Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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30679032
TITLE
Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and AlcoholUse.
ABSTRACT
BACKGROUND NlmCategory: BACKGROUND
Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences and to contribute to disease risk.
METHODS NlmCategory: METHODS
Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences and to contribute to disease risk. We analyzed ∼250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack-years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss-of-function coding variants. We performed a novel fine-mapping analysis to winnow the number of putative causal variants within associated loci.
RESULTS NlmCategory: RESULTS
Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences and to contribute to disease risk. We analyzed ∼250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack-years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss-of-function coding variants. We performed a novel fine-mapping analysis to winnow the number of putative causal variants within associated loci. Meta-analytic sample sizes ranged from 152,348 to 433,216, depending on the phenotype. Rare coding variation explained 1.1% to 2.2% of phenotypic variance, reflecting 11% to 18% of the total single nucleotide polymorphism heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between three and 10 variants for 65 loci. Twenty loci contained rare coding variants in the 95% credible intervals.
CONCLUSIONS NlmCategory: CONCLUSIONS
Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences and to contribute to disease risk. We analyzed ∼250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack-years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss-of-function coding variants. We performed a novel fine-mapping analysis to winnow the number of putative causal variants within associated loci. Meta-analytic sample sizes ranged from 152,348 to 433,216, depending on the phenotype. Rare coding variation explained 1.1% to 2.2% of phenotypic variance, reflecting 11% to 18% of the total single nucleotide polymorphism heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between three and 10 variants for 65 loci. Twenty loci contained rare coding variants in the 95% credible intervals. Rare coding variation significantly contributes to the heritability of smoking and alcohol use. Fine-mapping genome-wide association study loci identifies specific variants contributing to the biological etiology of substance use behavior.
Copyright 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
DATE PUBLISHED
2018 Dec 06
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2017/09/15
revised 2018/11/05
accepted 2018/11/29
entrez 2019/01/26 06:00
pubmed 2019/01/27 06:00
medline 2019/01/27 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Brazel DM Brazel David M DM Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, Colorado; Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, Colorado.
Jiang Y Jiang Yu Y Department of Public Health Sciences, Penn State College of Medicine, Hershey, Pennsylvania.
Hughey JM Hughey Jordan M JM Department of Public Health Sciences, Penn State College of Medicine, Hershey, Pennsylvania.
Turcot V Turcot Valérie V Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada; Montreal Heart Institute, Montreal, Quebec, Canada.
Zhan X Zhan Xiaowei X Department of Clinical Science, Center for Genetics of Host Defense, University of Texas Southwestern, Dallas, Texas.
Gong J Gong Jian J Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Batini C Batini Chiara C Department of Health Sciences, University of Leicester, Leicester, United Kingdom.
Weissenkampen JD Weissenkampen J Dylan JD Department of Public Health Sciences, Penn State College of Medicine, Hershey, Pennsylvania.
Liu M Liu MengZhen M Department of Psychology, University of Minnesota, Minneapolis, Minnesota.
CHD Exome+ Consortium
Consortium for Genetics of Smoking Behaviour
Barnes DR Barnes Daniel R DR Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
Bertelsen S Bertelsen Sarah S Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York.
Chou YL Chou Yi-Ling YL Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri.
Erzurumluoglu AM Erzurumluoglu A Mesut AM Department of Health Sciences, University of Leicester, Leicester, United Kingdom.
Faul JD Faul Jessica D JD Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, Michigan.
Haessler J Haessler Jeff J Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Hammerschlag AR Hammerschlag Anke R AR Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, University of Amsterdam, Amsterdam, the Netherlands.
Hsu C Hsu Chris C Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
Kapoor M Kapoor Manav M Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York.
Lai D Lai Dongbing D Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.
Le N Le Nhung N Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois.
de Leeuw CA de Leeuw Christiaan A CA Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, University of Amsterdam, Amsterdam, the Netherlands.
Loukola A Loukola Anu A Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Department of Public Health, University of Helsinki, Helsinki, Finland.
Mangino M Mangino Massimo M Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom; National Institute for Health Research Biomedical Research Centre at Guy's and St Thomas' Foundation Trust, London, United Kingdom.
