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; 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 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

doi:10.1007/s10519-015-9737-3

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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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 language	English
Pages (from-to)	151-169
Number of pages	19
Journal	Behavior genetics
Volume	46
Issue number	2
DOIs	https://doi.org/10.1007/s10519-015-9737-3
State	Published - Mar 1 2016

Keywords

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

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10.1007/s10519-015-9737-3

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Schwantes-An, T. H., Zhang, J., Chen, L. S., Hartz, S. M., Culverhouse, R. C., Chen, X., Coon, H., Frank, J., Kamens, H. M., Konte, B., Kovanen, L., Latvala, A., Legrand, L. N., Maher, B. S., Melroy, W. E., Nelson, E. C., Reid, M. W., Robinson, J. D., Shen, P. H., ... Saccone, N. L. (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, 46(2), 151-169. https://doi.org/10.1007/s10519-015-9737-3

@article{d0be8e95a9054c729093a9221074ed3b,

title = "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",

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",

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

note = "Publisher Copyright: {\textcopyright} 2015, Springer Science+Business Media New York.",

year = "2016",

month = mar,

day = "1",

doi = "10.1007/s10519-015-9737-3",

language = "English",

volume = "46",

pages = "151--169",

journal = "Behavior genetics",

issn = "0001-8244",

number = "2",

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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, HJ, 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

TY - JOUR

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 J.

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 - OPRM1

KW - Opioid receptor

KW - Single nucleotide polymorphism (SNP)

KW - Substance dependence

UR - http://www.scopus.com/inward/record.url?scp=84957967508&partnerID=8YFLogxK

U2 - 10.1007/s10519-015-9737-3

DO - 10.1007/s10519-015-9737-3

M3 - Article

C2 - 26392368

AN - SCOPUS:84957967508

SN - 0001-8244

VL - 46

SP - 151

EP - 169

JO - Behavior genetics

JF - Behavior genetics

IS - 2

ER -

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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