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 Yang & 90 others Judy 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 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

Research output: Contribution to journalArticle

34 Citations (Scopus)

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

Fingerprint

substance abuse
meta-analysis
liability
ancestry
Substance-Related Disorders
Meta-Analysis
narcotics
Marijuana Abuse
Cannabis
Addictive Behavior
smoking
cocaine
Cocaine-Related Disorders
Tobacco Use Disorder
smoking (habit)
Information Dissemination
nicotine
alcohol
allele
Medical Genetics

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Ecology, Evolution, Behavior and Systematics

Cite this

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

In: Behavior Genetics, Vol. 46, No. 2, 01.03.2016, p. 151-169.

Research output: Contribution to journalArticle

Schwantes-An, TH, Zhang, J, Chen, LS, Hartz, SM, Culverhouse, RC, Chen, X, Coon, H, Frank, J, Kamens, HM, Konte, B, Kovanen, L, Latvala, A, Legrand, LN, Maher, BS, Melroy, WE, Nelson, EC, Reid, MW, Robinson, JD, Shen, PH, Yang, BZ, Andrews, JA, Aveyard, P, Beltcheva, O, Brown, SA, Cannon, DS, Cichon, S, Corley, RP, Dahmen, N, Degenhardt, L, Foroud, T, Gaebel, W, Giegling, I, Glatt, SJ, Grucza, RA, Hardin, J, Hartmann, AM, Heath, AC, Herms, S, Hodgkinson, CA, Hoffmann, P, Hops, H, Huizinga, D, Ising, M, Johnson, EO, Johnstone, E, Kaneva, RP, Kendler, KS, Kiefer, F, Kranzler, HR, Krauter, KS, Levran, O, Lucae, S, Lynskey, MT, Maier, W, Mann, K, Martin, NG, Mattheisen, M, Montgomery, GW, Müller-Myhsok, B, Murphy, MF, Neale, MC, Nikolov, MA, Nishita, D, Nöthen, MM, Nurnberger, J, Partonen, T, Pergadia, ML, Reynolds, M, Ridinger, M, Rose, RJ, Rouvinen-Lagerström, N, Scherbaum, N, Schmäl, C, Soyka, M, Stallings, MC, Steffens, M, Treutlein, J, Tsuang, M, Wall, TL, Wodarz, N, Yuferov, V, Zill, P, Bergen, AW, Chen, J, Cinciripini, PM, Edenberg, H, Ehringer, MA, Ferrell, RE, Gelernter, J, Goldman, D, Hewitt, JK, Hopfer, CJ, Iacono, WG, Kaprio, J, Kreek, MJ, Kremensky, IM, Madden, PAF, McGue, M, Munafò, MR, Philibert, RA, Rietschel, M, Roy, A, Rujescu, D, Saarikoski, ST, Swan, GE, Todorov, AA, Vanyukov, MM, Weiss, RB, Bierut, LJ & Saccone, NL 2016, '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', Behavior Genetics, vol. 46, no. 2, pp. 151-169. https://doi.org/10.1007/s10519-015-9737-3
Schwantes-An, Tae Hwi ; Zhang, Juan ; Chen, Li Shiun ; Hartz, Sarah M. ; Culverhouse, Robert C. ; Chen, Xiangning ; Coon, Hilary ; Frank, Josef ; Kamens, Helen M. ; Konte, Bettina ; Kovanen, Leena ; Latvala, Antti ; Legrand, Lisa N. ; Maher, Brion S. ; Melroy, Whitney E. ; Nelson, Elliot C. ; Reid, Mark W. ; Robinson, Jason D. ; Shen, Pei Hong ; Yang, Bao Zhu ; Andrews, Judy A. ; Aveyard, Paul ; Beltcheva, Olga ; Brown, Sandra A. ; Cannon, Dale S. ; Cichon, Sven ; Corley, Robin P. ; Dahmen, Norbert ; Degenhardt, Louisa ; Foroud, Tatiana ; Gaebel, Wolfgang ; Giegling, Ina ; Glatt, Stephen J. ; Grucza, Richard A. ; Hardin, Jill ; Hartmann, Annette M. ; Heath, Andrew C. ; Herms, Stefan ; Hodgkinson, Colin A. ; Hoffmann, Per ; Hops, Hyman ; Huizinga, David ; Ising, Marcus ; Johnson, Eric O. ; Johnstone, Elaine ; Kaneva, Radka P. ; Kendler, Kenneth S. ; Kiefer, Falk ; Kranzler, Henry R. ; Krauter, Ken S. ; Levran, Orna ; Lucae, Susanne ; Lynskey, Michael T. ; Maier, Wolfgang ; Mann, Karl ; Martin, Nicholas G. ; Mattheisen, Manuel ; Montgomery, Grant W. ; Müller-Myhsok, Bertram ; Murphy, Michael F. ; Neale, Michael C. ; Nikolov, Momchil A. ; Nishita, Denise ; Nöthen, Markus M. ; Nurnberger, John ; Partonen, Timo ; Pergadia, Michele L. ; Reynolds, Maureen ; Ridinger, Monika ; Rose, Richard J. ; Rouvinen-Lagerström, Noora ; Scherbaum, Norbert ; Schmäl, Christine ; Soyka, Michael ; Stallings, Michael C. ; Steffens, Michael ; Treutlein, Jens ; Tsuang, Ming ; Wall, Tamara L. ; Wodarz, Norbert ; Yuferov, Vadim ; Zill, Peter ; Bergen, Andrew W. ; Chen, Jingchun ; Cinciripini, Paul M. ; Edenberg, Howard ; Ehringer, Marissa A. ; Ferrell, Robert E. ; Gelernter, Joel ; Goldman, David ; Hewitt, John K. ; Hopfer, Christian J. ; Iacono, William G. ; Kaprio, Jaakko ; Kreek, Mary Jeanne ; Kremensky, Ivo M. ; Madden, Pamela A F ; McGue, Matt ; Munafò, Marcus R. ; Philibert, Robert A. ; Rietschel, Marcella ; Roy, Alec ; Rujescu, Dan ; Saarikoski, Sirkku T. ; Swan, Gary E. ; Todorov, Alexandre A. ; Vanyukov, Michael M. ; Weiss, Robert B. ; Bierut, Laura J. ; Saccone, Nancy L. / 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. In: Behavior Genetics. 2016 ; Vol. 46, No. 2. pp. 151-169.
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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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T1 - 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

