Genetic diversity fuels gene discovery for tobacco and alcohol use

Gretchen R.B. Saunders; Xingyan Wang; Fang Chen; Dorret I. Boomsma; Jouke Jan Hottenga; Tinca J.C. Polderman; Gonneke Willemsen; Thorgeir E. Thorgeirsson; Dajiang J. Liu; Scott Vrieze; 23Andme Research Team; The Biobank Japan Project

doi:10.1038/s41586-022-05477-4

Genetic diversity fuels gene discovery for tobacco and alcohol use

Gretchen R.B. Saunders, Xingyan Wang, Fang Chen, Dorret I. Boomsma, Jouke Jan Hottenga, Tinca J.C. Polderman, Gonneke Willemsen, Thorgeir E. Thorgeirsson, Dajiang J. Liu, Scott Vrieze^*, 23Andme Research Team, The Biobank Japan Project

^*Corresponding author for this work

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

Abstract

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury^1–4. These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries⁵. Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.

Original language	English
Pages (from-to)	720-724
Number of pages	5
Journal	Nature
Volume	612
Issue number	7941
DOIs	https://doi.org/10.1038/s41586-022-05477-4
Publication status	Published - 22 Dec 2022

Bibliographical note

Funding Information:
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 R56HG011035, R01DA044283, R01DA042755 and U01DA041120 to S.V., and R01GM126479, R56HG011035, R03OD032630, R01HG011035 and R56HG012358 to D.J.L. G.R.B.S. was also supported by National Institutes of Health award T32DA050560. D.J.L. and X.W. were in part supported by the Penn State College of Medicine’s Biomedical Informatics and Artificial Intelligence Program in the Strategic Plan. A full list of acknowledgements is provided in the Supplementary Note.

Funding Information:
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 R56HG011035, R01DA044283, R01DA042755 and U01DA041120 to S.V., and R01GM126479, R56HG011035, R03OD032630, R01HG011035 and R56HG012358 to D.J.L. G.R.B.S. was also supported by National Institutes of Health award T32DA050560. D.J.L. and X.W. were in part supported by the Penn State College of Medicine’s Biomedical Informatics and Artificial Intelligence Program in the Strategic Plan. A full list of acknowledgements is provided in the .

Funding Information:
The spouse of N.L. Saccone is listed as an inventor on issued U.S. patent 8080371 ‘Markers of addiction’, covering the use of certain single-nucleotide polymorphisms in determining the diagnosis, prognosis and treatment of addiction. M.H.C. has received grant funding from GSK and Bayer, and speaking or consulting fees from AstraZeneca, Illumina and Genentech. R.T.-S. is a former employee and current shareholder of GSK and is currently a non-executive member of the ENA Respiratory board of directors. She reports personal fees from Teva, Immunomet, Vocalis Health and ENA Respiratory (until January 2021). D.A.S. is the founder and chief scientific officer of Eleven P15, a company focused on the early diagnosis of treatment of pulmonary fibrosis. J.B.N. and E.J. are employed by Regeneron Pharmaceuticals, Inc. The spouse of C.J.W. is employed by Regeneron Pharmaceuticals, Inc. L.J.B. is listed as an inventor on Issued U.S. Patent 8080371 ‘Markers for addiction’, covering the use of certain single-nucleotide polymorphisms in determining the diagnosis, prognosis and treatment of addiction. The 23andMe Research Team, including J.S. and S.S.S., are employees of 23andMe, Inc., and hold stock and/or stock options in 23andMe. T.E.T., D.F.G., H.S., G.B. and K. Stefansson are employees of deCODE genetics/AMGEN. M. Moll received grant support from Bayer. A.W.B. is listed as a co-inventor on a U.S. patent application ‘Biosignature discovery for substance use disorder using statistical learning’ assigned to BioRealm, LLC, and serves as a scientific advisor and consultant to BioRealm, LLC. All other authors declare no competing interests.

Publisher Copyright:
© 2022, The Author(s).

