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

Mengzhen Liu; Jouke Jan Hottenga; Philip R. Jansen; Gonneke Willemsen; Dorret I. Boomsma; Gareth E. Davies; Tinca J.C. Polderman; Danielle Posthuma; Scott Vrieze; 23Andme Research Team; HUNT All-In Psychiatry

doi:10.1038/s41588-018-0307-5

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

Mengzhen Liu, Jouke Jan Hottenga, Philip R. Jansen, Gonneke Willemsen, Dorret I. Boomsma, Gareth E. Davies, Tinca J.C. Polderman, Danielle Posthuma, Scott Vrieze^*, 23Andme Research Team, HUNT All-In Psychiatry

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

144 Downloads (Pure)

Abstract

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders ¹ . 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.

Original language	English
Pages (from-to)	237-244
Number of pages	8
Journal	Nature Genetics
Volume	51
Issue number	2
Early online date	14 Jan 2019
DOIs	https://doi.org/10.1038/s41588-018-0307-5
Publication status	Published - Feb 2019

Funding

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.

Funders	Funder number
National Institutes of Health	R21DA040177, R01HG008983, R01DA037904
National Institute on Drug Abuse	U01DA046413

Cohort Studies

Netherlands Twin Register (NTR)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41588-018-0307-5

Association studies of up to 1-2 million individuals yield new insights into the genetic etiology of tobacco and alcohol useFinal published version, 1.57 MBLicence: Article 25fa Dutch Copyright Act

Persistent URL (handle)

Persistent link

Cite this

Liu, M., Hottenga, J. J., Jansen, P. R., Willemsen, G., Boomsma, D. I., Davies, G. E., Polderman, T. J. C., Posthuma, D., Vrieze, S., 23Andme Research Team, & HUNT All-In Psychiatry (2019). Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use. Nature Genetics, 51(2), 237-244. https://doi.org/10.1038/s41588-018-0307-5

@article{d4f99f7796f4405ebbd077e4e9dde885,

title = "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 disorders 1 . 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. ",

author = "Mengzhen Liu and Yu Jiang and Robbee Wedow and Yue Li and Brazel, {David M.} and Fang Chen and Gargi Datta and Jose Davila-Velderrain and Daniel McGuire and Chao Tian and Xiaowei Zhan and Michelle Agee and Babak Alipanahi and Adam Auton and Bell, {Robert K.} and Katarzyna Bryc and Elson, {Sarah L.} and Pierre Fontanillas and Furlotte, {Nicholas A.} and Hinds, {David A.} and Hromatka, {Bethann S.} and Huber, {Karen E.} and Aaron Kleinman and Litterman, {Nadia K.} and McIntyre, {Matthew H.} and Mountain, {Joanna L.} and Northover, {Carrie A.M.} and Sathirapongsasuti, {J. Fah} and Sazonova, {Olga V.} and Shelton, {Janie F.} and Suyash Shringarpure and Chao Tian and Tung, {Joyce Y.} and Vladimir Vacic and Wilson, {Catherine H.} and Pitts, {Steven J.} and Amy Mitchell and Skogholt, {Anne Heidi} and Winsvold, {Bendik Slagsvold} and B{\o}rge Sivertsen and Eystein Stordal and Gunnar Morken and H{\aa}vard Kallestad and Ingrid Heuch and Zwart, {John Anker} and Fjukstad, {Katrine Kveli} and Pedersen, {Linda M.} and Gabrielsen, {Maiken Elvestad} and Johnsen, {Marianne Bakke} and Marit Skrove and Indredavik, {Marit S{\ae}b{\o}} and Drange, {Ole Kristian} and Ottar Bjerkeset and Sigrid B{\o}rte and Stensland, {Synne {\O}ien} and H{\'e}l{\`e}ne Choquet and Docherty, {Anna R.} and Faul, {Jessica D.} and Foerster, {Johanna R.} and Fritsche, {Lars G.} and Gabrielsen, {Maiken Elvestad} and Gordon, {Scott D.} and Jeffrey Haessler and Hottenga, {Jouke Jan} and Hongyan Huang and Jang, {Seon Kyeong} and Jansen, {Philip R.} and Yueh Ling and Reedik M{\"a}gi and Nana Matoba and George McMahon and Antonella Mulas and Valeria Orr{\`u} and Teemu Palviainen and Anita Pandit and Reginsson, {Gunnar W.} and Skogholt, {Anne Heidi} and Smith, {Jennifer A.} and Taylor, {Amy E.} and Constance Turman and Gonneke Willemsen and Hannah Young and Young, {Kendra A.} and Zajac, {Gregory J.M.} and Wei Zhao and Wei Zhou and Gyda Bjornsdottir and Boardman, {Jason D.} and Michael Boehnke and Boomsma, {Dorret I.} and Chu Chen and Francesco Cucca and Davies, {Gareth E.} and Eaton, {Charles B.} and Ehringer, {Marissa A.} and T{\~o}nu Esko and Edoardo Fiorillo and Gillespie, {Nathan A.} and Gudbjartsson, {Daniel F.} and Toomas Haller and Harris, {Kathleen Mullan} and Heath, {Andrew C.} and Hewitt, {John K.} and Hickie, {Ian B.} and Hokanson, {John E.} and Hopfer, {Christian J.} and Hunter, {David J.} and Iacono, {William G.} and Johnson, {Eric O.} and Yoichiro Kamatani and Kardia, {Sharon L.R.} and Keller, {Matthew C.} and Manolis Kellis and Charles Kooperberg and Peter Kraft and Krauter, {Kenneth S.} and Markku Laakso and Lind, {Penelope A.} and Anu Loukola and Lutz, {Sharon M.} and Madden, {Pamela A.F.} and Martin, {Nicholas G.} and Matt McGue and McQueen, {Matthew B.} and Medland, {Sarah E.} and Andres Metspalu and Mohlke, {Karen L.} and Nielsen, {Jonas B.} and Yukinori Okada and Ulrike Peters and Polderman, {Tinca J.C.} and Danielle Posthuma and Reiner, {Alexander P.} and Rice, {John P.} and Eric Rimm and Rose, {Richard J.} and Valgerdur Runarsdottir and Stallings, {Michael C.} and Alena Stan{\v c}{\'a}kov{\'a} and Hreinn Stefansson and Thai, {Khanh K.} and Tindle, {Hilary A.} and Thorarinn Tyrfingsson and Wall, {Tamara L.} and Weir, {David R.} and Constance Weisner and Whitfield, {John B.} and Winsvold, {Bendik Slagsvold} and Jie Yin and Luisa Zuccolo and Bierut, {Laura J.} and Kristian Hveem and Lee, {James J.} and Munaf{\`o}, {Marcus R.} and Saccone, {Nancy L.} and Willer, {Cristen J.} and Cornelis, {Marilyn C.} and David, {Sean P.} and Hinds, {David A.} and Eric Jorgenson and Jaakko Kaprio and Stitzel, {Jerry A.} and Kari Stefansson and Thorgeirsson, {Thorgeir E.} and Gon{\c c}alo Abecasis and Liu, {Dajiang J.} and Scott Vrieze and {23Andme Research Team} and {HUNT All-In Psychiatry}",

