Distinct Loci in the CHRNA5/CHRNA3/CHRNB4 Gene Cluster Are Associated With Onset of Regular Smoking

Sarah H Stephens; Sarah M Hartz; Nicole R Hoft; Nancy L Saccone; Robin C Corley; John K Hewitt; Christian J Hopfer; Naomi Breslau; Hilary Coon; Xiangning Chen; Francesca Ducci; Nicole Dueker; Nora Franceschini; Josef Frank; Younghun Han; Nadia N Hansel; Chenhui Jiang; Tellervo Korhonen; Penelope A Lind; Jason Liu; Leo-Pekka Lyytikäinen; Martha Michel; John R Shaffer; Susan E Short; Juzhong Sun; Alexander Teumer; John R Thompson; Nicole Vogelzangs; Jacqueline M Vink; Angela Wenzlaff; William Wheeler; Bao-Zhu Yang; Steven H Aggen; Anthony J Balmforth; Sebastian E Baumeister; Terri H Beaty; Daniel J Benjamin; Andrew W Bergen; Ulla Broms; David Cesarini; Nilanjan Chatterjee; Jingchun Chen; Yu-Ching Cheng; Sven Cichon; David Couper; Francesco Cucca; Danielle Dick; Tatiana Foroud; Helena Furberg; Ina Giegling; Nathan A Gillespie; Fangyi Gu; Alistair S Hall; Jenni Hällfors; Shizhong Han; Annette M Hartmann; Kauko Heikkilä; Ian B Hickie; Jouke Jan Hottenga; Pekka Jousilahti; Marika Kaakinen; Mika Kähönen; Philipp D Koellinger; Stephen Kittner; Bettina Konte; Maria-Teresa Landi; Tiina Laatikainen; Mark Leppert; Steven M Levy; Rasika A Mathias; Daniel W McNeil; Sarah E Medland; Grant W Montgomery; Tanda Murray; Matthias Nauck; Kari E North; Peter D Paré; Michele Pergadia; Ingo Ruczinski; Veikko Salomaa; Jorma Viikari; Gonneke Willemsen; Kathleen C Barnes; Eric Boerwinkle; Dorret I Boomsma; Neil Caporaso; Howard J Edenberg; Clyde Francks; Joel Gelernter; Hans Jörgen Grabe; Hyman Hops; Marjo-Riitta Jarvelin; Magnus Johannesson; Kenneth S Kendler; Terho Lehtimäki; Patrik K.E Magnusson; Mary L Marazita; Jonathan Marchini; Braxton D Mitchell; Markus M Nöthen; Brenda W Penninx; Olli Raitakari; Marcella Rietschel; Dan Rujescu; Nilesh J Samani; Ann G Schwartz; Sanjay Shete; Margaret Spitz; Gary E Swan; Henry Völzke; Juha Veijola; Qingyi Wei; Chris Amos; Dale S Cannon; Richard Grucza; Dorothy Hatsukami; Andrew Heath; Eric O Johnson; Jaakko Kaprio; Pamela Madden; Nicholas G Martin; Victoria L Stevens; Robert B Weiss; Peter Kraft; Laura J Bierut; Marissa A Ehringer

doi:10.1002/gepi.21760

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Distinct Loci in the CHRNA5/CHRNA3/CHRNB4 Gene Cluster Are Associated With Onset of Regular Smoking

Journal article

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Peer reviewed

Distinct Loci in the CHRNA5/CHRNA3/CHRNB4 Gene Cluster Are Associated With Onset of Regular Smoking

Sarah H Stephens, Sarah M Hartz, Nicole R Hoft, Nancy L Saccone, Robin C Corley, John K Hewitt, Christian J Hopfer, Naomi Breslau, Hilary Coon, Xiangning Chen, …

Genetic epidemiology, Vol.37(8), pp.846-859

2013-12

DOI: https://doi.org/10.1002/gepi.21760

PMCID: PMC3947535

PMID: 24186853

Abstract

meta-analysis

smoke

CHRNA3

CHRNB4

nicotine

CHRNA5

Neuronal nicotinic acetylcholine receptor (nAChR) genes ( CHRNA5 / CHRNA3 / CHRNB4 ) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI ( P = 0.59) or AOS ( P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.5 Neuroscience; 1.5.894 Nicotine
Web Of Science research areas: Genetics & Heredity; Mathematical & Computational Biology
ESI research areas: Molecular Biology & Genetics

