Meta-Analysis

. 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

Mengzhen Liu¹, Yu Jiang^{2

3}, Robbee Wedow^{4

5

6}, Yue Li^{7

8}, David M Brazel^{4

9

10}, Fang Chen^{2

3}, Gargi Datta¹, Jose Davila-Velderrain^{7

8}, Daniel McGuire^{2

3}, Chao Tian¹¹, Xiaowei Zhan^{12

13}; 23andMe Research Team; HUNT All-In Psychiatry; Hélène Choquet¹⁴, Anna R Docherty^{15

16}, Jessica D Faul¹⁷, Johanna R Foerster¹⁸, Lars G Fritsche¹⁸, Maiken Elvestad Gabrielsen¹⁹, Scott D Gordon²⁰, Jeffrey Haessler²¹, Jouke-Jan Hottenga²², Hongyan Huang^{23

24}, Seon-Kyeong Jang¹, Philip R Jansen^{25

26}, Yueh Ling^{2

9}, Reedik Mägi²⁷, Nana Matoba²⁸, George McMahon²⁹, Antonella Mulas³⁰, Valeria Orrù³⁰, Teemu Palviainen³¹, Anita Pandit¹⁸, Gunnar W Reginsson³², Anne Heidi Skogholt¹⁹, Jennifer A Smith^{17

33}, Amy E Taylor²⁹, Constance Turman^{23

24}, Gonneke Willemsen²², Hannah Young¹, Kendra A Young³⁴, Gregory J M Zajac¹⁸, Wei Zhao³³, Wei Zhou³⁵, Gyda Bjornsdottir³², Jason D Boardman^{4

5

6}, Michael Boehnke¹⁸, Dorret I Boomsma²², Chu Chen²¹, Francesco Cucca³⁰, Gareth E Davies³⁶, Charles B Eaton³⁷, Marissa A Ehringer^{4

38}, Tõnu Esko^{8

27}, Edoardo Fiorillo³⁰, Nathan A Gillespie^{15

20}, Daniel F Gudbjartsson^{32

39}, Toomas Haller²⁷, Kathleen Mullan Harris^{40

41}, Andrew C Heath⁴², John K Hewitt^{4

43}, Ian B Hickie⁴⁴, John E Hokanson³⁴, Christian J Hopfer^{4

45}, David J Hunter^{23

24

46}, William G Iacono¹, Eric O Johnson⁴⁷, Yoichiro Kamatani²⁸, Sharon L R Kardia³³, Matthew C Keller^{4

43}, Manolis Kellis^{7

8}, Charles Kooperberg²¹, Peter Kraft^{23

24

48}, Kenneth S Krauter^{4

9}, Markku Laakso^{49

50}, Penelope A Lind⁵¹, Anu Loukola³¹, Sharon M Lutz⁵², Pamela A F Madden⁴², Nicholas G Martin²⁰, Matt McGue¹, Matthew B McQueen^{4

38}, Sarah E Medland⁵¹, Andres Metspalu²⁷, Karen L Mohlke⁵³, Jonas B Nielsen⁵⁴, Yukinori Okada^{28

55}, Ulrike Peters^{21

56}, Tinca J C Polderman²⁵, Danielle Posthuma^{25

57}, Alexander P Reiner^{21

56}, John P Rice⁵⁸, Eric Rimm^{24

59}, Richard J Rose⁶⁰, Valgerdur Runarsdottir⁶¹, Michael C Stallings^{4

43}, Alena Stančáková⁴⁹, Hreinn Stefansson³², Khanh K Thai¹⁴, Hilary A Tindle⁶², Thorarinn Tyrfingsson⁶¹, Tamara L Wall⁶³, David R Weir¹⁷, Constance Weisner¹⁴, John B Whitfield²⁰, Bendik Slagsvold Winsvold⁶⁴, Jie Yin¹⁴, Luisa Zuccolo^{29

65}, Laura J Bierut⁵⁸, Kristian Hveem^{19

66

67}, James J Lee¹, Marcus R Munafò^{65

68}, Nancy L Saccone⁶⁹, Cristen J Willer^{35

54

70}, Marilyn C Cornelis⁷¹, Sean P David⁷², David A Hinds¹¹, Eric Jorgenson¹⁴, Jaakko Kaprio^{31