Melbourne CA Melbourne Carl A CA Department of Health Sciences, University of Leicester, Leicester, United Kingdom.
Pistis G Pistis Giorgio G Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato, Italy.
Qaiser B Qaiser Beenish B Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Department of Public Health, University of Helsinki, Helsinki, Finland.
Rohde R Rohde Rebecca R Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Shao Y Shao Yaming Y Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Stringham H Stringham Heather H Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan.
Wetherill L Wetherill Leah L Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.
Zhao W Zhao Wei W Department of Epidemiology, University of Michigan, Ann Arbor, Michigan.
Agrawal A Agrawal Arpana A Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri.
Bierut L Bierut Laura L Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri.
Chen C Chen Chu C Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Epidemiology, Head and Neck Surgery Center, University of Washington, Seattle, Washington; Department of Otolaryngology, Head and Neck Surgery Center, University of Washington, Seattle, Washington.
Eaton CB Eaton Charles B CB Department of Family Medicine, Brown University, Providence, Rhode Island.
Goate A Goate Alison A Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York.
Haiman C Haiman Christopher C Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
Heath A Heath Andrew A Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri.
Iacono WG Iacono William G WG Department of Psychology, University of Minnesota, Minneapolis, Minnesota.
Martin NG Martin Nicholas G NG Queensland Institute for Medical Research, Brisbane, Australia.
Polderman TJ Polderman Tinca J TJ Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, University of Amsterdam, Amsterdam, the Netherlands.
Reiner A Reiner Alex A Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Epidemiology, Head and Neck Surgery Center, University of Washington, Seattle, Washington.
Rice J Rice John J Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri; Department of Mathematics, Washington University in St. Louis, St. Louis, Missouri.
Schlessinger D Schlessinger David D National Institute on Aging, National Institutes of Health, Bethesda, Maryland.
Scholte HS Scholte H Steven HS Department of Psychology, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Brain and Cognition, University of Amsterdam, Amsterdam, the Netherlands.
Smith JA Smith Jennifer A JA Department of Epidemiology, University of Michigan, Ann Arbor, Michigan.
Tardif JC Tardif Jean-Claude JC Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada; Montreal Heart Institute, Montreal, Quebec, Canada.
Tindle HA Tindle Hilary A HA Department of Medicine, Vanderbilt University, Nashville, Tennessee.
van der Leij AR van der Leij Andries R AR Department of Psychology, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Brain and Cognition, University of Amsterdam, Amsterdam, the Netherlands.
Boehnke M Boehnke Michael M Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan.
Chang-Claude J Chang-Claude Jenny J Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
Cucca F Cucca Francesco F Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato, Italy.
David SP David Sean P SP Department of Medicine, Stanford University, Stanford, California.
Foroud T Foroud Tatiana T Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.
Howson JMM Howson Joanna M M JMM Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
Kardia SLR Kardia Sharon L R SLR Department of Epidemiology, University of Michigan, Ann Arbor, Michigan.
Kooperberg C Kooperberg Charles C Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Laakso M Laakso Markku M Department of Internal Medicine, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
Lettre G Lettre Guillaume G Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada; Montreal Heart Institute, Montreal, Quebec, Canada.
Madden P Madden Pamela P Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri.
McGue M McGue Matt M Department of Psychology, University of Minnesota, Minneapolis, Minnesota.
North K North Kari K Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Posthuma D Posthuma Danielle D Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, University of Amsterdam, Amsterdam, the Netherlands; Department of Clinical Genetics, VU University Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
Spector T Spector Timothy T Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
Stram D Stram Daniel D Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
Tobin MD Tobin Martin D MD Department of Health Sciences, University of Leicester, Leicester, United Kingdom.
Weir DR Weir David R DR Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, Michigan.
Kaprio J Kaprio Jaakko J Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Department of Public Health, University of Helsinki, Helsinki, Finland.
Abecasis GR Abecasis Gonçalo R GR Regeneron Pharmaceuticals, Tarrytown, New York; Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan.
Liu DJ Liu Dajiang J DJ Institute of Personalized Medicine, Penn State College of Medicine, Hershey, Pennsylvania. Electronic address: dajiang.liu@psu.edu.
