39
Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO, 80309, USA.
40
Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, 10065, USA.
41
Addictions Department, Institute of Psychiatry, King's College London, London, SE5 8BB, UK.
42
University of Bonn, 53113, Bonn, Germany.
43
Medical Faculty Mannheim, Central Institute of Mental Health, Heidelberg University, 68159, Mannheim, Germany.
44
Department of Genetic Epidemiology, Queensland Institute of Medical Research, Brisbane, QLD, 4029, Australia.
45
Harvard School of Public Health, Boston, MA, 02115, USA.
46
Aarhus University, Aarhus, 8000, Denmark.
47
Childhood Cancer Research Group, University of Oxford, Oxford, OX3 7LG, UK.
48
Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
49
Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
50
Department of Psychiatry, University Medical Center Regensburg, University of Regensburg, 8548, Regensburg, Germany.
51
Psychiatric Hospital, Konigsfelden, Windisch, Switzerland.
52
Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, 47405, USA.
53
Addiction Research Group at the Department of Psychiatry and Psychotherapy, LVR Hospital Essen, University of Duisburg-Essen, 45147, Essen, Germany.
54
Department of Psychiatry, University of Munich, 3860, Munich, Germany.
55
Private Hospital Meiringen, Meiringen, Switzerland.
56
Department of Psychology & Neuroscience, University of Colorado, Boulder, CO, 80309, USA.
57
Research Department, Federal Institute for Drugs and Medical Devices (BfArM), Kurt-Georg-Kiesinger-Allee 3, 53175, Bonn, Germany.
58
University of Munich, Munich, Germany.
59
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
60
Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
61
Department of Genetics, Yale University, New Haven, CT, 06516, USA.
62
Department of Neurobiology, Yale University, New Haven, CT, 06516, USA.
63
Department of Psychiatry, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
64
Institute for Molecular Medicine FIMM, University of Helsinki, 00014, Helsinki, Finland.
65
MRC Integrative Epidemiology Unit, UK Centre for Tobacco and Alcohol Studies, and School of Experimental Psychology, University of Bristol, Bristol, BS8 1TU, UK.
66
Department of Psychiatry, University of Iowa, Iowa City, IA, 52242, USA.
67
Psychiatry Service, Department of Veteran Affairs, New Jersey VA Health Care System, East Orange, NJ, 07018, USA.
68
Department of Medicine, Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, CA, 94304, USA.
69
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT, 84112, USA.
70
Department of Genetics, Washington University School of Medicine, 4523 Clayton Avenue, Campus Box 8232, St. Louis, MO, 63110, USA. nlims@genetics.wustl.edu.

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.

KEYWORDS:

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

PMID:
26392368
PMCID:
PMC4752855
[Available on 2017-03-01]
DOI:
10.1007/s10519-015-9737-3
[Indexed for MEDLINE]
Free PMC Article

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