73}, Jerry A Stitzel^{4

38}, Kari Stefansson^{32

74}, Thorgeir E Thorgeirsson³², Gonçalo Abecasis¹⁸, Dajiang J Liu^{75

76}, Scott Vrieze⁷⁷

Collaborators, Affiliations

Collaborators

Michelle Agee, Babak Alipanahi, Adam Auton, Robert K Bell, Katarzyna Bryc, Sarah L Elson, Pierre Fontanillas, Nicholas A Furlotte, David A Hinds, Bethann S Hromatka, Karen E Huber, Aaron Kleinman, Nadia K Litterman, Matthew H McIntyre, Joanna L Mountain, Carrie A M Northover, J Fah Sathirapongsasuti, Olga V Sazonova, Janie F Shelton, Suyash Shringarpure, Chao Tian, Joyce Y Tung, Vladimir Vacic, Catherine H Wilson, Steven J Pitts, Amy Mitchell, Anne Heidi Skogholt, Bendik S Winsvold, Børge Sivertsen, Eystein Stordal, Gunnar Morken, Håvard Kallestad, Ingrid Heuch, John-Anker Zwart, Katrine Kveli Fjukstad, Linda M Pedersen, Maiken Elvestad Gabrielsen, Marianne Bakke Johnsen, Marit Skrove, Marit Sæbø Indredavik, Ole Kristian Drange, Ottar Bjerkeset, Sigrid Børte, Synne Øien Stensland

Affiliations

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.

PMID: 30643251
PMCID: PMC6358542
DOI: 10.1038/s41588-018-0307-5

Meta-Analysis

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

Mengzhen Liu et al. Nat Genet. 2019 Feb.

. 2019 Feb;51(2):237-244.

doi: 10.1038/s41588-018-0307-5. Epub 2019 Jan 14.

Authors

Collaborators

Michelle Agee, Babak Alipanahi, Adam Auton, Robert K Bell, Katarzyna Bryc, Sarah L Elson, Pierre Fontanillas, Nicholas A Furlotte, David A Hinds, Bethann S Hromatka, Karen E Huber, Aaron Kleinman, Nadia K Litterman, Matthew H McIntyre, Joanna L Mountain, Carrie A M Northover, J Fah Sathirapongsasuti, Olga V Sazonova, Janie F Shelton, Suyash Shringarpure, Chao Tian, Joyce Y Tung, Vladimir Vacic, Catherine H Wilson, Steven J Pitts, Amy Mitchell, Anne Heidi Skogholt, Bendik S Winsvold, Børge Sivertsen, Eystein Stordal, Gunnar Morken, Håvard Kallestad, Ingrid Heuch, John-Anker Zwart, Katrine Kveli Fjukstad, Linda M Pedersen, Maiken Elvestad Gabrielsen, Marianne Bakke Johnsen, Marit Skrove, Marit Sæbø Indredavik, Ole Kristian Drange, Ottar Bjerkeset, Sigrid Børte, Synne Øien Stensland

Affiliations

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.

PMID: 30643251
PMCID: PMC6358542
DOI: 10.1038/s41588-018-0307-5

Abstract

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders¹. They are heritable^2,3 and etiologically related^4,5 behaviors that have been resistant to gene discovery efforts^6-11. 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.

PubMed Disclaimer

Conflict of interest statement

COMPETING INTERESTS STATEMENT: Laura J. Bierut and the spouse of Nancy L. Saccone are listed as inventors on Issued U.S. Patent 8,080,371, “Markers for Addiction” covering the use of certain SNPs in determining the diagnosis, prognosis, and treatment of addiction. Sean David is a scientific advisor to BaseHealth, Inc. Gyda Bjornsdottir, Daniel F. Gudbjartsson, Gunnar W. Reginsson, Hreinn Stefansson, Kari Stefansson, and Thorgeir E. Thorgeirsson are employees of deCODE Genetics/AMGEN, Inc. Chao Tian and David Hinds are employees of 23andMe, Inc.