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 R56HG011035, R01DA044283, R01DA042755 and U01DA041120 to S.V., and R01GM126479, R56HG011035, R03OD032630, R01HG011035 and R56HG012358 to D.J.L. G.R.B.S. was also supported by National Institutes of Health award T32DA050560. D.J.L. and X.W. were in part supported by the Penn State College of Medicine’s Biomedical Informatics and Artificial Intelligence Program in the Strategic Plan. A full list of acknowledgements is provided in the Supplementary Note. 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 R56HG011035, R01DA044283, R01DA042755 and U01DA041120 to S.V., and R01GM126479, R56HG011035, R03OD032630, R01HG011035 and R56HG012358 to D.J.L. G.R.B.S. was also supported by National Institutes of Health award T32DA050560. D.J.L. and X.W. were in part supported by the Penn State College of Medicine’s Biomedical Informatics and Artificial Intelligence Program in the Strategic Plan. A full list of acknowledgements is provided in the . The spouse of N.L. Saccone is listed as an inventor on issued U.S. patent 8080371 ‘Markers of addiction’, covering the use of certain single-nucleotide polymorphisms in determining the diagnosis, prognosis and treatment of addiction. M.H.C. has received grant funding from GSK and Bayer, and speaking or consulting fees from AstraZeneca, Illumina and Genentech. R.T.-S. is a former employee and current shareholder of GSK and is currently a non-executive member of the ENA Respiratory board of directors. She reports personal fees from Teva, Immunomet, Vocalis Health and ENA Respiratory (until January 2021). D.A.S. is the founder and chief scientific officer of Eleven P15, a company focused on the early diagnosis of treatment of pulmonary fibrosis. J.B.N. and E.J. are employed by Regeneron Pharmaceuticals, Inc. The spouse of C.J.W. is employed by Regeneron Pharmaceuticals, Inc. L.J.B. is listed as an inventor on Issued U.S. Patent 8080371 ‘Markers for addiction’, covering the use of certain single-nucleotide polymorphisms in determining the diagnosis, prognosis and treatment of addiction. The 23andMe Research Team, including J.S. and S.S.S., are employees of 23andMe, Inc., and hold stock and/or stock options in 23andMe. T.E.T., D.F.G., H.S., G.B. and K. Stefansson are employees of deCODE genetics/AMGEN. M. Moll received grant support from Bayer. A.W.B. is listed as a co-inventor on a U.S. patent application ‘Biosignature discovery for substance use disorder using statistical learning’ assigned to BioRealm, LLC, and serves as a scientific advisor and consultant to BioRealm, LLC. All other authors declare no competing interests.

Funders	Funder number
Penn State College of Medicine’s Biomedical Informatics and Artificial Intelligence Program in the Strategic Plan
National Institutes of Health	R01GM126479, R56HG012358, R03OD032630, R01HG011035, R01DA042755, U01DA041120, T32DA050560, R01DA044283
National Institute on Alcohol Abuse and Alcoholism	R44AA027675
Bayer
GlaxoSmithKline

UN SDGs

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

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@article{e050a03248fb4ebead70f63b19dffdc9,

title = "Genetic diversity fuels gene discovery for tobacco and alcohol use",

abstract = "Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury1–4. These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries5. Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.",

