Letter | Published:

Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use

Nature Geneticsvolume 51pages237244 (2019) | Download Citation

Abstract

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6,7,8,9,10,11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures.

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Code availability

All software used to perform these analyses is available online.

Data availability

GWAS summary statistics can be downloaded online (https://genome.psych.umn.edu/index.php/GSCAN). We provide association results for all SNPs that passed quality-control filters in a GWAS meta-analysis of each of our five substance use phenotypes that excludes the research participants from 23andMe.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Acknowledgements

This study was designed and carried out by the GWAS and Sequencing Consortium of Alcohol and Nicotine use (GSCAN). It was conducted by using the UK Biobank Resource under application number 16651. This study was supported by funding from US National Institutes of Health awards R01DA037904 to S.V., R01HG008983 to D. J. Liu., and R21DA040177 to D. J. Liu. Ethical review and approval was provided by the University of Minnesota institutional review board; all human subjects provided informed consent. A full list of acknowledgements is provided in the Supplementary Note.

23andMe Research Team

Michelle Agee11, Babak Alipanahi11, Adam Auton11, Robert K. Bell11, Katarzyna Bryc11, Sarah L. Elson11, Pierre Fontanillas11, Nicholas A. Furlotte11, David A. Hinds11, Bethann S. Hromatka11, Karen E. Huber11, Aaron Kleinman11, Nadia K. Litterman11, Matthew H. McIntyre11, Joanna L. Mountain11, Carrie A.M. Northover11, J. Fah Sathirapongsasuti11, Olga V. Sazonova11, Janie F. Shelton11, Suyash Shringarpure11, Chao Tian11, Joyce Y. Tung11, Vladimir Vacic11, Catherine H. Wilson11 and Steven J. Pitts11.

HUNT All-In Psychiatry

Amy Mitchell65, Anne Heidi Skogholt20, Bendik S Winsvold65,78, Børge Sivertsen79,80,81, Eystein Stordal80,82, Gunnar Morken80,83, Håvard Kallestad80,83, Ingrid Heuch81, John-Anker Zwart65,78,84, Katrine Kveli Fjukstad85,86, Linda M Pedersen65, Maiken Elvestad Gabrielsen20, Marianne Bakke Johnsen65,84, Marit Skrove87, Marit Sæbø Indredavik80,87, Ole Kristian Drange80,83, Ottar Bjerkeset80,88, Sigrid Børte65,84 and Synne Øien Stensland65,89

Author information

Author notes

  1. These authors contributed equally: Mengzhen Liu, Yu Jiang, Robbee Wedow, Yue Li.

  2. These authors jointly supervised this work: Dajiang Liu, Scott Vrieze.

  3. A full list of members and affiliations appears at the end of the paper.

Affiliations

  1. Department of Psychology, University of Minnesota Twin Cities, Minneapolis, MN, USA

    • Mengzhen Liu
    • , Gargi Datta
    • , Seon-Kyeong Jang
    • , Hannah Young
    • , William G. Iacono
    • , Matt McGue
    • , James J. Lee
    •  & Scott Vrieze
  2. Department of Public Health Sciences, College of Medicine, Pennsylvania State University, Hershey, PA, USA

    • Yu Jiang
    • , Fang Chen
    • , Daniel McGuire
    • , Yueh Ling
    •  & Dajiang J. Liu
  3. Institute of Personalized Medicine, College of Medicine, Pennsylvania State University, Hershey, PA, USA

    • Yu Jiang
    • , Fang Chen
    • , Daniel McGuire
    •  & Dajiang J. Liu
  4. Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA

    • Robbee Wedow
    • , David M. Brazel
    • , Jason D. Boardman
    • , Marissa A. Ehringer
    • , John K. Hewitt
    • , Christian J. Hopfer
    • , Matthew C. Keller
    • , Kenneth S. Krauter
    • , Matthew B. McQueen
    • , Michael C. Stallings
    •  & Jerry A. Stitzel
  5. Department of Sociology, University of Colorado Boulder, Boulder, CO, USA

    • Robbee Wedow
    •  & Jason D. Boardman
  6. Institute of Behavioral Science, University of Colorado Boulder, Boulder, CO, USA

    • Robbee Wedow
    •  & Jason D. Boardman
  7. Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA, USA

