. 2025 Aug 20:55:e234.

doi: 10.1017/S0033291725100883.

Multi-ancestral genome-wide association study of clinically defined nicotine dependence reveals strong genetic correlations with other substance use disorders and health-related traits

Emma C Johnson¹, Dongbing Lai², Jared V Balbona¹, Alex P Miller³, Alexander S Hatoum¹, Joseph D Deak^{4

5}, Mariela Jennings⁶, David A A Baranger⁷, Marco Galimberti^{5

8}, Kittipong Sanichwankul⁹, Thorgeir Thorgeirsson¹⁰, Sarah M C Colbert¹¹, Keyrun Adhikari^{5

8}, Anna R Docherty¹², Louisa Degenhardt¹³, Tobias Edwards¹⁴, Louis Fox¹, Alexandros Giannelis¹⁴, Paul W Jeffries¹, Tellervo Korhonen¹⁵, Claire L Morrison^{16

17}, Yaira Z Nunez^{5

8}, Teemu Palviainen¹⁵, Mei-Hsin Su¹⁸, Pamela N Romero Villela^{16

17}, Leah Wetherill², Emily A Willoughby¹⁴, Stephanie M Zellers¹⁵, Laura J Bierut¹, Jadwiga Buchwald¹⁵, William E Copeland¹⁹, Robin P Corley¹⁷, Naomi P Friedman^{16

17}, Tatiana M Foroud², Nathan A Gillespie^{18

20}, Ian R Gizer²¹, Andrew C Heath¹, Ian B Hickie²², Jaakko Kaprio¹⁵, Matthew C Keller^{16