author = "Saunders, {Gretchen R.B.} and Xingyan Wang and Fang Chen and Jang, {Seon Kyeong} and Mengzhen Liu and Chen Wang and Shuang Gao and Yu Jiang and Chachrit Khunsriraksakul and Otto, {Jacqueline M.} and Clifton Addison and Masato Akiyama and Albert, {Christine M.} and Fazil Aliev and Alvaro Alonso and Arnett, {Donna K.} and Ashley-Koch, {Allison E.} and Ashrani, {Aneel A.} and Barnes, {Kathleen C.} and Barr, {R. Graham} and Bartz, {Traci M.} and Becker, {Diane M.} and Bielak, {Lawrence F.} and Benjamin, {Emelia J.} and Bis, {Joshua C.} and Gyda Bjornsdottir and John Blangero and Bleecker, {Eugene R.} and Boardman, {Jason D.} and Eric Boerwinkle and Boomsma, {Dorret I.} and Boorgula, {Meher Preethi} and Bowden, {Donald W.} and Brody, {Jennifer A.} and Cade, {Brian E.} and Chasman, {Daniel I.} and Sameer Chavan and Chen, {Yii Der Ida} and Zhengming Chen and Iona Cheng and Cho, {Michael H.} and H{\'e}l{\`e}ne Choquet and Cole, {John W.} and Cornelis, {Marilyn C.} and Francesco Cucca and Curran, {Joanne E.} and {de Andrade}, Mariza and Dick, {Danielle M.} and Docherty, {Anna R.} and Ravindranath Duggirala and Eaton, {Charles B.} and Ehringer, {Marissa A.} and T{\~o}nu Esko and Faul, {Jessica D.} and Silva, {Lilian Fernandes} and Edoardo Fiorillo and Myriam Fornage and Freedman, {Barry I.} and Gabrielsen, {Maiken E.} and Garrett, {Melanie E.} and Gharib, {Sina A.} and Christian Gieger and Nathan Gillespie and Glahn, {David C.} and Gordon, {Scott D.} and Gu, {Charles C.} and Dongfeng Gu and Gudbjartsson, {Daniel F.} and Xiuqing Guo and Jeffrey Haessler and Hall, {Michael E.} and Toomas Haller and Harris, {Kathleen Mullan} and Jiang He and Pamela Herd and Hewitt, {John K.} and Ian Hickie and Bertha Hidalgo and Hokanson, {John E.} and Christian Hopfer and Hottenga, {Jouke Jan} and Lifang Hou and Hongyan Huang and Hung, {Yi Jen} and Hunter, {David J.} and Kristian Hveem and Hwang, {Shih Jen} and Hwu, {Chii Min} and William Iacono and Irvin, {Marguerite R.} and Jee, {Yon Ho} and Johnson, {Eric O.} and Joo, {Yoonjung Y.} and Eric Jorgenson and Justice, {Anne E.} and Yoichiro Kamatani and Kaplan, {Robert C.} and Jaakko Kaprio and Kardia, {Sharon L.R.} and Keller, {Matthew C.} and Kelly, {Tanika N.} and Charles Kooperberg and Tellervo Korhonen and Peter Kraft and Kenneth Krauter and Johanna Kuusisto and Markku Laakso and Jessica Lasky-Su and Lee, {Wen Jane} and Lee, {James J.} and Daniel Levy and Liming Li and Kevin Li and Yuqing Li and Kuang Lin and Lind, {Penelope A.} and Chunyu Liu and Lloyd-Jones, {Donald M.} and Lutz, {Sharon M.} and Jiantao Ma and Reedik M{\"a}gi and Ani Manichaikul and Martin, {Nicholas G.} and Ravi Mathur and Nana Matoba and McArdle, {Patrick F.} and Matt McGue and McQueen, {Matthew B.} and Medland, {Sarah E.} and Andres Metspalu and Meyers, {Deborah A.} and Millwood, {Iona Y.} and Mitchell, {Braxton D.} and Mohlke, {Karen L.} and Matthew Moll and Montasser, {May E.} and Morrison, {Alanna C.} and Antonella Mulas and Nielsen, {Jonas B.} and North, {Kari E.} and Oelsner, {Elizabeth C.} and Yukinori Okada and Valeria Orr{\`u} and Palmer, {Nicholette D.} and Teemu Palviainen and Anita Pandit and Park, {S. Lani} and Ulrike Peters and Annette Peters and Peyser, {Patricia A.} and Polderman, {Tinca J.C.} and Nicholas Rafaels and Susan Redline and Reed, {Robert M.} and Reiner, {Alex P.} and Rice, {John P.} and Rich, {Stephen S.} and Richmond, {Nicole E.} and Carol Roan and Rotter, {Jerome I.} and Rueschman, {Michael N.} and Valgerdur Runarsdottir and Saccone, {Nancy L.} and Schwartz, {David A.} and Shadyab, {Aladdin H.} and Jingchunzi Shi and Shringarpure, {Suyash S.} and Kamil Sicinski and Skogholt, {Anne Heidi} and Smith, {Jennifer A.} and Smith, {Nicholas L.} and Nona Sotoodehnia and Stallings, {Michael C.} and Hreinn Stefansson and Kari Stefansson and Stitzel, {Jerry A.} and Xiao Sun and Moin Syed and Ruth Tal-Singer and Taylor, {Amy E.} and Taylor, {Kent D.} and Telen, {Marilyn J.} and Thai, {Khanh K.} and Hemant Tiwari and Constance Turman and Thorarinn Tyrfingsson and Wall, {Tamara L.} and Walters, {Robin G.} and Weir, {David R.} and Weiss, {Scott T.} and White, {Wendy B.} and Whitfield, {John B.} and Wiggins, {Kerri L.} and Gonneke Willemsen and Willer, {Cristen J.} and Winsvold, {Bendik S.} and Huichun Xu and Yanek, {Lisa R.} and Jie Yin and Young, {Kristin L.} and Young, {Kendra A.} and Bing Yu and Wei Zhao and Wei Zhou and Sebastian Z{\"o}llner and Luisa Zuccolo and Chiara Batini and Bergen, {Andrew W.} and Bierut, {Laura J.} and David, {Sean P.} and {Gagliano Taliun}, {Sarah A.} and Hancock, {Dana B.} and Bibo Jiang and Munaf{\`o}, {Marcus R.} and Thorgeirsson, {Thorgeir E.} and Liu, {Dajiang J.} and Scott Vrieze and {23Andme Research Team} and {The Biobank Japan Project}",

