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

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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Fig. 1: Genetic correlations between substance use phenotypes and phenotypes from other large GWAS.
Fig. 2: Pleiotropy.
Fig. 3: Heritability and polygenic prediction.
Fig. 4: Correlations among exemplary DEPICT gene sets.

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.

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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

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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.

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Correspondence to Dajiang J. Liu or Scott Vrieze.

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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.

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Liu, M., Jiang, Y., Wedow, R. et al. Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use. Nat Genet 51, 237–244 (2019). https://doi.org/10.1038/s41588-018-0307-5

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