17}, James J Lee¹⁴, Penelope Lind^{20

23

24}, Pamela A Madden¹, Hermine H M Maes^{18

25

26}, Nicholas G Martin²⁰, Matt McGue¹⁴, Sarah E Medland^{20

27

28}, Elliot C Nelson¹, John Pearson^{20

29}, Bernice Porjesz³⁰, Michael C Stallings^{16

17}, Scott Vrieze¹⁴, Kirk C Wilhelmson^{31

32

33}, Henry R Kranzler^{34

35}, Raymond K Walters^{36

37

38}, Renato Polimanti^{4

39

40}, Robert Malison^{4

41}, Hang Zhou^{4

5}, Kari Stefansson^{10

42}, Sandra Sanchez-Roige^{6

43

44}, Marc Potenza^{4

40

45

46

47}, Apiwat Mutirangura⁴⁸, Vorasuk Shotelersuk^{49

50}, Rasmon Kalayasiri^{51

52}, Howard J Edenberg^{2

53}, Joel Gelernter^{4

5

8

54}, Arpana Agrawal¹

Affiliations

¹ Department of Psychiatry, Washington University School of Medicine in St Louis, Saint Louis, MO, USA.
² Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
³ Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA.
⁴ Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
⁵ Department of Psychiatry, Veterans Affairs Connecticut Healthcare Center, West Haven, CT, USA.
⁶ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
⁷ Department of Psychological and Brain Sciences, Washington University in St Louis, Saint Louis, MO, USA.
⁸ Department of Human Genetics, Yale University School of Medicine, New Haven, CT, USA.
⁹ Suanprung Psychiatric Hospital, Chiang Mai, Thailand.
¹⁰ deCODE Genetics/Amgen, Sturlugata 8, IS-101, Reykjavik, Iceland.
¹¹ Department of Genetics and Genomic Sciences, https://ror.org/04a9tmd77Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹² Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT, USA.
¹³ National Drug and Alcohol Research Centre, https://ror.org/03r8z3t63University of New South Wales, Sydney, Australia.
¹⁴ Department of Psychology, https://ror.org/017zqws13University of Minnesota Twin Cities, Minneapolis, MN, USA.
¹⁵ Institute for Molecular Medicine Finland, https://ror.org/040af2s02University of Helsinki, Helsinki, Finland.
¹⁶ Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
¹⁷ Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA.
¹⁸ Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.
¹⁹ Department of Psychiatry, College of Medicine, University of Vermont, Burlington, VT, USA.
²⁰ QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
²¹ Department of Psychological Sciences, https://ror.org/02ymw8z06University of Missouri, Columbia, MO, USA.
²² Brain and Mind Institute, https://ror.org/0384j8v12University of Sydney, Sydney, NSW, Australia.
²³ School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
²⁴ School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia.
²⁵ Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA.
²⁶ Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA.
²⁷ School of Psychology and Counselling, Queensland University of Technology, Brisbane, Australia.
²⁸ School of Psychology, University of Queensland, Brisbane, Australia.
²⁹ Faculty of Medicine, The University of Queensland, Brisbane, Australia.
³⁰ Henri Begleiter Neurodynamics Laboratory, Department of Psychiatry, SUNY Downstate Health Science University, Brooklyn, NY, USA.
³¹ Department of Neurology and Genetics and the Bowles Center of Alcohol Studies, University of North Carolina, Chapel Hill, NC, USA.
³² Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, USA.
³³ Renaissance Computing Institute, Chapel Hill, NC, USA.
³⁴ Mental Illness Research, Education and Clinical Center, Crescenz VAMC, Philadelphia, PA, USA.
³⁵ Center for Studies of Addiction, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
³⁶ Analytic and Translational Genetics Unit, https://ror.org/002pd6e78Massachusetts General Hospital, Boston, MA, USA.
³⁷ Harvard Medical School, Boston, MA, USA.
³⁸ Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
³⁹ Cooperative Studies Program Clinical Epidemiology Research Center (CSP-CERC), VA Connecticut Healthcare System, West Haven, CT, USA.
⁴⁰ Wu Tsai Institute, Yale University, New Haven, CT, USA.
⁴¹ The Clinical Neuroscience Research Unit, Connecticut Mental Health Center, New Haven, CT, USA.
⁴² Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
⁴³ Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA.
⁴⁴ Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁴⁵ Child Study Center, Yale School of Medicine, New Haven, CT, USA.
⁴⁶ Connecticut Council on Problem Gambling, Wethersfield, CT, USA.
⁴⁷ Connecticut Mental Health Center, New Haven, CT, USA.
⁴⁸ Department of Anatomy, Faculty of Medicine, https://ror.org/028wp3y58Chulalongkorn University, King Chulalongkorn Memorial Hospital, Bangkok, Thailand.
⁴⁹ Center of Excellence for Medical Genomics, Department of Pediatrics, Faculty of Medicine, https://ror.org/028wp3y58Chulalongkorn University, Bangkok, Thailand.
⁵⁰ Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, the Thai Red Cross Society, Bangkok, Thailand.
⁵¹ Department of Psychiatry, Epidemiology of Psychiatric Disorders and Mental Health Research Unit, Faculty of Medicine, https://ror.org/028wp3y58Chulalongkorn University, Bangkok, Thailand.
⁵² Department of Psychiatry, King Chulalongkorn Memorial Hospital, Bangkok, Thailand.
⁵³ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
⁵⁴ Department of Neuroscience, Yale University School of Medicine, New Haven, CT, USA.

PMID: 40831304
PMCID: PMC12360691
DOI: 10.1017/S0033291725100883

Multi-ancestral genome-wide association study of clinically defined nicotine dependence reveals strong genetic correlations with other substance use disorders and health-related traits

Emma C Johnson et al. Psychol Med. 2025.

. 2025 Aug 20:55:e234.

doi: 10.1017/S0033291725100883.