AU - Schwantes-An, Tae Hwi

AU - Zhang, Juan

AU - Chen, Li Shiun

AU - Hartz, Sarah M.

AU - Culverhouse, Robert C.

AU - Chen, Xiangning

AU - Coon, Hilary

AU - Frank, Josef

AU - Kamens, Helen M.

AU - Konte, Bettina

AU - Kovanen, Leena

AU - Latvala, Antti

AU - Legrand, Lisa N.

AU - Maher, Brion S.

AU - Melroy, Whitney E.

AU - Nelson, Elliot C.

AU - Reid, Mark W.

AU - Robinson, Jason D.

AU - Shen, Pei Hong

AU - Yang, Bao Zhu

AU - Andrews, Judy A.

AU - Aveyard, Paul

AU - Beltcheva, Olga

AU - Brown, Sandra A.

AU - Cannon, Dale S.

AU - Cichon, Sven

AU - Corley, Robin P.

AU - Dahmen, Norbert

AU - Degenhardt, Louisa

AU - Foroud, Tatiana

AU - Gaebel, Wolfgang

AU - Giegling, Ina

AU - Glatt, Stephen J.

AU - Grucza, Richard A.

AU - Hardin, Jill

AU - Hartmann, Annette M.

AU - Heath, Andrew C.

AU - Herms, Stefan

AU - Hodgkinson, Colin A.

AU - Hoffmann, Per

AU - Hops, Hyman

AU - Huizinga, David

AU - Ising, Marcus

AU - Johnson, Eric O.

AU - Johnstone, Elaine

AU - Kaneva, Radka P.

AU - Kendler, Kenneth S.

AU - Kiefer, Falk

AU - Kranzler, Henry R.

AU - Krauter, Ken S.

AU - Levran, Orna

AU - Lucae, Susanne

AU - Lynskey, Michael T.

AU - Maier, Wolfgang

AU - Mann, Karl

AU - Martin, Nicholas G.

AU - Mattheisen, Manuel

AU - Montgomery, Grant W.

AU - Müller-Myhsok, Bertram

AU - Murphy, Michael F.

AU - Neale, Michael C.

AU - Nikolov, Momchil A.

AU - Nishita, Denise

AU - Nöthen, Markus M.

AU - Nurnberger, John

AU - Partonen, Timo

AU - Pergadia, Michele L.

AU - Reynolds, Maureen

AU - Ridinger, Monika

AU - Rose, Richard J.

AU - Rouvinen-Lagerström, Noora

AU - Scherbaum, Norbert

AU - Schmäl, Christine

AU - Soyka, Michael

AU - Stallings, Michael C.

AU - Steffens, Michael

AU - Treutlein, Jens

AU - Tsuang, Ming

AU - Wall, Tamara L.

AU - Wodarz, Norbert

AU - Yuferov, Vadim

AU - Zill, Peter

AU - Bergen, Andrew W.

AU - Chen, Jingchun

AU - Cinciripini, Paul M.

AU - Edenberg, Howard

AU - Ehringer, Marissa A.

AU - Ferrell, Robert E.

AU - Gelernter, Joel

AU - Goldman, David

AU - Hewitt, John K.

AU - Hopfer, Christian J.

AU - Iacono, William G.

AU - Kaprio, Jaakko

AU - Kreek, Mary Jeanne

AU - Kremensky, Ivo M.

AU - Madden, Pamela A F

AU - McGue, Matt

AU - Munafò, Marcus R.

AU - Philibert, Robert A.

AU - Rietschel, Marcella

AU - Roy, Alec

AU - Rujescu, Dan

AU - Saarikoski, Sirkku T.

AU - Swan, Gary E.

AU - Todorov, Alexandre A.

AU - Vanyukov, Michael M.

AU - Weiss, Robert B.

AU - Bierut, Laura J.

AU - Saccone, Nancy L.

PY - 2016/3/1

Y1 - 2016/3/1

N2 - 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.

AB - 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.

KW - Addiction

KW - Genetic association

KW - Opioid receptor

KW - OPRM1

KW - Single nucleotide polymorphism (SNP)

KW - Substance dependence

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U2 - 10.1007/s10519-015-9737-3

DO - 10.1007/s10519-015-9737-3

M3 - Article

VL - 46

SP - 151

EP - 169

JO - Behavior Genetics

JF - Behavior Genetics

SN - 0001-8244

IS - 2

ER -