note = "Funding Information: 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 R56HG011035, R01DA044283, R01DA042755 and U01DA041120 to S.V., and R01GM126479, R56HG011035, R03OD032630, R01HG011035 and R56HG012358 to D.J.L. G.R.B.S. was also supported by National Institutes of Health award T32DA050560. D.J.L. and X.W. were in part supported by the Penn State College of Medicine{\textquoteright}s Biomedical Informatics and Artificial Intelligence Program in the Strategic Plan. A full list of acknowledgements is provided in the Supplementary Note. Funding Information: 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 R56HG011035, R01DA044283, R01DA042755 and U01DA041120 to S.V., and R01GM126479, R56HG011035, R03OD032630, R01HG011035 and R56HG012358 to D.J.L. G.R.B.S. was also supported by National Institutes of Health award T32DA050560. D.J.L. and X.W. were in part supported by the Penn State College of Medicine{\textquoteright}s Biomedical Informatics and Artificial Intelligence Program in the Strategic Plan. A full list of acknowledgements is provided in the . Funding Information: The spouse of N.L. Saccone is listed as an inventor on issued U.S. patent 8080371 {\textquoteleft}Markers of addiction{\textquoteright}, covering the use of certain single-nucleotide polymorphisms in determining the diagnosis, prognosis and treatment of addiction. M.H.C. has received grant funding from GSK and Bayer, and speaking or consulting fees from AstraZeneca, Illumina and Genentech. R.T.-S. is a former employee and current shareholder of GSK and is currently a non-executive member of the ENA Respiratory board of directors. She reports personal fees from Teva, Immunomet, Vocalis Health and ENA Respiratory (until January 2021). D.A.S. is the founder and chief scientific officer of Eleven P15, a company focused on the early diagnosis of treatment of pulmonary fibrosis. J.B.N. and E.J. are employed by Regeneron Pharmaceuticals, Inc. The spouse of C.J.W. is employed by Regeneron Pharmaceuticals, Inc. L.J.B. is listed as an inventor on Issued U.S. Patent 8080371 {\textquoteleft}Markers for addiction{\textquoteright}, covering the use of certain single-nucleotide polymorphisms in determining the diagnosis, prognosis and treatment of addiction. The 23andMe Research Team, including J.S. and S.S.S., are employees of 23andMe, Inc., and hold stock and/or stock options in 23andMe. T.E.T., D.F.G., H.S., G.B. and K. Stefansson are employees of deCODE genetics/AMGEN. M. Moll received grant support from Bayer. A.W.B. is listed as a co-inventor on a U.S. patent application {\textquoteleft}Biosignature discovery for substance use disorder using statistical learning{\textquoteright} assigned to BioRealm, LLC, and serves as a scientific advisor and consultant to BioRealm, LLC. All other authors declare no competing interests. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