Authors

Affiliations

¹ Department of Psychiatry, Washington University School of Medicine in St Louis, Saint Louis, MO, USA.
² Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
³ Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA.
⁴ Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
⁵ Department of Psychiatry, Veterans Affairs Connecticut Healthcare Center, West Haven, CT, USA.
⁶ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
⁷ Department of Psychological and Brain Sciences, Washington University in St Louis, Saint Louis, MO, USA.
⁸ Department of Human Genetics, Yale University School of Medicine, New Haven, CT, USA.
⁹ Suanprung Psychiatric Hospital, Chiang Mai, Thailand.
¹⁰ deCODE Genetics/Amgen, Sturlugata 8, IS-101, Reykjavik, Iceland.
¹¹ Department of Genetics and Genomic Sciences, https://ror.org/04a9tmd77Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹² Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT, USA.
¹³ National Drug and Alcohol Research Centre, https://ror.org/03r8z3t63University of New South Wales, Sydney, Australia.
¹⁴ Department of Psychology, https://ror.org/017zqws13University of Minnesota Twin Cities, Minneapolis, MN, USA.
¹⁵ Institute for Molecular Medicine Finland, https://ror.org/040af2s02University of Helsinki, Helsinki, Finland.
¹⁶ Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
¹⁷ Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA.
¹⁸ Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.
¹⁹ Department of Psychiatry, College of Medicine, University of Vermont, Burlington, VT, USA.
²⁰ QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
²¹ Department of Psychological Sciences, https://ror.org/02ymw8z06University of Missouri, Columbia, MO, USA.
²² Brain and Mind Institute, https://ror.org/0384j8v12University of Sydney, Sydney, NSW, Australia.
²³ School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
²⁴ School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia.
²⁵ Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA.
²⁶ Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA.
²⁷ School of Psychology and Counselling, Queensland University of Technology, Brisbane, Australia.
²⁸ School of Psychology, University of Queensland, Brisbane, Australia.
²⁹ Faculty of Medicine, The University of Queensland, Brisbane, Australia.
³⁰ Henri Begleiter Neurodynamics Laboratory, Department of Psychiatry, SUNY Downstate Health Science University, Brooklyn, NY, USA.
³¹ Department of Neurology and Genetics and the Bowles Center of Alcohol Studies, University of North Carolina, Chapel Hill, NC, USA.
³² Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, USA.
³³ Renaissance Computing Institute, Chapel Hill, NC, USA.
³⁴ Mental Illness Research, Education and Clinical Center, Crescenz VAMC, Philadelphia, PA, USA.
³⁵ Center for Studies of Addiction, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
³⁶ Analytic and Translational Genetics Unit, https://ror.org/002pd6e78Massachusetts General Hospital, Boston, MA, USA.
³⁷ Harvard Medical School, Boston, MA, USA.
³⁸ Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
³⁹ Cooperative Studies Program Clinical Epidemiology Research Center (CSP-CERC), VA Connecticut Healthcare System, West Haven, CT, USA.
⁴⁰ Wu Tsai Institute, Yale University, New Haven, CT, USA.
⁴¹ The Clinical Neuroscience Research Unit, Connecticut Mental Health Center, New Haven, CT, USA.
⁴² Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
⁴³ Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA.
⁴⁴ Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁴⁵ Child Study Center, Yale School of Medicine, New Haven, CT, USA.
⁴⁶ Connecticut Council on Problem Gambling, Wethersfield, CT, USA.
⁴⁷ Connecticut Mental Health Center, New Haven, CT, USA.
⁴⁸ Department of Anatomy, Faculty of Medicine, https://ror.org/028wp3y58Chulalongkorn University, King Chulalongkorn Memorial Hospital, Bangkok, Thailand.
⁴⁹ Center of Excellence for Medical Genomics, Department of Pediatrics, Faculty of Medicine, https://ror.org/028wp3y58Chulalongkorn University, Bangkok, Thailand.
⁵⁰ Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, the Thai Red Cross Society, Bangkok, Thailand.
⁵¹ Department of Psychiatry, Epidemiology of Psychiatric Disorders and Mental Health Research Unit, Faculty of Medicine, https://ror.org/028wp3y58Chulalongkorn University, Bangkok, Thailand.
⁵² Department of Psychiatry, King Chulalongkorn Memorial Hospital, Bangkok, Thailand.
⁵³ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
⁵⁴ Department of Neuroscience, Yale University School of Medicine, New Haven, CT, USA.

