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Nat Genet. 2019 Feb;51(2):237-244. doi: 10.1038/s41588-018-0307-5. Epub 2019 Jan 14.

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

Liu M1, Jiang Y2,3, Wedow R4,5,6, Li Y7,8, Brazel DM4,9,10, Chen F2,3, Datta G1, Davila-Velderrain J7,8, McGuire D2,3, Tian C11, Zhan X12,13; 23andMe Research Team; HUNT All-In Psychiatry, Choquet H14, Docherty AR15,16, Faul JD17, Foerster JR18, Fritsche LG18, Gabrielsen ME19, Gordon SD20, Haessler J21, Hottenga JJ22, Huang H23,24, Jang SK1, Jansen PR25,26, Ling Y2,9, Mägi R27, Matoba N28, McMahon G29, Mulas A30, Orrù V30, Palviainen T31, Pandit A18, Reginsson GW32, Skogholt AH19, Smith JA17,33, Taylor AE29, Turman C23,24, Willemsen G22, Young H1, Young KA34, Zajac GJM18, Zhao W33, Zhou W35, Bjornsdottir G32, Boardman JD4,5,6, Boehnke M18, Boomsma DI22, Chen C21, Cucca F30, Davies GE36, Eaton CB37, Ehringer MA4,38, Esko T8,27, Fiorillo E30, Gillespie NA15,20, Gudbjartsson DF32,39, Haller T27, Harris KM40,41, Heath AC42, Hewitt JK4,43, Hickie IB44, Hokanson JE34, Hopfer CJ4,45, Hunter DJ23,24,46, Iacono WG1, Johnson EO47, Kamatani Y28, Kardia SLR33, Keller MC4,43, Kellis M7,8, Kooperberg C21, Kraft P23,24,48, Krauter KS4,9, Laakso M49,50, Lind PA51, Loukola A31, Lutz SM52, Madden PAF42, Martin NG20, McGue M1, McQueen MB4,38, Medland SE51, Metspalu A27, Mohlke KL53, Nielsen JB54, Okada Y28,55, Peters U21,56, Polderman TJC25, Posthuma D25,57, Reiner AP21,56, Rice JP58, Rimm E24,59, Rose RJ60, Runarsdottir V61, Stallings MC4,43, Stančáková A49, Stefansson H32, Thai KK14, Tindle HA62, Tyrfingsson T61, Wall TL63, Weir DR17, Weisner C14, Whitfield JB20, Winsvold BS64, Yin J14, Zuccolo L29,65, Bierut LJ58, Hveem K19,66,67, Lee JJ1, Munafò MR65,68, Saccone NL69, Willer CJ35,54,70, Cornelis MC71, David SP72, Hinds DA11, Jorgenson E14, Kaprio J31,73, Stitzel JA4,38, Stefansson K32,74, Thorgeirsson TE32, Abecasis G18, Liu DJ75,76, Vrieze S77.

Author information

1
Department of Psychology, University of Minnesota Twin Cities, Minneapolis, MN, USA.
2
Department of Public Health Sciences, College of Medicine, Pennsylvania State University, Hershey, PA, USA.
3
Institute of Personalized Medicine, College of Medicine, Pennsylvania State University, Hershey, PA, USA.
4
Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA.
5
Department of Sociology, University of Colorado Boulder, Boulder, CO, USA.
6
Institute of Behavioral Science, University of Colorado Boulder, Boulder, CO, USA.
7
Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA, USA.
8
The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
9
Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, CO, USA.
10
Interdisciplinary Quantitative Biology Graduate Group, University of Colorado Boulder, Boulder, CO, USA.
11
23andMe, Inc., Mountain View, CA, USA.
12
Quantitative Biomedical Research Center, Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA.
13
Center for the Genetics of Host Defense, Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA.
14
Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
15
Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.
16
Department of Psychiatry and Human Genetics, University of Utah, Salt Lake City, UT, USA.
17
Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
18
Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
19
K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway.
20
Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
21
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
22
Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
23
Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
24
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
25
Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
26
Department of Child and Adolescent Psychiatry, Erasmus MC Rotterdam, Rotterdam, the Netherlands.
27
Estonian Genome Center, University of Tartu, Tartu, Estonia.
28
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama City, Japan.
29
Department of Population Health Science, Bristol Medical School, Oakfield Grove, Bristol, UK.
30
Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato, Italy.
31
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
32
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
33
Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA.
34
Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
35
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
36
Avera Institute for Human Genetics, Sioux Falls, SD, USA.
37
Department of Family Medicine and Community Health, Alpert Medical School, Brown University, Providence, RI, USA.
38
Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA.
39
School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
40
Department of Sociology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
41
Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
42
Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA.
43
Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
44
Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia.
45
Department of Psychiatry, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
46
Nuffield Department of Population Health, University of Oxford, Oxford, UK.
47
Fellows Program, RTI International, Research Triangle Park, NC, USA.
48
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
49
Department of Internal Medicine, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
50
Department of Medicine, Kuopio University Hospital, Kuopio, Finland.
51
Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
52
Department of Biostatistics and Bioinformatics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
53
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
54
Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, USA.
55
Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
56
Department of Epidemiology, University of Washington, Seattle, WA, USA.
57
Department of Clinical Genetics, VU Medical Centre Amsterdam, Amsterdam, the Netherlands.
58
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
59
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
60
Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA.
61
SAA-National Center of Addiction Medicine, Vogur Hospital, Reykjavik, Iceland.
62
Department of Medicine, Vanderbilt University, Nashville, TN, USA.
63
Department of Psychiatry, University of California, San Diego, San Diego, CA, USA.
64
FORMI and Department of Neurology, Oslo University Hospital, Oslo, Norway.
65
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
66
HUNT Research Centre, Department of Public Health and Nursing, Norwegian University of Science and Technology, Levanger, Norway.
67
Department of Medicine, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway.
68
UK Centre for Tobacco and Alcohol Studies, School of Psychological Science, University of Bristol, Bristol, UK.
69
Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
70
Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
71
Department of Preventative Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
72
Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
73
Department of Public Health, University of Helsinki, Helsinki, Finland.
74
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
75
Department of Public Health Sciences, College of Medicine, Pennsylvania State University, Hershey, PA, USA. dajiang.liu@psu.edu.
76
Institute of Personalized Medicine, College of Medicine, Pennsylvania State University, Hershey, PA, USA. dajiang.liu@psu.edu.
77
Department of Psychology, University of Minnesota Twin Cities, Minneapolis, MN, USA. vrieze@umn.edu.

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 efforts6-11. 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.

PMID:
30643251
PMCID:
PMC6358542
DOI:
10.1038/s41588-018-0307-5
[Indexed for MEDLINE]
Free PMC Article

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