Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders

Jouke Jan Hottenga; Lannie Ligthart; Hamdi Mbarek; Dorret I. Boomsma; 23Andme Research Team

doi:10.1038/s41593-018-0275-1

Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders

Jouke Jan Hottenga, Lannie Ligthart, Hamdi Mbarek, Dorret I. Boomsma, 23Andme Research Team

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Abstract

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case–control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 × 10^–13) and African ancestries (rs2066702; P = 2.2 × 10^–9). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit–hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.

Original language	English
Pages (from-to)	1656-1669
Number of pages	14
Journal	Nature Neuroscience
Volume	21
Issue number	12
Early online date	26 Nov 2018
DOIs	https://doi.org/10.1038/s41593-018-0275-1
Publication status	Published - Dec 2018

Funding

L.J.B., A.M.G., J.P.R., J.-C.W. and the spouse of N.L.S. are listed as inventors on Issued US Patent 8080,371, “Markers for Addiction” covering the use of certain SNPs in determining the diagnosis, prognosis, and treatment of addiction. N.W. has received funding from the German Research Foundation (DFG) and Federal Ministry of Education and Research Germany (BMBF); he has received speaker’s honoraria and travel funds from Janssen-Cilag and Indivior. He took part in industry-sponsored multicenter randomized trials by D&A Pharma and Lundbeck. M. Ridinger received compensation from Lundbeck Switzerland and Lundbeck institute for advisory boards and expert meetings, and from Lundbeck and Lilly Suisse for workshops and presentations. K.M. received honoraria from Lundbeck, Pfizer, Novartis, and AbbVie. K.M. also received Honoraria (Advisory Board) from Lundbeck and Pfizer and speaker fees from Janssen Cilag. H.K. has been an advisory board member, consultant, or continuing medical education speaker for Indivior, Lundbeck, and Otsuka. He is a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which was sponsored in the past three years by AbbVie, Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Ethypharm, Indivior, Lilly, Lundbeck, Otsuka, and Pfizer. H.K. and J.G. are named as inventors on PCT patent application #15/878,640, entitled “Genotype-guided dosing of opioid agonists,” filed 24 January 2018. P.F., S.L.E., and members of the 23andMe Research Team are employees of 23andMe. M.A.F. has received grant support from Assurex Health, Mayo Foundation, Myriad, NIAAA, National Institute of Mental Health (NIMH), and Pfizer; he has been a consultant for Intra-Cellular Therapies, Inc., Janssen, Mitsubishi Tanabe Pharma Corporation, Myriad, Neuralstem Inc., Otsuka American Pharmaceutical, Sunovion, and Teva Pharmaceuticals. H.d.W. has received support from Insys Therapeutics and Indivior for studies unrelated to this project, and she has consulted for Marinus and Jazz Pharmaceuticals, also unrelated to this project. T.L.W. has previously received funds from ABMRF. J.N. is an investigator for Janssen and Assurex. M.M.N. has received honoraria from the Lundbeck Foundation and the Robert Bosch Stiftung for membership on advisory boards. M. Ridinger has received honoraria from Lundbeck Switzerland and the Lundbeck Institute for membership of advisory boards and participation in expert meetings, and from Lundbeck and Lilly Suisse for workshops and presentations. N.S. has received honoraria from Abbvie, Sanofi-Aventis, Reckitt Benckiser, Indivior, Lundbeck, and Janssen-Cilag for advisory board membership and the preparation of lectures, manuscripts, and educational materials. Since 2013, N.S. has also participated in clinical trials financed by Reckitt Benckiser and Indivior. N.W. received speaker’s honoraria and travel expenses from Janssen-Cilag and Indivior; has also participated in industry-sponsored multicenter randomized trials conducted by D&A Pharma and Lundbeck. W.G. has received symposia support from Janssen-Cilag GmbH, Neuss, Lilly Deutschland GmbH, Bad Homburg, and Servier, Munich, and is a member of the Faculty of the Lundbeck International Neuroscience Foundation (LINF), Denmark. J.A.K. has provided consultations on nicotine dependence for Pfizer (Finland) 2012–2015. In the past three years, L.D. has received investigator-initiated untied educational grants for studies of opioid medications in Australia from Indivior, Mundipharma, and Seqirus. B.M.N. is a member of the scientific advisory board for Deep Genomics and has consulted for Camp4 Therapeutics Corporation, Merck & Co., and Avanir Pharmaceuticals, Inc. A.A. previously received peer-reviewed funding and travel reimbursement from ABMRF for unrelated research.

