Multi-trait genome-wide association study of opioid addiction: OPRM1 and beyond

Nathan Gaddis; Ravi Mathur; Jesse Marks; Linran Zhou; Bryan Quach; Alex Waldrop; Orna Levran; Arpana Agrawal; Matthew Randesi; Miriam Adelson; Paul W. Jeffries; Nicholas G. Martin; Louisa Degenhardt; Grant W. Montgomery; Leah Wetherill; Dongbing Lai; Kathleen Bucholz; Tatiana Foroud; Bernice Porjesz; Valgerdur Runarsdottir; Thorarinn Tyrfingsson; Gudmundur Einarsson; Daniel F. Gudbjartsson; Bradley Todd Webb; Richard C. Crist; Henry R. Kranzler; Richard Sherva; Hang Zhou; Gary Hulse; Dieter Wildenauer; Erin Kelty; John Attia; Elizabeth G. Holliday; Mark McEvoy; Rodney J. Scott; Sibylle G. Schwab; Brion S. Maher; Richard Gruza; Mary Jeanne Kreek; Elliot C. Nelson; Thorgeir Thorgeirsson; Kari Stefansson; Wade H. Berrettini; Joel Gelernter; Howard J. Edenberg; Laura Bierut; Dana B. Hancock; Eric Otto Johnson

doi:10.1038/s41598-022-21003-y

Multi-trait genome-wide association study of opioid addiction: OPRM1 and beyond

Nathan Gaddis, Ravi Mathur, Jesse Marks, Linran Zhou, Bryan Quach, Alex Waldrop, Orna Levran, Arpana Agrawal, Matthew Randesi, Miriam Adelson, Paul W. Jeffries, Nicholas G. Martin, Louisa Degenhardt, Grant W. Montgomery, Leah Wetherill, Dongbing Lai, Kathleen Bucholz, Tatiana Foroud, Bernice Porjesz, Valgerdur RunarsdottirThorarinn Tyrfingsson, Gudmundur Einarsson, Daniel F. Gudbjartsson, Bradley Todd Webb, Richard C. Crist, Henry R. Kranzler, Richard Sherva, Hang Zhou, Gary Hulse, Dieter Wildenauer, Erin Kelty, John Attia, Elizabeth G. Holliday, Mark McEvoy, Rodney J. Scott, Sibylle G. Schwab, Brion S. Maher, Richard Gruza, Mary Jeanne Kreek, Elliot C. Nelson, Thorgeir Thorgeirsson, Kari Stefansson, Wade H. Berrettini, Joel Gelernter, Howard J. Edenberg, Laura Bierut, Dana B. Hancock, Eric Otto Johnson

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Abstract

Opioid addiction (OA) is moderately heritable, yet only rs1799971, the A118G variant in OPRM1, has been identified as a genome-wide significant association with OA and independently replicated. We applied genomic structural equation modeling to conduct a GWAS of the new Genetics of Opioid Addiction Consortium (GENOA) data together with published studies (Psychiatric Genomics Consortium, Million Veteran Program, and Partners Health), comprising 23,367 cases and effective sample size of 88,114 individuals of European ancestry. Genetic correlations among the various OA phenotypes were uniformly high (r_g > 0.9). We observed the strongest evidence to date for OPRM1: lead SNP rs9478500 (p = 2.56 × 10^–9). Gene-based analyses identified novel genome-wide significant associations with PPP6C and FURIN. Variants within these loci appear to be pleiotropic for addiction and related traits.

Original language	English
Article number	16873
Journal	Scientific reports
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41598-022-21003-y
State	Published - Dec 2022

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Gaddis, N., Mathur, R., Marks, J., Zhou, L., Quach, B., Waldrop, A., Levran, O., Agrawal, A., Randesi, M., Adelson, M., Jeffries, P. W., Martin, N. G., Degenhardt, L., Montgomery, G. W., Wetherill, L., Lai, D., Bucholz, K., Foroud, T., Porjesz, B., ... Johnson, E. O. (2022). Multi-trait genome-wide association study of opioid addiction: OPRM1 and beyond. Scientific reports, 12(1), [16873]. https://doi.org/10.1038/s41598-022-21003-y

