Cigarette smoking is a leading cause of preventable mortality worldwide. Nicotine dependence, which reduces the likelihood of quitting smoking, is a heritable trait with firmly established associations with sequence variants in nicotine acetylcholine receptor genes and at other loci. To search for additional loci, we conducted a genome-wide association study (GWAS) meta-analysis of nicotine dependence, totaling 38,602 smokers (28,677 Europeans/European Americans and 9925 African Americans) across 15 studies. In this largest-ever GWAS meta-analysis for nicotine dependence and the largest-ever cross-ancestry GWAS meta-analysis for any smoking phenotype, we reconfirmed the well-known CHRNA5-CHRNA3-CHRNB4 genes and further yielded a novel association in the DNA methyltransferase gene DNMT3B. The intronic DNMT3B rs910083-C allele (frequency=44–77%) was associated with increased risk of nicotine dependence at P=3.7 × 10−8 (odds ratio (OR)=1.06 and 95% confidence interval (CI)=1.04–1.07 for severe vs mild dependence). The association was independently confirmed in the UK Biobank (N=48,931) using heavy vs never smoking as a proxy phenotype (P=3.6 × 10−4, OR=1.05, and 95% CI=1.02–1.08). Rs910083-C is also associated with increased risk of squamous cell lung carcinoma in the International Lung Cancer Consortium (N=60,586, meta-analysis P=0.0095, OR=1.05, and 95% CI=1.01–1.09). Moreover, rs910083-C was implicated as a cis-methylation quantitative trait locus (QTL) variant associated with higher DNMT3B methylation in fetal brain (N=166, P=2.3 × 10−26) and a cis-expression QTL variant associated with higher DNMT3B expression in adult cerebellum from the Genotype-Tissue Expression project (N=103, P=3.0 × 10−6) and the independent Brain eQTL Almanac (N=134, P=0.028). This novel DNMT3B cis-acting QTL variant highlights the importance of genetically influenced regulation in brain on the risks of nicotine dependence, heavy smoking and consequent lung cancer.

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We thank the many study participants. We also thank Michael E. Hall for reviewing the manuscript. This work was supported by the National Institute on Drug Abuse grant numbers R01 DA035825, R01 DA036583 and R01 DA042090. Acknowledgments for the nicotine dependence studies are included in the Supplementary Information. Funding for lung cancer studies was provided by the National Cancer Institute grant number U19 CA148127.

Author information


  1. Behavioral and Urban Health Program, Behavioral Health and Criminal Justice Division, RTI International, Research Triangle Park, NC, USA

    • D B Hancock
    • , C A Markunas
    •  & C Glasheen
  2. Center for Genomics in Public Health and Medicine, RTI International, Research Triangle Park, NC, USA

    • Y Guo
  3. deCODE Genetics/Amgen, Reykjavik, Iceland

    • G W Reginsson
    • , D F Gudbjartsson
    • , T E Thorgeirsson
    •  & K Stefansson
  4. Research Computing Division, RTI International, Research Triangle Park, NC, USA

    • N C Gaddis
  5. Department of Biostatistics and Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    • S M Lutz
  6. Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA

    • R Sherva
    •  & L A Farrer
  7. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland

    • A Loukola
    • , B Qaiser
    •  & J Kaprio
  8. Department of Biological Psychology, Vrije Universiteit, Amsterdam, The Netherlands

    • C C Minica
    • , J Vink
    •  & D I Boomsma
  9. Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, NH, USA

    • Y Han
    •  & C I Amos
  10. Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    • K A Young
    •  & J E Hokanson
  11. Department of Engineering and Natural Sciences, University of Iceland, Reykjavík, Iceland

    • D F Gudbjartsson
  12. Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, USA

    • F Gu
    • , M T Landi
    •  & N E Caporaso
  13. Department of Psychology, West Virginia University, Morgantown, WV, USA

    • D W McNeil
  14. Department of Dental Practice and Rural Health, West Virginia University, Morgantown, WV, USA

    • D W McNeil
  15. Public Health Informatics Program, eHealth, Quality and Analytics Division, RTI International, Research Triangle Park, NC, USA

    • S Olson
  16. Department of Psychiatry, Washington University, St. Louis, MO, USA

    • P A F Madden
    •  & L J Bierut
  17. Department of Neurology, Boston University School of Medicine, Boston, MA, USA

    • L A Farrer
  18. Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA

    • L A Farrer
  19. Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA

    • L A Farrer
  20. Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA

    • L A Farrer
  21. Behavioural Science Institute, Radboud University, Nijmegen, The Netherlands

    • J Vink
  22. Department of Genetics, Washington University, St. Louis, MO, USA

    • N L Saccone
  23. Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA

    • M C Neale
  24. Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA

    • M C Neale
  25. Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    • H R Kranzler
  26. Crescenz VA Medical Center, Philadelphia, PA, USA

    • H R Kranzler
  27. International Agency for Research on Cancer, World Health Organization, Lyon, France

    • J McKay
  28. Lunenfeld-Tanenbaum Research Institute, Sinai Health System, University of Toronto, Toronto, ON, Canada

    • R J Hung
  29. Center for Craniofacial and Dental Genetics, Department of Oral Biology, University of Pittsburgh, Pittsburgh, PA, USA

    • M L Marazita
  30. Center for Tobacco Research and Intervention, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    • T B Baker
  31. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    • J Gelernter
  32. Department of Genetics, Yale University School of Medicine, New Haven, CT, USA

    • J Gelernter
  33. Department of Neuroscience, Yale University School of Medicine, New Haven, CT, USA

    • J Gelernter
  34. VA CT Healthcare Center, Department of Psychiatry, West Haven, CT, USA

    • J Gelernter
  35. Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland

    • J Kaprio
  36. Fellow Program and Behavioral Health and Criminal Justice Division, RTI International, Research Triangle Park, NC, USA

    • E O Johnson


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Conflict of Interest

Dr Bierut and the spouse of Dr Saccone are listed as inventors on U.S. Patent 8,080,371, ‘Markers for Addiction’ covering the use of certain SNPs in determining the diagnosis, prognosis and treatment of addiction. Authors listed with the affiliation deCODE Genetics/AMGEN are employees of deCODE genetics/AMGEN. Although unrelated to this research, Dr Kranzler has been a consultant or advisory board member for Lundbeck and Indivior and is a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which was supported in the last 3 years by AbbVie, Alkermes, Ethypharm, Indivior, Lilly, Lundbeck, Otsuka, Pfizer, Arbor and Amygdala Neurosciences. Dr Kaprio has consulted for Pfizer in 2012–2014 on nicotine dependence. The remaining authors declare no conflict of interest.

Corresponding author

Correspondence to D B Hancock.

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