Funders	Funder number
National Institute of Mental Health
National Institute on Alcohol Abuse and Alcoholism	T32AA007464
Pfizer
California Department of Fish and Game
Teva Pharmaceutical Industries
Mayo Foundation for Medical Education and Research
Janssen Pharmaceuticals
Otsuka America Pharmaceutical
Sunovion
Assurex Health
Myriad Genetics
Deutsche Forschungsgemeinschaft
Bundesministerium für Bildung und Forschung

Cohort Studies

Netherlands Twin Register (NTR)

UN SDGs

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

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10.1038/s41593-018-0275-1

Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disordersFinal published version, 4.04 MBLicence: Article 25fa Dutch Copyright Act

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@article{c28775f1af5b420593cc8fc89d2429b3,

title = "Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders",

abstract = "Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case–control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 × 10–13) and African ancestries (rs2066702; P = 2.2 × 10–9). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit–hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.",

author = "Walters, {Raymond K.} and Renato Polimanti and Johnson, {Emma C.} and McClintick, {Jeanette N.} and Adams, {Mark J.} and Adkins, {Amy E.} and Fazil Aliev and Bacanu, {Silviu Alin} and Anthony Batzler and Sarah Bertelsen and Biernacka, {Joanna M.} and Bigdeli, {Tim B.} and Chen, {Li Shiun} and Clarke, {Toni Kim} and Chou, {Yi Ling} and Franziska Degenhardt and Docherty, {Anna R.} and Edwards, {Alexis C.} and Pierre Fontanillas and Foo, {Jerome C.} and Louis Fox and Josef Frank and Ina Giegling and Scott Gordon and Hack, {Laura M.} and Hartmann, {Annette M.} and Hartz, {Sarah M.} and Stefanie Heilmann-Heimbach and Stefan Herms and Colin Hodgkinson and Per Hoffmann and Hottenga, {Jouke Jan} and Kennedy, {Martin A.} and Mervi Alanne-Kinnunen and Bettina Konte and Jari Lahti and Marius Lahti-Pulkkinen and Dongbing Lai and Lannie Ligthart and Anu Loukola and Maher, {Brion S.} and Hamdi Mbarek and McIntosh, {Andrew M.} and McQueen, {Matthew B.} and Meyers, {Jacquelyn L.} and Yuri Milaneschi and Teemu Palviainen and Pearson, {John F.} and Peterson, {Roseann E.} and Samuli Ripatti and Euijung Ryu and Saccone, {Nancy L.} and Salvatore, {Jessica E.} and Sandra Sanchez-Roige and Melanie Schwandt and Richard Sherva and Fabian Streit and Jana Strohmaier and Nathaniel Thomas and Wang, {Jen Chyong} and Webb, {Bradley T.} and Robbee Wedow and Leah Wetherill and Wills, {Amanda G.} 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 Huber, {Karen E.} and Aaron Kleinman and Litterman, {Nadia K.} and McCreight, {Jennifer C.} and McIntyre, {Matthew H.} and Mountain, {Joanna L.} and Noblin, {Elizabeth S.} and Northover, {Carrie A.M.} and Pitts, {Steven J.} 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 Boardman, {Jason D.} and Danfeng Chen and Choi, {Doo Sup} and Copeland, {William E.} and Culverhouse, {Robert C.} and Norbert Dahmen and Louisa Degenhardt and Domingue, {Benjamin W.} and Elson, {Sarah L.} and Frye, {Mark A.} and Wolfgang G{\"a}bel and Caroline Hayward and Marcus Ising and Margaret Keyes and Falk Kiefer and John Kramer and Samuel Kuperman and Susanne Lucae and Lynskey, {Michael T.} and Wolfgang Maier and Karl Mann and Satu M{\"a}nnist{\"o} and Bertram M{\"u}ller-Myhsok and Murray, {Alison D.} and Nurnberger, {John I.} and Aarno Palotie and Ulrich Preuss and Katri R{\"a}ikk{\"o}nen and Reynolds, {Maureen D.} and Monika Ridinger and Norbert Scherbaum and Schuckit, {Marc A.} and Michael Soyka and Jens Treutlein and Stephanie Witt and Norbert Wodarz and Peter Zill and Adkins, {Daniel E.} and Boden, {Joseph M.} and Boomsma, {Dorret I.} and Bierut, {Laura J.} and Brown, {Sandra A.} and Bucholz, {Kathleen K.} and Sven Cichon and Costello, {E. Jane} and {de Wit}, Harriet and Nancy Diazgranados and Dick, {Danielle M.} and Eriksson, {Johan G.} and Farrer, {Lindsay A.} and Foroud, {Tatiana M.} and Gillespie, {Nathan A.} and Goate, {Alison M.} and David Goldman and Grucza, {Richard A.} and Hancock, {Dana B.} and Harris, {Kathleen Mullan} and Heath, {Andrew C.} and Victor Hesselbrock and Hewitt, {John K.} and Hopfer, {Christian J.} and John Horwood and William Iacono and Johnson, {Eric O.} and Kaprio, {Jaakko A.} and Karpyak, {Victor M.} and Kendler, {Kenneth S.} and Kranzler, {Henry R.} and Kenneth Krauter and Paul Lichtenstein and Lind, {Penelope A.} and Matt McGue and James MacKillop and Madden, {Pamela A.F.} and Maes, {Hermine H.} and Patrik Magnusson and Martin, {Nicholas G.} and Medland, {Sarah E.} and Montgomery, {Grant W.} and Nelson, {Elliot C.} and N{\"o}then, {Markus M.} and Palmer, {Abraham A.} and Pedersen, {Nancy L.} and Penninx, {Brenda W.J.H.} and Bernice Porjesz and Rice, {John P.} and Marcella Rietschel and Riley, {Brien P.} and Richard Rose and Dan Rujescu and Shen, {Pei Hong} and Judy Silberg and Stallings, {Michael C.} and Tarter, {Ralph E.} and Vanyukov, {Michael M.} and Scott Vrieze and Wall, {Tamara L.} and Whitfield, {John B.} and Hongyu Zhao and Neale, {Benjamin M.} and Joel Gelernter and Edenberg, {Howard J.} and Arpana Agrawal and {23Andme Research Team}",