    • Yue Li
    • , Jose Davila-Velderrain
    •  & Manolis Kellis
  8. The Broad Institute of MIT and Harvard, Cambridge, MA, USA

    • Yue Li
    • , Jose Davila-Velderrain
    • , Tõnu Esko
    •  & Manolis Kellis
  9. Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, CO, USA

    • David M. Brazel
    • , Yueh Ling
    •  & Kenneth S. Krauter
  10. Interdisciplinary Quantitative Biology Graduate Group, University of Colorado Boulder, Boulder, CO, USA

    • David M. Brazel
  11. 23andMe, Inc., Mountain View, CA, USA

    • Chao Tian
    • , Michelle Agee
    • , Babak Alipanahi
    • , Adam Auton
    • , Robert K. Bell
    • , Katarzyna Bryc
    • , Sarah L. Elson
    • , Pierre Fontanillas
    • , Nicholas A. Furlotte
    • , David A. Hinds
    • , Bethann S. Hromatka
    • , Karen E. Huber
    • , Aaron Kleinman
    • , Nadia K. Litterman
    • , Matthew H. McIntyre
    • , Joanna L. Mountain
    • , Carrie A. M. Northover
    • , J. Fah Sathirapongsasuti
    • , Olga V. Sazonova
    • , Janie F. Shelton
    • , Suyash Shringarpure
    • , Chao Tian
    • , Joyce Y. Tung
    • , Vladimir Vacic
    • , Catherine H. Wilson
    • , Steven J. Pitts
    •  & David A. Hinds
  12. Quantitative Biomedical Research Center, Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA

    • Xiaowei Zhan
  13. Center for the Genetics of Host Defense, Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA

    • Xiaowei Zhan
  14. Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA

    • Hélène Choquet
    • , Khanh K. Thai
    • , Constance Weisner
    • , Jie Yin
    •  & Eric Jorgenson
  15. Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA

    • Anna R. Docherty
    •  & Nathan A. Gillespie
  16. Department of Psychiatry and Human Genetics, University of Utah, Salt Lake City, UT, USA

    • Anna R. Docherty
  17. Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA

    • Jessica D. Faul
    • , Jennifer A. Smith
    •  & David R. Weir
  18. Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA

    • Johanna R. Foerster
    • , Lars G. Fritsche
    • , Anita Pandit
    • , Gregory J. M. Zajac
    • , Michael Boehnke
    •  & Gonçalo Abecasis
  19. K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway

    • Anne Heidi Skogholt
    • , Maiken Elvestad Gabrielsen
    • , Maiken Elvestad Gabrielsen
    • , Anne Heidi Skogholt
    •  & Kristian Hveem
  20. Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

    • Scott D. Gordon
    • , Nathan A. Gillespie
    • , Nicholas G. Martin
    •  & John B. Whitfield
  21. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    • Jeffrey Haessler
    • , Chu Chen
    • , Charles Kooperberg
    • , Ulrike Peters
    •  & Alexander P. Reiner
  22. Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands

    • Jouke-Jan Hottenga
    • , Gonneke Willemsen
    •  & Dorret I. Boomsma
  23. Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    • Hongyan Huang
    • , Constance Turman
    • , David J. Hunter
    •  & Peter Kraft
  24. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    • Hongyan Huang
    • , Constance Turman
    • , David J. Hunter
    • , Peter Kraft
    •  & Eric Rimm
  25. Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands

    • Philip R. Jansen
    • , Tinca J. C. Polderman
    •  & Danielle Posthuma
  26. Department of Child and Adolescent Psychiatry, Erasmus MC Rotterdam, Rotterdam, the Netherlands

    • Philip R. Jansen
  27. Estonian Genome Center, University of Tartu, Tartu, Estonia

    • Reedik Mägi
    • , Tõnu Esko
    • , Toomas Haller
    •  & Andres Metspalu
  28. Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama City, Japan

    • Nana Matoba
    • , Yoichiro Kamatani
    •  & Yukinori Okada
  29. Department of Population Health Science, Bristol Medical School, Oakfield Grove, Bristol, UK

    • George McMahon
    • , Amy E. Taylor
    •  & Luisa Zuccolo
  30. Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato, Italy

    • Antonella Mulas
    • , Valeria Orrù
    • , Francesco Cucca
    •  & Edoardo Fiorillo
  31. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland

