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Genome-wide association meta-analysis of nicotine metabolism and cigarette consumption measures in smokers of European descent

Molecular Psychiatry volume 26, pages 2212–2223 (2021)Cite this article

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Abstract

Smoking behaviors, including amount smoked, smoking cessation, and tobacco-related diseases, are altered by the rate of nicotine clearance. Nicotine clearance can be estimated using the nicotine metabolite ratio (NMR) (ratio of 3′hydroxycotinine/cotinine), but only in current smokers. Advancing the genomics of this highly heritable biomarker of CYP2A6, the main metabolic enzyme for nicotine, will also enable investigation of never and former smokers. We performed the largest genome-wide association study (GWAS) to date of the NMR in European ancestry current smokers (n = 5185), found 1255 genome-wide significant variants, and replicated the chromosome 19 locus. Fine-mapping of chromosome 19 revealed 13 putatively causal variants, with nine of these being highly putatively causal and mapping to CYP2A6, MAP3K10, ADCK4, and CYP2B6. We also identified a putatively causal variant on chromosome 4 mapping to TMPRSS11E and demonstrated an association between TMPRSS11E variation and a UGT2B17 activity phenotype. Together the 14 putatively causal SNPs explained ~38% of NMR variation, a substantial increase from the ~20 to 30% previously explained. Our additional GWASs of nicotine intake biomarkers showed that cotinine and smoking intensity (cotinine/cigarettes per day (CPD)) shared chromosome 19 and chromosome 4 loci with the NMR, and that cotinine and a more accurate biomarker, cotinine + 3′hydroxycotinine, shared a chromosome 15 locus near CHRNA5 with CPD and Pack-Years (i.e., cumulative exposure). Understanding the genetic factors influencing smoking-related traits facilitates epidemiological studies of smoking and disease, as well as assists in optimizing smoking cessation support, which in turn will reduce the enormous personal and societal costs associated with smoking.

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Fig. 1: Chromosomal location and annotation for all genome-wide significant SNPs for all six phenotypes.
Fig. 2: Associations in the meta-GWAS of the Nicotine Metabolite Ratio (NMR) were found in chromosome 4 and chromosome 19.
Fig. 3: Number and overlap of genome-wide significant SNP associations with the six phenotypes.

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Acknowledgements

This work is supported by the NIH (PGRN grant DA020830 and CA197461), CIHR (FDN-154294 and PJY-159710), a Canada Research Chair, Wellcome Trust Sanger Institute, Broad Institute, European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007, grant agreement number 201413, NIAAA (AA-12502/AA-00145/AA-09203/AA15416/K02AA018755), the Academy of Finland (100499/205585/118555/141054/264146/308248/312073/288509/312076/285380/312062/286284/134309/126925/121584/124282/129378/117787/41071/265240/263278), Finnish Foundation for Cardiovascular Research, Sigrid Juselius Foundation, University of Helsinki HiLIFE Fellow grant, Social Insurance Institution of Finland, Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals (grant X51001), Juho Vainio Foundation, Paavo Nurmi Foundation, Finnish Cultural Foundation, Tampere Tuberculosis Foundation, Emil Aaltonen Foundation, Yrjö Jahnsson Foundation, Signe and Ane Gyllenberg Foundation, Diabetes Research Foundation of Finnish Diabetes Association, EU Horizon 2020 (755320), European Research Council (742927), Tampere University Hospital Supporting Foundation, Doctoral Program in Population Health (University of Helsinki), Finnish Research Foundation of the Pulmonary Diseases, Biomedicum Helsinki Foundation, and the Cancer Foundation Finland. We thank Dr Aino Kankaanpää, Maria Novalen, Leanne McNeill, and Tabatha Goncalves for laboratory work.

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Author notes

  1. These authors contributed equally: Jadwiga Buchwald, Meghan J. Chenoweth

  2. These authors jointly supervised this work: Anu Loukola, Rachel F. Tyndale

Authors and Affiliations

  1. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland

    Jadwiga Buchwald, Teemu Palviainen, Christian Benner, Tellervo Korhonen, Samuli Ripatti, Matti Pirinen, Jaakko Kaprio & Anu Loukola

  2. Campbell Family Mental Health Research Institute, CAMH, and Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, Canada

    Meghan J. Chenoweth & Rachel F. Tyndale

  3. QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia

    Gu Zhu, Scott Gordon & Nicholas G. Martin

  4. Department of Public Health, University of Helsinki, Helsinki, Finland

    Samuli Ripatti, Matti Pirinen & Jaakko Kaprio

  5. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Samuli Ripatti

  6. Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA

    Pamela A. F. Madden

  7. Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center, Tampere, Finland

    Terho Lehtimäki

  8. Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland

    Terho Lehtimäki

  9. Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland

    Olli T. Raitakari

  10. Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland

    Olli T. Raitakari

  11. Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland

    Olli T. Raitakari

  12. Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki, Finland

    Veikko Salomaa

  13. Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA

    Richard J. Rose

  14. Division of Addictions, Centre for Addiction and Mental Health, Toronto, ON, Canada

    Tony P. George & Rachel F. Tyndale

  15. Division of Brain and Therapeutics, Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    Tony P. George

  16. USC Norris Comprehensive Cancer Center at Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Caryn Lerman

  17. Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland

    Matti Pirinen

  18. Department of Pathology, Medicum, University of Helsinki, Helsinki, Finland

    Anu Loukola

  19. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    Rachel F. Tyndale

Authors
  1. Jadwiga Buchwald
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  2. Meghan J. Chenoweth
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  3. Teemu Palviainen
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  4. Gu Zhu
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Contributions

JB, MJC, TP, MP, NGM, JK, AL, and RFT contributed to the project design and data analysis plan. TK, SR, PAFM, TL, OR, VS, RJR, TPG, CL, NGM, JK, and RFT contributed to the collection and/or analysis of original cohort data. JB, MJC, TP, GZ, CB, and SG performed data analysis. JB, MJC, MP, JK, AL, and RFT interpreted the data. JB, MJC, MP, NGM, JK, AL, and RFT wrote the paper. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Rachel F. Tyndale.

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Conflict of interest

TK has consulted for Pfizer Finland. VS attended a conference trip sponsored by Novo Nordisk, received an advisory board meeting honorarium, and collaborates with Bayer ltd. RFT has consulted for Quinn Emmanual and Ethismos.

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Buchwald, J., Chenoweth, M.J., Palviainen, T. et al. Genome-wide association meta-analysis of nicotine metabolism and cigarette consumption measures in smokers of European descent. Mol Psychiatry 26, 2212–2223 (2021). https://doi.org/10.1038/s41380-020-0702-z

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