day = "22",

doi = "10.1038/s41586-022-05477-4",

language = "English",

volume = "612",

pages = "720--724",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7941",

}

TY - JOUR

T1 - Genetic diversity fuels gene discovery for tobacco and alcohol use

AU - Saunders, Gretchen R.B.

AU - Wang, Xingyan

AU - Chen, Fang

AU - Jang, Seon Kyeong

AU - Liu, Mengzhen

AU - Wang, Chen

AU - Gao, Shuang

AU - Jiang, Yu

AU - Khunsriraksakul, Chachrit

AU - Otto, Jacqueline M.

AU - Addison, Clifton

AU - Akiyama, Masato

AU - Albert, Christine M.

AU - Aliev, Fazil

AU - Alonso, Alvaro

AU - Arnett, Donna K.

AU - Ashley-Koch, Allison E.

AU - Ashrani, Aneel A.

AU - Barnes, Kathleen C.

AU - Barr, R. Graham

AU - Bartz, Traci M.

AU - Becker, Diane M.

AU - Bielak, Lawrence F.

AU - Benjamin, Emelia J.

AU - Bis, Joshua C.

AU - Bjornsdottir, Gyda

AU - Blangero, John

AU - Bleecker, Eugene R.

AU - Boardman, Jason D.

AU - Boerwinkle, Eric

AU - Boomsma, Dorret I.

AU - Boorgula, Meher Preethi

AU - Bowden, Donald W.

AU - Brody, Jennifer A.

AU - Cade, Brian E.

AU - Chasman, Daniel I.

AU - Chavan, Sameer

AU - Chen, Yii Der Ida

AU - Chen, Zhengming

AU - Cheng, Iona

AU - Cho, Michael H.

AU - Choquet, Hélène

AU - Cole, John W.

AU - Cornelis, Marilyn C.

AU - Cucca, Francesco

AU - Curran, Joanne E.

AU - de Andrade, Mariza

AU - Dick, Danielle M.

AU - Docherty, Anna R.

AU - Duggirala, Ravindranath

AU - Eaton, Charles B.

AU - Ehringer, Marissa A.

AU - Esko, Tõnu

AU - Faul, Jessica D.

AU - Silva, Lilian Fernandes

AU - Fiorillo, Edoardo

AU - Fornage, Myriam

AU - Freedman, Barry I.

AU - Gabrielsen, Maiken E.

AU - Garrett, Melanie E.

AU - Gharib, Sina A.

AU - Gieger, Christian

AU - Gillespie, Nathan

AU - Glahn, David C.

AU - Gordon, Scott D.

AU - Gu, Charles C.

AU - Gu, Dongfeng

AU - Gudbjartsson, Daniel F.

AU - Guo, Xiuqing

AU - Haessler, Jeffrey

AU - Hall, Michael E.

AU - Haller, Toomas

AU - Harris, Kathleen Mullan

AU - He, Jiang

AU - Herd, Pamela

AU - Hewitt, John K.

AU - Hickie, Ian

AU - Hidalgo, Bertha

AU - Hokanson, John E.

AU - Hopfer, Christian

AU - Hottenga, Jouke Jan

AU - Hou, Lifang

AU - Huang, Hongyan

AU - Hung, Yi Jen

AU - Hunter, David J.