Vrieze S Vrieze Scott S Department of Psychology, University of Minnesota, Minneapolis, Minnesota. Electronic address: vrieze@umn.edu.
INVESTIGATORS
LASTNAME FORENAME INITIALS AFFILIATION
Surendran Praveen P
Young Robin R
Barnes Daniel R DR
Nielsen Sune Fallgaard SF
Rasheed Asif A
Samuel Maria M
Zhao Wei W
Kontto Jukka J
Perola Markus M
Caslake Muriel M
de Craen Anton J M AJM
Trompet Stella S
Uria-Nickelsen Maria M
Malarstig Anders A
Reily Dermot F DF
Hoek Maarten M
Vogt Thomas T
Jukema J Wouter JW
Sattar Naveed N
Ford Ian I
Packard Chris J CJ
Alam Dewan S DS
Majumder Abdulla Al Shafi AAS
Di Angelantonio Emanuele E
Chowdhury Rajiv R
Amouyel Philippe P
Arveiler Dominique D
Blankenberg Stefan S
Ferrières Jean J
Kee Frank F
Kuulasmaa Kari K
Müller-Nurasyid Martina M
Veronesi Giovanni G
Virtamo Jarmo J
Epic-Cvd Consortium
Frossard Philippe P
Nordestgaard Børge Grønne BG
Saleheen Danish D
Danesh John J
Butterworth Adam S AS
Howson Joanna M M JMM
Erzurumluoglu A Mesut AM
Jackson Victoria E VE
Melbourne Carl A CA
Varga Tibor V TV
Warren Helen R HR
Tragante Vinicius V
Tachmazidou Ioanna I
Harris Sarah E SE
Evangelou Evangelos E
Marten Jonathan J
Zhang Weihua W
Altmaier Elisabeth E
Luan Jian'an J
Langenberg Claudia C
Scott Robert A RA
Yaghootkar Hanieh H
Stirrups Kathleen K
Kanoni Stavroula S
Marouli Eirini E
Karpe Fredrik F
Dominiczak Anna F AF
Sever Peter P
Poulter Neil N
Rolandsson Olov O
Baumbach Clemens C
Afaq Saima S
Chambers John C JC
Kooner Jaspal S JS
Wareham Nicholas J NJ
Renström Frida F
Hallmans Göran G
Marioni Riccardo E RE
Corley Janie J
Starr John M JM
Verweij Niek N
de Boer Rudolf A RA
van der Meer Peter P
Yavas Ersin E
Vaartjes Ilonca I
Bots Michiel L ML
Asselbergs Folkert W FW
Grabe Hans J HJ
Völzke Henry H
Nauck Matthias M
Weiss Stefan S
Pharoah Paul D P PDP
Dunning Alison M AM
Dennis Joe G JG
Thompson Deborah J DJ
Michailidou Kyriaki K
Easton Douglas F DF
Antoniou Antonis C AC
Tyrrell Jessica J
Mihailov Evelin E
Samani Nilesh J NJ
Zhou Kaixin K
Neville Matthew J MJ
Metspalu Andres A
Palmer Colin N A CNA
Hall Ian P IP
Strachan David P DP
Deary Ian J IJ
Frayling Tim M TM
Hayward Caroline C
van der Harst Pim P
Zeggini Eleftheria E
Understanding Society Scientific Group
Munroe Patricia B PB
Jansson Jan-Håkan JH
Franks Paul W PW
Deloukas Panos P
Caulfield Mark J MJ
Wain Louise V LV
Tobin Martin D MD
JOURNAL
VOLUME:
ISSUE:
TITLE: Biological psychiatry
ISOABBREVIATION: Biol. Psychiatry
YEAR: 2018
MONTH: Dec
DAY: 06
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1873-2402
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Biol Psychiatry
COUNTRY: United States
ISSNLINKING: 0006-3223
NLMUNIQUEID: 0213264
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
COMMENTS AND CORRECTIONS
GRANTS
GENERAL NOTE
KEYWORDS
KEYWORD
Alcohol
Behavioral genetics
GWAS
Heritability
Nicotine
Tobacco
MESH HEADINGS
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
OTHER ID's