PMID: 40831304
PMCID: PMC12360691
DOI: 10.1017/S0033291725100883

Abstract

Background: Genetic research on nicotine dependence has utilized multiple assessments that are in weak agreement.

Methods: We conducted a genome-wide association study (GWAS) of nicotine dependence defined using the Diagnostic and Statistical Manual of Mental Disorders (DSM-NicDep) in 61,861 individuals (47,884 of European ancestry [EUR], 10,231 of African ancestry, and 3,746 of East Asian ancestry) and compared the results to other nicotine-related phenotypes.

Results: We replicated the well-known association at the CHRNA5 locus (lead single-nucleotide polymorphism [SNP]: rs147144681, p = 1.27E-11 in EUR; lead SNP = rs2036527, p = 6.49e-13 in cross-ancestry analysis). DSM-NicDep showed strong positive genetic correlations with cannabis use disorder, opioid use disorder, problematic alcohol use, lung cancer, material deprivation, and several psychiatric disorders, and negative correlations with respiratory function and educational attainment. A polygenic score of DSM-NicDep predicted DSM-5 tobacco use disorder criterion count and all 11 individual diagnostic criteria in the independent National Epidemiologic Survey on Alcohol and Related Conditions-III sample. In genomic structural equation models, DSM-NicDep loaded more strongly on a previously identified factor of general addiction liability than a "problematic tobacco use" factor (a combination of cigarettes per day and nicotine dependence defined by the Fagerström Test for Nicotine Dependence). Finally, DSM-NicDep showed a strong genetic correlation with a GWAS of tobacco use disorder as defined in electronic health records (EHRs).

Conclusions: Our results suggest that combining the wide availability of diagnostic EHR data with nuanced criterion-level analyses of DSM tobacco use disorder may produce new insights into the genetics of this disorder.

Keywords: addiction; genome-wide association study; nicotine dependence; polygenic risk; psychiatric disorders.

PubMed Disclaimer

Conflict of interest statement

The authors declare none.

Figures

**Figure 1.**
Comparing genetic correlations (r _g) for DSM-NicDep, FTND, ICD-TUD, and CPD with other traits in European ancestry data. Traits include other substance use disorders (CanUD, cannabis use disorder [Levey et al., 2023]; OUD, opioid use disorder [Deak et al., 2022]; PAU, problematic alcohol use [Zhou et al., 2023]; ICD-TUD, ICD-based tobacco use disorder [Toikumo et al., 2024]), substance use behaviors (CanUse, cannabis ever-use [Pasman et al., 2018]; DPW, drinks per week [Saunders et al., 2022]; SmkInit, smoking initiation [Saunders et al., 2022]; SmkCessation, smoking cessation [Saunders et al., 2022]), psychiatric disorders and other mental health phenotypes (ADHD, attention deficit hyperactivity disorder [Demontis et al., 2023]; PTSD, post-traumatic stress disorder [Nievergelt et al., 2019]), biomarkers (Cot + HC, cotinine +3-hydroxycotinine [Buchwald et al., 2021]), lung health-related traits (FEV1, forced expiratory volume in 1 s), risk tolerance (Linnér et al., 2019), socioeconomic status-related traits (Edu attainment, educational attainment [Lee et al., 2018]; TDI, Townsend Deprivation Index]), executive function (EF [Hatoum, Morrison, et al., 2023]), and anthropometric measures (BMI, body mass index [Yengo et al., 2018]; height [Yengo et al., 2022]). * indicates r _gs that significantly differ between DSM-NicDep and FTND at 𝛼 = 0.002 (Bonferroni correction for 24 comparisons).