@article{ad8dcd4e2a06459bb695ef51cf3768db,

title = "Multi-trait genome-wide association study of opioid addiction: OPRM1 and beyond",

abstract = "Opioid addiction (OA) is moderately heritable, yet only rs1799971, the A118G variant in OPRM1, has been identified as a genome-wide significant association with OA and independently replicated. We applied genomic structural equation modeling to conduct a GWAS of the new Genetics of Opioid Addiction Consortium (GENOA) data together with published studies (Psychiatric Genomics Consortium, Million Veteran Program, and Partners Health), comprising 23,367 cases and effective sample size of 88,114 individuals of European ancestry. Genetic correlations among the various OA phenotypes were uniformly high (rg > 0.9). We observed the strongest evidence to date for OPRM1: lead SNP rs9478500 (p = 2.56 × 10–9). Gene-based analyses identified novel genome-wide significant associations with PPP6C and FURIN. Variants within these loci appear to be pleiotropic for addiction and related traits.",

author = "Nathan Gaddis and Ravi Mathur and Jesse Marks and Linran Zhou and Bryan Quach and Alex Waldrop and Orna Levran and Arpana Agrawal and Matthew Randesi and Miriam Adelson and Jeffries, {Paul W.} and Martin, {Nicholas G.} and Louisa Degenhardt and Montgomery, {Grant W.} and Leah Wetherill and Dongbing Lai and Kathleen Bucholz and Tatiana Foroud and Bernice Porjesz and Valgerdur Runarsdottir and Thorarinn Tyrfingsson and Gudmundur Einarsson and Gudbjartsson, {Daniel F.} and Webb, {Bradley Todd} and Crist, {Richard C.} and Kranzler, {Henry R.} and Richard Sherva and Hang Zhou and Gary Hulse and Dieter Wildenauer and Erin Kelty and John Attia and Holliday, {Elizabeth G.} and Mark McEvoy and Scott, {Rodney J.} and Schwab, {Sibylle G.} and Maher, {Brion S.} and Richard Gruza and Kreek, {Mary Jeanne} and Nelson, {Elliot C.} and Thorgeir Thorgeirsson and Kari Stefansson and Berrettini, {Wade H.} and Joel Gelernter and Edenberg, {Howard J.} and Laura Bierut and Hancock, {Dana B.} and Johnson, {Eric Otto}",

note = "Funding Information: The late Dr. Mary Jeanne Kreek from the Laboratory of the Biology of Addictive Diseases at the Rockefeller University, New York, NY, was a key contributor to the research presented in this manuscript. The authors thank Nancy Saccone, Weimin Duan, Yi-Ling Chou Duan and Congcong Zhu for assisting with protocol development and testing. Funding Information: Funders had no role in the conceptualization, design, data collection, analysis, decision to publish, or preparation of the manuscript. The National Institute on Drug Abuse: R01DA044014, R01DA038632, R33DA027486 (EOJ, NG, DBH); K01DA036751 (RCC), U10DA13043 (WHB), R01DA04401 (RCC, WHB). National Institute on Alcoholism and Alcohol Abuse U10AA008401 (LW, DL, KB, TF, AA, BP, HE). The Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (OL, MR, MJK), The Clinical and Translational Science Award UL1RR024143 from the National Center for Advancing Translational Sciences of the NIH (MJK). Pennsylvania State Department of Health Tobacco Settlement non-formulary grant Pharmacogenetics of Opioid Use Disorder (RCC, WHB). deCODE authors (GE, DFG, TT, KS) acknowledge financial support from the European Commission to the painFACT project (H2020-2020–848099). The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from: GTEx Analysis v8 of the GTEx Portal on 05/18/21 and/or dbGaP accession number phs000424.v8.p2 on 02/17/2021. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41598-022-21003-y",

language = "English",

volume = "12",

journal = "Scientific Reports",

issn = "2045-2322",

number = "1",

}

Gaddis, N, Mathur, R, Marks, J, Zhou, L, Quach, B, Waldrop, A, Levran, O, Agrawal, A, Randesi, M, Adelson, M, Jeffries, PW, Martin, NG, Degenhardt, L, Montgomery, GW, Wetherill, L, Lai, D, Bucholz, K, Foroud, T, Porjesz, B, Runarsdottir, V, Tyrfingsson, T, Einarsson, G, Gudbjartsson, DF, Webb, BT, Crist, RC, Kranzler, HR, Sherva, R, Zhou, H, Hulse, G, Wildenauer, D, Kelty, E, Attia, J, Holliday, EG, McEvoy, M, Scott, RJ, Schwab, SG, Maher, BS, Gruza, R, Kreek, MJ, Nelson, EC, Thorgeirsson, T, Stefansson, K, Berrettini, WH, Gelernter, J, Edenberg, HJ, Bierut, L, Hancock, DB & Johnson, EO 2022, 'Multi-trait genome-wide association study of opioid addiction: OPRM1 and beyond', Scientific reports, vol. 12, no. 1, 16873. https://doi.org/10.1038/s41598-022-21003-y

TY - JOUR

T1 - Multi-trait genome-wide association study of opioid addiction

T2 - OPRM1 and beyond

AU - Gaddis, Nathan

AU - Mathur, Ravi

AU - Marks, Jesse

AU - Zhou, Linran

AU - Quach, Bryan

AU - Waldrop, Alex

AU - Levran, Orna

AU - Agrawal, Arpana

AU - Randesi, Matthew

AU - Adelson, Miriam

AU - Jeffries, Paul W.