    • Teemu Palviainen
    • , Anu Loukola
    •  & Jaakko Kaprio
  32. deCODE Genetics/Amgen, Inc., Reykjavik, Iceland

    • Gunnar W. Reginsson
    • , Gyda Bjornsdottir
    • , Daniel F. Gudbjartsson
    • , Hreinn Stefansson
    • , Kari Stefansson
    •  & Thorgeir E. Thorgeirsson
  33. Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA

    • Jennifer A. Smith
    • , Wei Zhao
    •  & Sharon L. R. Kardia
  34. Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    • Kendra A. Young
    •  & John E. Hokanson
  35. Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA

    • Wei Zhou
    •  & Cristen J. Willer
  36. Avera Institute for Human Genetics, Sioux Falls, SD, USA

    • Gareth E. Davies
  37. Department of Family Medicine and Community Health, Alpert Medical School, Brown University, Providence, RI, USA

    • Charles B. Eaton
  38. Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA

    • Marissa A. Ehringer
    • , Matthew B. McQueen
    •  & Jerry A. Stitzel
  39. School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland

    • Daniel F. Gudbjartsson
  40. Department of Sociology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    • Kathleen Mullan Harris
  41. Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    • Kathleen Mullan Harris
  42. Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA

    • Andrew C. Heath
    •  & Pamela A. F. Madden
  43. Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA

    • John K. Hewitt
    • , Matthew C. Keller
    •  & Michael C. Stallings
  44. Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia

    • Ian B. Hickie
  45. Department of Psychiatry, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    • Christian J. Hopfer
  46. Nuffield Department of Population Health, University of Oxford, Oxford, UK

    • David J. Hunter
  47. Fellows Program, RTI International, Research Triangle Park, NC, USA

    • Eric O. Johnson
  48. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    • Peter Kraft
  49. Department of Internal Medicine, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland

    • Markku Laakso
    •  & Alena Stančáková
  50. Department of Medicine, Kuopio University Hospital, Kuopio, Finland

    • Markku Laakso
  51. Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

    • Penelope A. Lind
    •  & Sarah E. Medland
  52. Department of Biostatistics and Bioinformatics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    • Sharon M. Lutz
  53. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    • Karen L. Mohlke
  54. Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, USA

    • Jonas B. Nielsen
    •  & Cristen J. Willer
  55. Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan

    • Yukinori Okada
  56. Department of Epidemiology, University of Washington, Seattle, WA, USA

    • Ulrike Peters
    •  & Alexander P. Reiner
  57. Department of Clinical Genetics, VU Medical Centre Amsterdam, Amsterdam, the Netherlands

    • Danielle Posthuma
  58. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA

    • John P. Rice
    •  & Laura J. Bierut
  59. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    • Eric Rimm
  60. Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA

    • Richard J. Rose
  61. SAA—National Center of Addiction Medicine, Vogur Hospital, Reykjavik, Iceland

    • Valgerdur Runarsdottir
    •  & Thorarinn Tyrfingsson
  62. Department of Medicine, Vanderbilt University, Nashville, TN, USA

    • Hilary A. Tindle
  63. Department of Psychiatry, University of California, San Diego, San Diego, CA, USA

    • Tamara L. Wall
  64. FORMI and Department of Neurology, Oslo University Hospital, Oslo, Norway

    • Amy Mitchell
    • , Bendik S. Winsvold
    • , John-Anker Zwart
    • , Linda M. Pedersen
    • , Marianne Bakke Johnsen
    • , Sigrid Børte
    • , Synne Øien Stensland
    •  & Bendik Slagsvold Winsvold
  65. MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK

    • Luisa Zuccolo
    •  & Marcus R. Munafò
  66. HUNT Research Centre, Department of Public Health and Nursing, Norwegian University of Science and Technology, Levanger, Norway

    • Kristian Hveem
  67. Department of Medicine, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway

    • Kristian Hveem
  68. UK Centre for Tobacco and Alcohol Studies, School of Psychological Science, University of Bristol, Bristol, UK

    • Marcus R. Munafò
  69. Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA

    • Nancy L. Saccone
  70. Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA

    • Cristen J. Willer
  71. Department of Preventative Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    • Marilyn C. Cornelis
  72. Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA

    • Sean P. David
  73. Department of Public Health, University of Helsinki, Helsinki, Finland