AU - Hveem, Kristian

AU - Hwang, Shih Jen

AU - Hwu, Chii Min

AU - Iacono, William

AU - Irvin, Marguerite R.

AU - Jee, Yon Ho

AU - Johnson, Eric O.

AU - Joo, Yoonjung Y.

AU - Jorgenson, Eric

AU - Justice, Anne E.

AU - Kamatani, Yoichiro

AU - Kaplan, Robert C.

AU - Kaprio, Jaakko

AU - Kardia, Sharon L.R.

AU - Keller, Matthew C.

AU - Kelly, Tanika N.

AU - Kooperberg, Charles

AU - Korhonen, Tellervo

AU - Kraft, Peter

AU - Krauter, Kenneth

AU - Kuusisto, Johanna

AU - Laakso, Markku

AU - Lasky-Su, Jessica

AU - Lee, Wen Jane

AU - Lee, James J.

AU - Levy, Daniel

AU - Li, Liming

AU - Li, Kevin

AU - Li, Yuqing

AU - Lin, Kuang

AU - Lind, Penelope A.

AU - Liu, Chunyu

AU - Lloyd-Jones, Donald M.

AU - Lutz, Sharon M.

AU - Ma, Jiantao

AU - Mägi, Reedik

AU - Manichaikul, Ani

AU - Martin, Nicholas G.

AU - Mathur, Ravi

AU - Matoba, Nana

AU - McArdle, Patrick F.

AU - McGue, Matt

AU - McQueen, Matthew B.

AU - Medland, Sarah E.

AU - Metspalu, Andres

AU - Meyers, Deborah A.

AU - Millwood, Iona Y.

AU - Mitchell, Braxton D.

AU - Mohlke, Karen L.

AU - Moll, Matthew

AU - Montasser, May E.

AU - Morrison, Alanna C.

AU - Mulas, Antonella

AU - Nielsen, Jonas B.

AU - North, Kari E.

AU - Oelsner, Elizabeth C.

AU - Okada, Yukinori

AU - Orrù, Valeria

AU - Palmer, Nicholette D.

AU - Palviainen, Teemu

AU - Pandit, Anita

AU - Park, S. Lani

AU - Peters, Ulrike

AU - Peters, Annette

AU - Peyser, Patricia A.

AU - Polderman, Tinca J.C.

AU - Rafaels, Nicholas

AU - Redline, Susan

AU - Reed, Robert M.

AU - Reiner, Alex P.

AU - Rice, John P.

AU - Rich, Stephen S.

AU - Richmond, Nicole E.

AU - Roan, Carol

AU - Rotter, Jerome I.

AU - Rueschman, Michael N.

AU - Runarsdottir, Valgerdur

AU - Saccone, Nancy L.

AU - Schwartz, David A.

AU - Shadyab, Aladdin H.

AU - Shi, Jingchunzi

AU - Shringarpure, Suyash S.

AU - Sicinski, Kamil

AU - Skogholt, Anne Heidi

AU - Smith, Jennifer A.

AU - Smith, Nicholas L.

AU - Sotoodehnia, Nona

AU - Stallings, Michael C.

AU - Stefansson, Hreinn

AU - Stefansson, Kari

AU - Stitzel, Jerry A.

AU - Sun, Xiao

AU - Syed, Moin

AU - Tal-Singer, Ruth

AU - Taylor, Amy E.

AU - Taylor, Kent D.

AU - Telen, Marilyn J.

AU - Thai, Khanh K.

AU - Tiwari, Hemant

AU - Turman, Constance

AU - Tyrfingsson, Thorarinn

AU - Wall, Tamara L.

AU - Walters, Robin G.

AU - Weir, David R.

AU - Weiss, Scott T.

AU - White, Wendy B.

AU - Whitfield, John B.

AU - Wiggins, Kerri L.

AU - Willemsen, Gonneke

AU - Willer, Cristen J.

AU - Winsvold, Bendik S.

AU - Xu, Huichun

AU - Yanek, Lisa R.

AU - Yin, Jie

AU - Young, Kristin L.