AU - Martin, Nicholas G.

AU - Degenhardt, Louisa

AU - Montgomery, Grant W.

AU - Wetherill, Leah

AU - Lai, Dongbing

AU - Bucholz, Kathleen

AU - Foroud, Tatiana

AU - Porjesz, Bernice

AU - Runarsdottir, Valgerdur

AU - Tyrfingsson, Thorarinn

AU - Einarsson, Gudmundur

AU - Gudbjartsson, Daniel F.

AU - Webb, Bradley Todd

AU - Crist, Richard C.

AU - Kranzler, Henry R.

AU - Sherva, Richard

AU - Zhou, Hang

AU - Hulse, Gary

AU - Wildenauer, Dieter

AU - Kelty, Erin

AU - Attia, John

AU - Holliday, Elizabeth G.

AU - McEvoy, Mark

AU - Scott, Rodney J.

AU - Schwab, Sibylle G.

AU - Maher, Brion S.

AU - Gruza, Richard

AU - Kreek, Mary Jeanne

AU - Nelson, Elliot C.

AU - Thorgeirsson, Thorgeir

AU - Stefansson, Kari

AU - Berrettini, Wade H.

AU - Gelernter, Joel

AU - Edenberg, Howard J.

AU - Bierut, Laura

AU - Hancock, Dana B.

AU - Johnson, Eric Otto

N1 - Funding Information: The late Dr. Mary Jeanne Kreek from the Laboratory of the Biology of Addictive Diseases at the Rockefeller University, New York, NY, was a key contributor to the research presented in this manuscript. The authors thank Nancy Saccone, Weimin Duan, Yi-Ling Chou Duan and Congcong Zhu for assisting with protocol development and testing. Funding Information: Funders had no role in the conceptualization, design, data collection, analysis, decision to publish, or preparation of the manuscript. The National Institute on Drug Abuse: R01DA044014, R01DA038632, R33DA027486 (EOJ, NG, DBH); K01DA036751 (RCC), U10DA13043 (WHB), R01DA04401 (RCC, WHB). National Institute on Alcoholism and Alcohol Abuse U10AA008401 (LW, DL, KB, TF, AA, BP, HE). The Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (OL, MR, MJK), The Clinical and Translational Science Award UL1RR024143 from the National Center for Advancing Translational Sciences of the NIH (MJK). Pennsylvania State Department of Health Tobacco Settlement non-formulary grant Pharmacogenetics of Opioid Use Disorder (RCC, WHB). deCODE authors (GE, DFG, TT, KS) acknowledge financial support from the European Commission to the painFACT project (H2020-2020–848099). The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from: GTEx Analysis v8 of the GTEx Portal on 05/18/21 and/or dbGaP accession number phs000424.v8.p2 on 02/17/2021. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - Opioid addiction (OA) is moderately heritable, yet only rs1799971, the A118G variant in OPRM1, has been identified as a genome-wide significant association with OA and independently replicated. We applied genomic structural equation modeling to conduct a GWAS of the new Genetics of Opioid Addiction Consortium (GENOA) data together with published studies (Psychiatric Genomics Consortium, Million Veteran Program, and Partners Health), comprising 23,367 cases and effective sample size of 88,114 individuals of European ancestry. Genetic correlations among the various OA phenotypes were uniformly high (rg > 0.9). We observed the strongest evidence to date for OPRM1: lead SNP rs9478500 (p = 2.56 × 10–9). Gene-based analyses identified novel genome-wide significant associations with PPP6C and FURIN. Variants within these loci appear to be pleiotropic for addiction and related traits.

AB - Opioid addiction (OA) is moderately heritable, yet only rs1799971, the A118G variant in OPRM1, has been identified as a genome-wide significant association with OA and independently replicated. We applied genomic structural equation modeling to conduct a GWAS of the new Genetics of Opioid Addiction Consortium (GENOA) data together with published studies (Psychiatric Genomics Consortium, Million Veteran Program, and Partners Health), comprising 23,367 cases and effective sample size of 88,114 individuals of European ancestry. Genetic correlations among the various OA phenotypes were uniformly high (rg > 0.9). We observed the strongest evidence to date for OPRM1: lead SNP rs9478500 (p = 2.56 × 10–9). Gene-based analyses identified novel genome-wide significant associations with PPP6C and FURIN. Variants within these loci appear to be pleiotropic for addiction and related traits.

UR - http://www.scopus.com/inward/record.url?scp=85139570882&partnerID=8YFLogxK

U2 - 10.1038/s41598-022-21003-y

DO - 10.1038/s41598-022-21003-y

M3 - Article

C2 - 36207451

AN - SCOPUS:85139570882

VL - 12

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 16873

ER -

Multi-trait genome-wide association study of opioid addiction: OPRM1 and beyond

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