year = "2019",

month = feb,

doi = "10.1038/s41588-018-0307-5",

language = "English",

volume = "51",

pages = "237--244",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "2",

}

Liu, M, Hottenga, JJ , Jansen, PR, Willemsen, G, Boomsma, DI, Davies, GE, Polderman, TJC , Posthuma, D, Vrieze, S, 23Andme Research Team & HUNT All-In Psychiatry 2019, 'Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use', Nature Genetics, vol. 51, no. 2, pp. 237-244. https://doi.org/10.1038/s41588-018-0307-5

TY - JOUR

T1 - Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use

AU - Liu, Mengzhen

AU - Jiang, Yu

AU - Wedow, Robbee

AU - Li, Yue

AU - Brazel, David M.

AU - Chen, Fang

AU - Datta, Gargi

AU - Davila-Velderrain, Jose

AU - McGuire, Daniel

AU - Tian, Chao

AU - Zhan, Xiaowei

AU - Agee, Michelle

AU - Alipanahi, Babak

AU - Auton, Adam

AU - Bell, Robert K.

AU - Bryc, Katarzyna

AU - Elson, Sarah L.

AU - Fontanillas, Pierre

AU - Furlotte, Nicholas A.

AU - Hinds, David A.

AU - Hromatka, Bethann S.

AU - Huber, Karen E.

AU - Kleinman, Aaron

AU - Litterman, Nadia K.

AU - McIntyre, Matthew H.

AU - Mountain, Joanna L.

AU - Northover, Carrie A.M.

AU - Sathirapongsasuti, J. Fah

AU - Sazonova, Olga V.

AU - Shelton, Janie F.

AU - Shringarpure, Suyash

AU - Tian, Chao

AU - Tung, Joyce Y.

AU - Vacic, Vladimir

AU - Wilson, Catherine H.

AU - Pitts, Steven J.

AU - Mitchell, Amy

AU - Skogholt, Anne Heidi

AU - Winsvold, Bendik Slagsvold

AU - Sivertsen, Børge

AU - Stordal, Eystein

AU - Morken, Gunnar

AU - Kallestad, Håvard

AU - Heuch, Ingrid

AU - Zwart, John Anker

AU - Fjukstad, Katrine Kveli

AU - Pedersen, Linda M.

AU - Gabrielsen, Maiken Elvestad

AU - Johnsen, Marianne Bakke

AU - Skrove, Marit

AU - Indredavik, Marit Sæbø

AU - Drange, Ole Kristian

AU - Bjerkeset, Ottar

AU - Børte, Sigrid

AU - Stensland, Synne Øien

AU - Choquet, Hélène

AU - Docherty, Anna R.

