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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55 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)151-169
Number of pages19
JournalBehavior genetics
Volume46
Issue number2
DOIs
StatePublished - Mar 1 2016

Bibliographical note

Funding Information:
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 (N??then, Rietschel) from National Genome Research Network (NGFN Plus). Drs. Cichon and N??then 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 Munaf?? 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.

Funding Information:
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.

Publisher Copyright:
© 2015, Springer Science+Business Media New York.

Keywords

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

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