Abstract

. 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.

Authors	Liu, Mengzhen; Jiang, Yu; Wedow, Robbee; Li, Yue; Brazel, David M; Chen, Fang; Datta, Gargi; Davila-Velderrain, Jose; McGuire, Daniel; Tian, Chao; Zhan, Xiaowei; , ; , ; Choquet, Hélène; Docherty, Anna R; Faul, Jessica D; Foerster, Johanna R; Fritsche, Lars G; Gabrielsen, Maiken Elvestad; Gordon, Scott D; Haessler, Jeffrey; Hottenga, Jouke-Jan; Huang, Hongyan; Jang, Seon-Kyeong; Jansen, Philip R; Ling, Yueh; Mägi, Reedik; Matoba, Nana; McMahon, George; Mulas, Antonella; Orrù, Valeria; Palviainen, Teemu; Pandit, Anita; Reginsson, Gunnar W; Skogholt, Anne Heidi; Smith, Jennifer A; Taylor, Amy E; Turman, Constance; Willemsen, Gonneke; Young, Hannah; Young, Kendra A; Zajac, Gregory J M; Zhao, Wei; Zhou, Wei; Bjornsdottir, Gyda; Boardman, Jason D; Boehnke, Michael; Boomsma, Dorret I; Chen, Chu; Cucca, Francesco; Davies, Gareth E; Eaton, Charles B; Ehringer, Marissa A; Esko, Tõnu; Fiorillo, Edoardo; Gillespie, Nathan A; Gudbjartsson, Daniel F; Haller, Toomas; Harris, Kathleen Mullan; Heath, Andrew C; Hewitt, John K; Hickie, Ian B; Hokanson, John E; Hopfer, Christian J; Hunter, David J; Iacono, William G; Johnson, Eric O; Kamatani, Yoichiro; Kardia, Sharon L R; Keller, Matthew C; Kellis, Manolis; Kooperberg, Charles; Kraft, Peter; Krauter, Kenneth S; Laakso, Markku; Lind, Penelope A; Loukola, Anu; Lutz, Sharon M; Madden, Pamela A F; Martin, Nicholas G; McGue, Matt; McQueen, Matthew B; Medland, Sarah E; Metspalu, Andres; Mohlke, Karen L; Nielsen, Jonas B; Okada, Yukinori; Peters, Ulrike; Polderman, Tinca J C; Posthuma, Danielle; Reiner, Alexander P; Rice, John P; Rimm, Eric; Rose, Richard J; Runarsdottir, Valgerdur; Stallings, Michael C; Stancáková, Alena; Stefansson, Hreinn; Thai, Khanh K; Tindle, Hilary A; Tyrfingsson, Thorarinn; Wall, Tamara L; Weir, David R; Weisner, Constance; Whitfield, John B; Winsvold, Bendik Slagsvold; Yin, Jie; Zuccolo, Luisa; Bierut, Laura J; Hveem, Kristian; Lee, James J; Munafò, Marcus R; Saccone, Nancy L; Willer, Cristen J; Cornelis, Marilyn C; David, Sean P; Hinds, David A; Jorgenson, Eric; Kaprio, Jaakko; Stitzel, Jerry A; Stefansson, Kari; Thorgeirsson, Thorgeir E; Abecasis, Gonçalo; Liu, Dajiang J; Vrieze, Scott
Journal	NATURE GENETICS
Pages	237-244
Volume	51
Date	1/01/2019
Grant ID	R21 DA040177
Funding Body	NIDA NIH HHS
URL	http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1038/s41588-018-0307-5
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