    • Jaakko Kaprio
  74. Faculty of Medicine, University of Iceland, Reykjavik, Iceland

    • Kari Stefansson
  75. Department of Neurology, Oslo University Hospital, Oslo, Norway

    • Bendik S. Winsvold
    •  & John-Anker Zwart
  76. Department of Health Promotion, Norwegian Institute of Public Health, Bergen, Norway

    • Børge Sivertsen
  77. Department of Mental Health, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway

    • Børge Sivertsen
    • , Eystein Stordal
    • , Gunnar Morken
    • , Håvard Kallestad
    • , Marit Sæbø Indredavik
    • , Ole Kristian Drange
    •  & Ottar Bjerkeset
  78. Department of Research and Innovation, Helse-Fonna HF, Haugesund, Norway

    • Børge Sivertsen
    •  & Ingrid Heuch
  79. Department of Psychiatry, Hospital Namsos, Nord-Trøndelag Health Trust, Namsos, Norway

    • Eystein Stordal
  80. Division of Mental Health Care, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway

    • Gunnar Morken
    • , Håvard Kallestad
    •  & Ole Kristian Drange
  81. Institute of Clinical Medicine, University of Oslo, Oslo, Norway

    • John-Anker Zwart
    • , Marianne Bakke Johnsen
    •  & Sigrid Børte
  82. Department of Psychiatry, Nord-Trøndelag Hospital Trust, Levanger Hospital, Levanger, Norway

    • Katrine Kveli Fjukstad
  83. Department of Laboratory Medicine, Children’s and Women’s Health, Norwegian University of Science and Technology, Trondheim, Norway

    • Katrine Kveli Fjukstad
  84. Regional Centre for Child and Youth Mental Health and Child Welfare, Department of Mental Health, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway

    • Marit Skrove
    •  & Marit Sæbø Indredavik
  85. Faculty of Nursing and Health Sciences, Nord University, Levanger, Norway

    • Ottar Bjerkeset
  86. Norwegian Centre for Violence and Traumatic Stress Studies, Oslo, Norway

    • Synne Øien Stensland

Authors

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Consortia

  1. 23andMe Research Team

  1. HUNT All-In Psychiatry

Contributions

G.A., D.J.L., and S.V. designed the study. D.J.L. and S.V. led and oversaw the study. M. Liu was the study’s lead analyst. She was assisted by Y.J., D.J.L., S.V., R.W., D.M.B., and G.D. Bonferroni thresholds were calculated by D.M. Phenotype definitions were developed by L.J.B., M.C.C., D.A.H., J.K., E.J., D.J.L., M.M., M.R.M., S.V., and L.Z. Software development was carried out by Y.J., D.J.L., and X.Z. Conditional analyses were performed by Y.J. and M. Liu. Heritability, genetic correlation, and polygenic scoring analyses were performed by R.W. Multivariate analyses were performed by Y.J., M. Liu, and D.J.L. Bioinformatics analyses were performed and interpreted by F. Chen, J.D., J.J.L., Y. Li, M. Liu, J. A. Stitzel, S.V., and R.W. The LocusZoom website was designed by G.D. Figures were created by M. Liu, R.W., Y. Li, and S.V. M.A.E. and M.C.K. helped with data access. R.W. coordinated authorship and acknowledgement details. M.C.C., S.P.D., E.J., J.K., and J. A. Stitzel provided helpful advice and feedback on study design and the manuscript. All authors contributed to and critically reviewed the manuscript. Y. Li, D.J.L., M. Liu, S.V., and R.W. made major contributions to the writing and editing.

Competing interests

L.J.B. and the spouse of N.L.S. are listed as inventors on issued US patent number 8,080,371, ‘Markers for Addiction’, covering the use of certain SNPs in determining the diagnosis, prognosis, and treatment of addiction. S.P.D. is a scientific advisor to BaseHealth, Inc. G.B., D.F.G., G.W.R., H.S., K.S., and T.E.T. are employees of deCODE Genetics/Amgen, Inc. C.T. and D.H. are employees of 23andMe, Inc.

Corresponding authors

Correspondence to Dajiang J. Liu or Scott Vrieze.

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Figures 1–18 and Supplementary Note

  2. Reporting Summary

  3. Supplementary Tables

    Supplementary Tables 1–31

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/s41588-018-0307-5