AU - Faul, Jessica D.

AU - Foerster, Johanna R.

AU - Fritsche, Lars G.

AU - Gabrielsen, Maiken Elvestad

AU - Gordon, Scott D.

AU - Haessler, Jeffrey

AU - Hottenga, Jouke Jan

AU - Huang, Hongyan

AU - Jang, Seon Kyeong

AU - Jansen, Philip R.

AU - Ling, Yueh

AU - Mägi, Reedik

AU - Matoba, Nana

AU - McMahon, George

AU - Mulas, Antonella

AU - Orrù, Valeria

AU - Palviainen, Teemu

AU - Pandit, Anita

AU - Reginsson, Gunnar W.

AU - Skogholt, Anne Heidi

AU - Smith, Jennifer A.

AU - Taylor, Amy E.

AU - Turman, Constance

AU - Willemsen, Gonneke

AU - Young, Hannah

AU - Young, Kendra A.

AU - Zajac, Gregory J.M.

AU - Zhao, Wei

AU - Zhou, Wei

AU - Bjornsdottir, Gyda

AU - Boardman, Jason D.

AU - Boehnke, Michael

AU - Boomsma, Dorret I.

AU - Chen, Chu

AU - Cucca, Francesco

AU - Davies, Gareth E.

AU - Eaton, Charles B.

AU - Ehringer, Marissa A.

AU - Esko, Tõnu

AU - Fiorillo, Edoardo

AU - Gillespie, Nathan A.

AU - Gudbjartsson, Daniel F.

AU - Haller, Toomas

AU - Harris, Kathleen Mullan

AU - Heath, Andrew C.

AU - Hewitt, John K.

AU - Hickie, Ian B.

AU - Hokanson, John E.

AU - Hopfer, Christian J.

AU - Hunter, David J.

AU - Iacono, William G.

AU - Johnson, Eric O.

AU - Kamatani, Yoichiro

AU - Kardia, Sharon L.R.

AU - Keller, Matthew C.

AU - Kellis, Manolis

AU - Kooperberg, Charles

AU - Kraft, Peter

AU - Krauter, Kenneth S.

AU - Laakso, Markku

AU - Lind, Penelope A.

AU - Loukola, Anu

AU - Lutz, Sharon M.

AU - Madden, Pamela A.F.

AU - Martin, Nicholas G.

AU - McGue, Matt

AU - McQueen, Matthew B.

AU - Medland, Sarah E.

AU - Metspalu, Andres

AU - Mohlke, Karen L.

AU - Nielsen, Jonas B.

AU - Okada, Yukinori

AU - Peters, Ulrike

AU - Polderman, Tinca J.C.

AU - Posthuma, Danielle

AU - Reiner, Alexander P.

AU - Rice, John P.

AU - Rimm, Eric

AU - Rose, Richard J.

AU - Runarsdottir, Valgerdur

AU - Stallings, Michael C.

AU - Stančáková, Alena

AU - Stefansson, Hreinn

AU - Thai, Khanh K.

AU - Tindle, Hilary A.

AU - Tyrfingsson, Thorarinn

AU - Wall, Tamara L.

AU - Weir, David R.

AU - Weisner, Constance

AU - Whitfield, John B.

AU - Winsvold, Bendik Slagsvold

AU - Yin, Jie

AU - Zuccolo, Luisa

AU - Bierut, Laura J.

AU - Hveem, Kristian

AU - Lee, James J.

AU - Munafò, Marcus R.

AU - Saccone, Nancy L.

AU - Willer, Cristen J.

AU - Cornelis, Marilyn C.

AU - David, Sean P.

AU - Hinds, David A.

AU - Jorgenson, Eric

AU - Kaprio, Jaakko

AU - Stitzel, Jerry A.

AU - Stefansson, Kari

AU - Thorgeirsson, Thorgeir E.

AU - Abecasis, Gonçalo

AU - Liu, Dajiang J.

AU - Vrieze, Scott

AU - 23Andme Research Team

AU - HUNT All-In Psychiatry

PY - 2019/2

Y1 - 2019/2

N2 - Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders 1 . 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.

AB - Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders 1 . 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.

UR - http://www.scopus.com/inward/record.url?scp=85060099159&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85060099159&partnerID=8YFLogxK

U2 - 10.1038/s41588-018-0307-5

DO - 10.1038/s41588-018-0307-5

M3 - Article

C2 - 30643251

SN - 1061-4036

VL - 51

SP - 237

EP - 244

JO - Nature Genetics

JF - Nature Genetics

IS - 2

ER -

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

Abstract

Funding

Cohort Studies

UN SDGs

Access to Document

Persistent URL (handle)

Other files and links

Fingerprint

Cite this