year = "2018",

month = dec,

doi = "10.1038/s41593-018-0275-1",

language = "English",

volume = "21",

pages = "1656--1669",

journal = "Nature Neuroscience",

issn = "1097-6256",

publisher = "Nature Publishing Group",

number = "12",

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TY - JOUR

T1 - Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders

AU - Walters, Raymond K.

AU - Polimanti, Renato

AU - Johnson, Emma C.

AU - McClintick, Jeanette N.

AU - Adams, Mark J.

AU - Adkins, Amy E.

AU - Aliev, Fazil

AU - Bacanu, Silviu Alin

AU - Batzler, Anthony

AU - Bertelsen, Sarah

AU - Biernacka, Joanna M.

AU - Bigdeli, Tim B.

AU - Chen, Li Shiun

AU - Clarke, Toni Kim

AU - Chou, Yi Ling

AU - Degenhardt, Franziska

AU - Docherty, Anna R.

AU - Edwards, Alexis C.

AU - Fontanillas, Pierre

AU - Foo, Jerome C.

AU - Fox, Louis

AU - Frank, Josef

AU - Giegling, Ina

AU - Gordon, Scott

AU - Hack, Laura M.

AU - Hartmann, Annette M.

AU - Hartz, Sarah M.

AU - Heilmann-Heimbach, Stefanie

AU - Herms, Stefan

AU - Hodgkinson, Colin

AU - Hoffmann, Per

AU - Hottenga, Jouke Jan

AU - Kennedy, Martin A.

AU - Alanne-Kinnunen, Mervi

AU - Konte, Bettina

AU - Lahti, Jari

AU - Lahti-Pulkkinen, Marius

AU - Lai, Dongbing

AU - Ligthart, Lannie

AU - Loukola, Anu

AU - Maher, Brion S.

AU - Mbarek, Hamdi

AU - McIntosh, Andrew M.

AU - McQueen, Matthew B.

AU - Meyers, Jacquelyn L.

AU - Milaneschi, Yuri

AU - Palviainen, Teemu

AU - Pearson, John F.

AU - Peterson, Roseann E.

AU - Ripatti, Samuli

AU - Ryu, Euijung

AU - Saccone, Nancy L.

AU - Salvatore, Jessica E.

AU - Sanchez-Roige, Sandra

AU - Schwandt, Melanie

AU - Sherva, Richard

AU - Streit, Fabian

AU - Strohmaier, Jana

AU - Thomas, Nathaniel

AU - Wang, Jen Chyong

AU - Webb, Bradley T.

AU - Wedow, Robbee

AU - Wetherill, Leah

AU - Wills, Amanda G.

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 - Huber, Karen E.

AU - Kleinman, Aaron

AU - Litterman, Nadia K.

AU - McCreight, Jennifer C.

AU - McIntyre, Matthew H.

AU - Mountain, Joanna L.

