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

23Andme Research Team, Mengzhen Liu, Yu Jiang, Robbee Wedow, Yue Li, David M Brazel, Fang Chen, Gargi Datta, Jose Davila-Velderrain, Daniel McGuire, Chao Tian, Xiaowei Zhan, Hélène Choquet, Anna R Docherty, Jessica D Faul, Johanna R Foerster, Lars G Fritsche, Maiken Elvestad Gabrielsen, Scott D Gordon, Jeffrey Haessler & 104 others Jouke-Jan Hottenga, Hongyan Huang, Seon-Kyeong Jang, Philip R Jansen, Yueh Ling, Reedik Mägi, Nana Matoba, George McMahon, Antonella Mulas, Valeria Orrù, Teemu Palviainen, Anita Pandit, Gunnar W Reginsson, Anne Heidi Skogholt, Jennifer A Smith, Amy E Taylor, Constance Turman, Gonneke Willemsen, Hannah Young, Kendra A Young, Gregory J M Zajac, Wei Zhao, Wei Zhou, Gyda Bjornsdottir, Jason D Boardman, Michael Boehnke, Dorret I Boomsma, Chu Chen, Francesco Cucca, Gareth E Davies, Charles B Eaton, Marissa A Ehringer, Tõnu Esko, Edoardo Fiorillo, Nathan A Gillespie, Daniel F Gudbjartsson, Toomas Haller, Kathleen Mullan Harris, Andrew C Heath, John K Hewitt, Ian B Hickie, John E Hokanson, Christian J Hopfer, David J Hunter, William G Iacono, Eric O Johnson, Yoichiro Kamatani, Sharon L R Kardia, Matthew C Keller, Manolis Kellis, Charles Kooperberg, Peter Kraft, Kenneth S Krauter, Markku Laakso, Penelope A Lind, Anu Loukola, Sharon M Lutz, Pamela A F Madden, Nicholas G Martin, Matt McGue, Matthew B McQueen, Sarah E Medland, Andres Metspalu, Karen L Mohlke, Jonas B Nielsen, Yukinori Okada, Ulrike Peters, Tinca J C Polderman, Danielle Posthuma, Alexander P Reiner, John P Rice, Eric Rimm, Richard J Rose, Valgerdur Runarsdottir, Michael C Stallings, Alena Stančáková, Hreinn Stefansson, Khanh K Thai, Hilary A Tindle, Thorarinn Tyrfingsson, Tamara L Wall, David R Weir, Constance Weisner, John B Whitfield, Bendik Slagsvold Winsvold, Jie Yin, Luisa Zuccolo, Laura J Bierut, Kristian Hveem, James J Lee, Marcus R Munafò, Nancy L Saccone, Cristen J Willer, Marilyn C Cornelis, Sean P David, David A Hinds, Eric Jorgenson, Jaakko Kaprio, Jerry A Stitzel, Kari Stefansson, Thorgeir E Thorgeirsson, Gonçalo Abecasis, Dajiang J Liu, Scott Vrieze

Research output: Contribution to JournalArticleAcademicpeer-review

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.

LanguageEnglish
Pages237-244
Number of pages8
JournalNature Genetics
Volume51
Issue number2
DOIs
StatePublished - Feb 2019

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Tobacco Use
Alcohols
Tobacco Use Cessation
Genetic Association Studies
Synaptic Transmission
Sample Size
Smoking
Phenotype
Mortality
Health
Genes

Cite this

@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 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.",
author = "{23Andme Research Team} and 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 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 Jouke-Jan Hottenga and Hongyan Huang and Seon-Kyeong Jang 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 Stanč{\'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{\cc}alo Abecasis and Liu, {Dajiang J} and Scott Vrieze",
year = "2019",
month = "2",
doi = "10.1038/s41588-018-0307-5",
language = "English",
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journal = "Nature Genetics",
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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. / 23Andme Research Team.

In: Nature Genetics, Vol. 51, No. 2, 02.2019, p. 237-244.

Research output: Contribution to JournalArticleAcademicpeer-review

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 - 23Andme Research Team

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 - 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

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AB - 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.

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DO - 10.1038/s41588-018-0307-5

M3 - Article

VL - 51

SP - 237

EP - 244

JO - Nature Genetics

T2 - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 2

ER -