**Figure 2.**
A modified Addiction-Risk-Factor model. This model is patterned upon the common factor model in Figure 1A of Hatoum et al., , but updated with new, larger versions of the OUD (Deak et al., 2022), PAU (Zhou et al., 2023), and CanUD GWAS (Levey et al., 2023) and using three different phenotypes for tobacco GWAS. (a) DSM-NicDep. (b) PTU (Hatoum et al., 2022) GWAS. (c) ICD-TUD (Toikumo et al., 2024). *Significant loadings at p < 0.05. Addiction-rf, the Addiction-Risk-Factor; CanUD, cannabis use disorder; DSM-NicDep, nicotine dependence; ICD-TUD, ICD-based tobacco use disorder; OUD, opioid use disorder; PAU, problematic alcohol use.

**Figure 3.**
Polygenic scores (PGSs) for DSM-NicDep (a), FTND (b), and DSM-NicDep, FTND, ICD-TUD, and CPD (c) predict individual DSM-5 nicotine use disorder and FTND criteria and total criterion or item counts, respectively, in the European ancestry subset of the NESARC-III sample. Filled circles represent estimates that were significant after FDR correction, while open circles represent estimates that were not significant after FDR correction. Hazardous = Recurrent use in physically hazardous situations; Fail = Recurrent use resulting in failure to fulfill major role obligations at work, school, or home; Tolerance = Marked need for increased amount to get the same effect or diminished effect of the same amount; TimeSpent = Great deal of time spent in activities necessary to obtain or use; GiveUp = Important recreational, social, or occupational activities given up or reduced; Problems = Use despite knowledge of persistent/recurrent physical/psychological problems; Larger = Taken over larger amounts/longer periods than intended; Withdrawal = Withdrawal syndrome or use to relieve/avoid syndrome; Cutdown = Persistent desire or unsuccessful attempts to cut down or control use; Crave = Craving or strong urge or desire to use; Social = Persistent use despite recurring social/interpersonal problems caused or exacerbated by use; FTND1_within30min = How soon after you wake up do you smoke your first cigarette?; FTND2_prohibited = Do you find it difficult to refrain from smoking in places where it is forbidden?; FTND3_morning = Which cigarette would you hate most to give up?; FTND5_waking = Do you smoke more frequently during the first hours after waking than during the rest of the day?

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Update of

Multi-ancestral genome-wide association study of clinically defined nicotine dependence reveals strong genetic correlations with other substance use disorders and health-related traits.
Johnson EC, Lai D, Miller AP, Hatoum AS, Deak JD, Balbona JV, Baranger DA, Galimberti M, Sanichwankul K, Thorgeirsson T, Colbert SM, Sanchez-Roige S, Adhikari K, Docherty A, Degenhardt L, Edwards T, Fox L, Giannelis A, Jeffries P, Korhonen T, Morrison C, Nunez YZ, Palviainen T, Su MH, Villela PNR, Wetherill L, Willoughby EA, Zellers S, Bierut L, Buchwald J, Copeland W, Corley R, Friedman NP, Foroud TM, Gillespie NA, Gizer IR, Heath AC, Hickie IB, Kaprio JA, Keller MC, Lee JL, Lind PA, Madden PA, Maes HH, Martin NG, McGue M, Medland SE, Nelson EC, Pearson JV, Porjesz B, Stallings M, Vrieze S, Wilhelmsen KC, Walters RK, Polimanti R, Malison RT, Zhou H, Stefansson K, Potenza MN, Mutirangura A, Shotelersuk V, Kalayasiri R, Edenberg HJ, Gelernter J, Agrawal A. Johnson EC, et al. medRxiv [Preprint]. 2025 Feb 3:2025.01.29.25320962. doi: 10.1101/2025.01.29.25320962. medRxiv. 2025. Update in: Psychol Med. 2025 Aug 20;55:e234. doi: 10.1017/S0033291725100883. PMID: 39974067 Free PMC article. Updated. Preprint.

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Multi-ancestral genome-wide association study of clinically defined nicotine dependence reveals strong genetic correlations with other substance use disorders and health-related traits

Affiliations

Multi-ancestral genome-wide association study of clinically defined nicotine dependence reveals strong genetic correlations with other substance use disorders and health-related traits

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