Figures

**Figure 1.. Genetic correlations between substance use phenotypes and phenotypes from other large genome-wide association studies.**
Genetic correlations between each of the phenotypes are shown in the first 5 rows, with heritability estimates displayed down the diagonal. All genetic correlations and heritability estimates were calculated using LD Score Regression. Blue shading represents negative genetic correlations, and red shading represents positive correlations, with increasing color intensity reflecting increasing strength of a correlation. A single asterisk reflects significant genetic correlations at the p<.05 level. Double asterisks reflect significant genetic correlations at the Bonferroni-correction p<.000278 level (corrected for 180 independent tests). Note that SmkCes was oriented such that higher scores reflected current smoking, and for AgeSmk lower scores reflect earlier ages of initiation, both of which are typically associated with negative outcomes. AgeSmk=Age of Initiation of Smoking; CigDay=Cigarettes per Day; SmkInit=Smoking Initiation; SmkCes=Smoking Cessation; DrnkWk=Drinks per Week.

**Figure 2.. Pleiotropy.**
Depicted here are results from the multivariate analysis of pleiotropy. For each locus, the method returns the best fitting solution of which phenotypes were associated with that locus. All loci with one or more associated phenotypes are shown here. For example, every locus associated with AgeSmk was found to be pleiotropic for other phenotypes (green, blue, red, purple, and fuchsia bars), and no locus showed association with only AgeSmk (no dark grey bar for AgeSmk). When sample sizes are unequal across phenotypes, the method also improves power for those phenotypes with smaller samples. The total number of loci associated with each trait (whether pleiotropic or not) from these analyses was 40 (AgeSmk), 48 (SmkCes), 72 (CigDay), 111 (DrnkWk), and 278 (SmkInit). Full information is in Supplementary Table 11.

**Figure 3.. Heritability and polygenic prediction.**
The light gray bars reflect SNP heritability, estimated with LD Score Regression. The light blue and gold bars reflect the predictive power of polygenic risk scores in Add Health and the Health and Retirement Study (HRS), respectively. Despite the 41-year generational gap between participants from these two studies, and major tobacco-related policy changes during that time, the polygenic scores are similarly predictive in both samples. Error bars are 95% confidence intervals estimated with 1000 bootstrapped repetitions. Dark gray bars represent the total phenotypic variance explained by only genome-wide significant SNPs. H²=heritability.

**Figure 4.. Correlations among exemplary DEPICT gene sets.**
There were 68 clusters available for Smoking initiation and 10 for Drinks Per Week (CigDay, AgeSmk, and SmkCes did not have > 1 exemplary sets.) Blue shading represents positive correlations, and red shading represents negative correlations, with increasing color intensity reflecting increasing strength of a correlation. Cluster names are truncated for space, with a full list of all names in Supplementary Table 18. The number after each name is the number of gene sets in each cluster. The matrix naturally falls into three blue superclusters along the diagonal. The largest supercluster contains primarily gene sets related to neurotransmitter receptors, ion channels (sodium, potassium, calcium), learning/memory, and other aspects of CNS function. The middle supercluster includes gene sets defined by regulation of transcription and translation, including RNA binding and transcription factor activity. The final supercluster is composed primarily of gene sets related to development of the nervous system.

See this image and copyright information in PMC

References

1. Ezzati M et al. Selected major risk factors and global and regional burden of disease. Lancet 360, 1347–1360 (2002). - PubMed
1. Hicks BM,Schalet BD, Malone SM,Iacono WG & McGue M Psychometric and genetic architecture of substance use disorder and behavioral disinhibition measures for gene association studies. Behavior Genetics 41, 459–75 (2011). - PMC - PubMed
1. Polderman TJ et al. Meta-analysis of the heritability of human traits based on fifty years of twin studies. Nat Genet (2015). - PubMed
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1. Kendler KS, Prescott CA, Myers J & Neale MC The structure of genetic and environmental risk factors for common psychiatric and substance use disorders in men and women. Archives of General Psychiatry 60, 929–937 (2003). - PubMed

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1. Das S et al. Next-generation genotype imputation service and methods. Nat Genet (2016). - PMC - PubMed
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Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use

Collaborators

Affiliations

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

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

METHODS ONLY REFERENCES

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Molecular Biology Databases