AU - Noblin, Elizabeth S.

AU - Northover, Carrie A.M.

AU - Pitts, Steven J.

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 - Boardman, Jason D.

AU - Chen, Danfeng

AU - Choi, Doo Sup

AU - Copeland, William E.

AU - Culverhouse, Robert C.

AU - Dahmen, Norbert

AU - Degenhardt, Louisa

AU - Domingue, Benjamin W.

AU - Elson, Sarah L.

AU - Frye, Mark A.

AU - Gäbel, Wolfgang

AU - Hayward, Caroline

AU - Ising, Marcus

AU - Keyes, Margaret

AU - Kiefer, Falk

AU - Kramer, John

AU - Kuperman, Samuel

AU - Lucae, Susanne

AU - Lynskey, Michael T.

AU - Maier, Wolfgang

AU - Mann, Karl

AU - Männistö, Satu

AU - Müller-Myhsok, Bertram

AU - Murray, Alison D.

AU - Nurnberger, John I.

AU - Palotie, Aarno

AU - Preuss, Ulrich

AU - Räikkönen, Katri

AU - Reynolds, Maureen D.

AU - Ridinger, Monika

AU - Scherbaum, Norbert

AU - Schuckit, Marc A.

AU - Soyka, Michael

AU - Treutlein, Jens

AU - Witt, Stephanie

AU - Wodarz, Norbert

AU - Zill, Peter

AU - Adkins, Daniel E.

AU - Boden, Joseph M.

AU - Boomsma, Dorret I.

AU - Bierut, Laura J.

AU - Brown, Sandra A.

AU - Bucholz, Kathleen K.

AU - Cichon, Sven

AU - Costello, E. Jane

AU - de Wit, Harriet

AU - Diazgranados, Nancy

AU - Dick, Danielle M.

AU - Eriksson, Johan G.

AU - Farrer, Lindsay A.

AU - Foroud, Tatiana M.

AU - Gillespie, Nathan A.

AU - Goate, Alison M.

AU - Goldman, David

AU - Grucza, Richard A.

AU - Hancock, Dana B.

AU - Harris, Kathleen Mullan

AU - Heath, Andrew C.

AU - Hesselbrock, Victor

AU - Hewitt, John K.

AU - Hopfer, Christian J.

AU - Horwood, John

AU - Iacono, William

AU - Johnson, Eric O.

AU - Kaprio, Jaakko A.

AU - Karpyak, Victor M.

AU - Kendler, Kenneth S.

AU - Kranzler, Henry R.

AU - Krauter, Kenneth

AU - Lichtenstein, Paul

AU - Lind, Penelope A.

AU - McGue, Matt

AU - MacKillop, James

AU - Madden, Pamela A.F.

AU - Maes, Hermine H.

AU - Magnusson, Patrik

AU - Martin, Nicholas G.

AU - Medland, Sarah E.

AU - Montgomery, Grant W.

AU - Nelson, Elliot C.

AU - Nöthen, Markus M.

AU - Palmer, Abraham A.

AU - Pedersen, Nancy L.

AU - Penninx, Brenda W.J.H.

AU - Porjesz, Bernice

AU - Rice, John P.

AU - Rietschel, Marcella

AU - Riley, Brien P.

AU - Rose, Richard

AU - Rujescu, Dan

AU - Shen, Pei Hong

AU - Silberg, Judy

AU - Stallings, Michael C.

AU - Tarter, Ralph E.

AU - Vanyukov, Michael M.

AU - Vrieze, Scott

AU - Wall, Tamara L.

AU - Whitfield, John B.

AU - Zhao, Hongyu

AU - Neale, Benjamin M.

AU - Gelernter, Joel

AU - Edenberg, Howard J.

AU - Agrawal, Arpana

AU - 23Andme Research Team

PY - 2018/12

Y1 - 2018/12

N2 - Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case–control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 × 10–13) and African ancestries (rs2066702; P = 2.2 × 10–9). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit–hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.

AB - Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case–control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 × 10–13) and African ancestries (rs2066702; P = 2.2 × 10–9). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit–hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.

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UR - http://www.scopus.com/inward/citedby.url?scp=85057260886&partnerID=8YFLogxK

U2 - 10.1038/s41593-018-0275-1

DO - 10.1038/s41593-018-0275-1

M3 - Article

C2 - 30482948

SN - 1097-6256

VL - 21

SP - 1656

EP - 1669

JO - Nature Neuroscience

JF - Nature Neuroscience

IS - 12

ER -

Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders

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Cohort Studies

UN SDGs

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