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 efforts6–11. 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.
Bibliographical noteFunding Information:
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.
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use
Liu, M., Jiang, Y., Wedow, R., Li, Y., Brazel, D. M., Chen, F., Datta, G., Davila-Velderrain, J., McGuire, D., Tian, C., Zhan, X., Choquet, H., Docherty, A. R., Faul, J. D., Foerster, J. R., Fritsche, L. G., Gabrielsen, M. E., Gordon, S. D., Haessler, J., Hottenga, J. J., Huang, H., Jang, S., Jansen, P. R., Ling, Y., Reedik, M., Matoba, N., McMahon, G., Mulas, A., Orrú, V., Palviainen, T., Pandit, A., Reginsson, G. W., Skogholt, A. H., Smith, J. A., Taylor, A. E., Turman, C., Willemsen, G., Young, H., Young, K. A., Zajac, G. J. M., Zhao, W., Bjornsdottir, G., Boardman, J., Boehnke, M., Boomsma, D. I., Chen, C., Cucca, F., Davies, G. E., Eaton, C. B., Ehringer, M., Esko, T., Fiorillo, E., Gillespie, N. A., Gudbjartsson, D. F., Haller, T., Harris, K. M., Heath, A. C., Hewitt, J. K., Hickie, I. B., Hokanson, J. E., Hunter, D. J., Iacono, W. G., Johnson, E. O., Kamatani, Y., Kardia, S. L. R., Keller, M. C., Kellis, M., Kooperberg, C., Kraft, P., Krauter, K., Laakso, M., Lind, P. A., Loukola, A., Lutz, S. M., Madden, P. A. F., Martin, N. G., Mc Gue, M., McQueen, M. B., Medland, S. E., Metspalu, A., Mohlke, K. L., Nielsen, J. B., Okada, Y., Peters, U., Polderman, T. J. C., Posthuma, D., Reiner, A. P., Rice, J. P., Rimm, E., Rose, R. J., Runarsdottir, V., Stallings, M. C., Stančáková, A., Stefansson, H., Thai, K. K., Tindle, H., Tyrfingsson, T., Wall, T. L., Weir, D. R., Weisner, C., Whitfield, J. B., Winsvold, B. S., Yin, J., Zuccolo, L., Bierut, L. J., Hveem, K., Lee, J. J., Munafò, M. R., Saccone, N. L., Willer, C. J., Cornelis, M. C., David, S. P., Hinds, D. A., Jorgenson, E., Kaprio, J., Stitzel, J. A., Stefansson, K., Thorgeirsson, T. E., Abecasis, G. R., Liu, D. J. & Vrieze, S. I., Data Repository for the University of Minnesota, 2019