AU - Young, Kendra A.

AU - Yu, Bing

AU - Zhao, Wei

AU - Zhou, Wei

AU - Zöllner, Sebastian

AU - Zuccolo, Luisa

AU - Batini, Chiara

AU - Bergen, Andrew W.

AU - Bierut, Laura J.

AU - David, Sean P.

AU - Gagliano Taliun, Sarah A.

AU - Hancock, Dana B.

AU - Jiang, Bibo

AU - Munafò, Marcus R.

AU - Thorgeirsson, Thorgeir E.

AU - Liu, Dajiang J.

AU - Vrieze, Scott

AU - 23Andme Research Team

AU - The Biobank Japan Project

N1 - Funding Information: 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 R56HG011035, R01DA044283, R01DA042755 and U01DA041120 to S.V., and R01GM126479, R56HG011035, R03OD032630, R01HG011035 and R56HG012358 to D.J.L. G.R.B.S. was also supported by National Institutes of Health award T32DA050560. D.J.L. and X.W. were in part supported by the Penn State College of Medicine’s Biomedical Informatics and Artificial Intelligence Program in the Strategic Plan. A full list of acknowledgements is provided in the Supplementary Note. Funding Information: 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 R56HG011035, R01DA044283, R01DA042755 and U01DA041120 to S.V., and R01GM126479, R56HG011035, R03OD032630, R01HG011035 and R56HG012358 to D.J.L. G.R.B.S. was also supported by National Institutes of Health award T32DA050560. D.J.L. and X.W. were in part supported by the Penn State College of Medicine’s Biomedical Informatics and Artificial Intelligence Program in the Strategic Plan. A full list of acknowledgements is provided in the . Funding Information: The spouse of N.L. Saccone is listed as an inventor on issued U.S. patent 8080371 ‘Markers of addiction’, covering the use of certain single-nucleotide polymorphisms in determining the diagnosis, prognosis and treatment of addiction. M.H.C. has received grant funding from GSK and Bayer, and speaking or consulting fees from AstraZeneca, Illumina and Genentech. R.T.-S. is a former employee and current shareholder of GSK and is currently a non-executive member of the ENA Respiratory board of directors. She reports personal fees from Teva, Immunomet, Vocalis Health and ENA Respiratory (until January 2021). D.A.S. is the founder and chief scientific officer of Eleven P15, a company focused on the early diagnosis of treatment of pulmonary fibrosis. J.B.N. and E.J. are employed by Regeneron Pharmaceuticals, Inc. The spouse of C.J.W. is employed by Regeneron Pharmaceuticals, Inc. L.J.B. is listed as an inventor on Issued U.S. Patent 8080371 ‘Markers for addiction’, covering the use of certain single-nucleotide polymorphisms in determining the diagnosis, prognosis and treatment of addiction. The 23andMe Research Team, including J.S. and S.S.S., are employees of 23andMe, Inc., and hold stock and/or stock options in 23andMe. T.E.T., D.F.G., H.S., G.B. and K. Stefansson are employees of deCODE genetics/AMGEN. M. Moll received grant support from Bayer. A.W.B. is listed as a co-inventor on a U.S. patent application ‘Biosignature discovery for substance use disorder using statistical learning’ assigned to BioRealm, LLC, and serves as a scientific advisor and consultant to BioRealm, LLC. All other authors declare no competing interests. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12/22

Y1 - 2022/12/22

N2 - Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury1–4. These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries5. Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.

AB - Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury1–4. These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries5. Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.

UR - http://www.scopus.com/inward/record.url?scp=85143637078&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85143637078&partnerID=8YFLogxK

U2 - 10.1038/s41586-022-05477-4

DO - 10.1038/s41586-022-05477-4

M3 - Article

C2 - 36477530

AN - SCOPUS:85143637078

SN - 0028-0836

VL - 612

SP - 720

EP - 724

JO - Nature

JF - Nature

IS - 7941

ER -

Genetic diversity fuels gene discovery for tobacco and alcohol use

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