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Title: Distinct Loci in the CHRNA5/CHRNA3/CHRNB4 Gene Cluster Are Associated With Onset of Regular Smoking
Creators: Sarah H Stephens - Department of Epidemiology and Public Health, University of Maryland, Baltimore, Maryland, United States of America
Sarah M Hartz - Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, United States of America
Nicole R Hoft - Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado, United States of America
Nancy L Saccone - Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, United States of America
Robin C Corley - Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado, United States of America
John K Hewitt - Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado, United States of America
Christian J Hopfer - Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado, United States of America
Naomi Breslau - Department of Epidemiology, Michigan State University, East Lansing, Michigan, United States of America
Hilary Coon - Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, Utah, United States of America
Xiangning Chen - Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, United States of America
Francesca Ducci - Institute of Psychiatry, King’s College London and Department of Mental Health, St George’s University, London, United Kingdom
Nicole Dueker - Department of Epidemiology and Public Health, University of Maryland, Baltimore, Maryland, United States of America
Nora Franceschini - Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, United States of America
Josef Frank - Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Clinical Faculty Mannheim / Heidelberg University, Mannheim, Germany
Younghun Han - Department of Epidemiology, MD Anderson, Houston, Texas, United States of America
Nadia N Hansel - Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America
Chenhui Jiang - Departments of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, United States of America
Tellervo Korhonen - Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland
Penelope A Lind - Department of Epidemiology, Queensland Institute of Medical Research, Brisbane, Queensland, Australia
Jason Liu - Department of Statistics, University of Oxford, Oxford, United Kingdom
Leo-Pekka Lyytikäinen - Department of Clinical Chemistry, Fimlab Laboratories, Tampere University Hospital and University of Tampere School of Medicine, Tampere, Finland
Martha Michel - Center for Health Sciences, SRI International, Menlo Park, California, United States of America
John R Shaffer - Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
Susan E Short - Department of Sociology, Brown University, Providence, Rhode Island, United States of America
Juzhong Sun - Department of Epidemiology Research, American Cancer Society, Atlanta, Georgia, United States of America
Alexander Teumer - University Medicine Greifswald, University of Greifswald, Greifswald, Germany
John R Thompson - Department of Health Sciences, University of Leicester, Leicester, United Kingdom
Nicole Vogelzangs - Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands
Jacqueline M Vink - Department of Biological Psychology, VU University, Amsterdam, Amsterdam, The Netherlands
Angela Wenzlaff - Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, United States of America
William Wheeler - Division of Cancer Epidemiology and Genetics, National Institute of Health, Bethesda, Maryland, United States of America
Bao-Zhu Yang - Departments of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, United States of America
Steven H Aggen - Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, United States of America
Anthony J Balmforth - LIGHT Research Institute, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom
Sebastian E Baumeister - University Medicine Greifswald, University of Greifswald, Greifswald, Germany
Terri H Beaty - Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America
Daniel J Benjamin - Department of Economics, Cornell University, Ithaca, New York, United States of America
Andrew W Bergen - Center for Health Sciences, SRI International, Menlo Park, California, United States of America
Ulla Broms - Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland
David Cesarini - Department of Economics, New York University, New York, New York, United States of America
Nilanjan Chatterjee - Division of Cancer Epidemiology and Genetics, National Institutes of Health, Bethesda, Maryland, United States of America
Jingchun Chen - Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, United States of America
Yu-Ching Cheng - Department of Epidemiology and Public Health, University of Maryland, Baltimore, Maryland, United States of America
Sven Cichon - Institute of Neuroscience and Medicine (INM-1); Structural and Functional Organization of the Brain Genomic Imaging; Department of Genomics, Life and Brain Center; Research Center Juelich, Juelich, Germany; Life and Brain Center and Institute of Human Genetics, University of Bonn, Bonn, Germany
David Couper - Department of Psychiatry, Neurobiology, Pharmacology, and Biotechnology, University of Pisa, Pisa, Italy
Francesco Cucca - Istituto di Ricerca Genetica e Biomedica, CNR, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy
Danielle Dick - Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, United States of America
Tatiana Foroud - Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
Helena Furberg - Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America
Ina Giegling - Department of Psychiatry, University of Munich (LMU), Munich, Germany
Nathan A Gillespie - Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, United States of America
Fangyi Gu - Division of Cancer Epidemiology and Genetics, National Institutes of Health, Bethesda, Maryland, United States of America
Alistair S Hall - LIGHT Research Institute, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom
Jenni Hällfors - Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland
Shizhong Han - Departments of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, United States of America
Annette M Hartmann - Department of Psychiatry, University of Munich (LMU), Munich, Germany
Kauko Heikkilä - Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland
Ian B Hickie - Brain and Mind Research Institute, University of Sydney, Sydney, Australia
Jouke Jan Hottenga - Department of Biological Psychology, VU University, Amsterdam, Amsterdam, The Netherlands
Pekka Jousilahti - Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland
Marika Kaakinen - Institute of Health Sciences and Biocenter Oulu, University of Oulu, Finland
Mika Kähönen - Department of Clinical Physiology, Tampere University Hospital and University of Tampere School of Medicine, Tampere, Finland
Philipp D Koellinger - Department of Applied Economics, Erasmus Universiteit Rotterdam, Rotterdam, Netherlands
Stephen Kittner - Department of Neurology, Baltimore Veterans Affairs Medical Center, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
Bettina Konte - Department of Psychiatry, University of Munich (LMU), Munich, Germany
Maria-Teresa Landi - Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America
Tiina Laatikainen - Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland
Mark Leppert - Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, Utah, United States of America
Steven M Levy - Department of Preventive and Community Dentistry and Department of Epidemiology, University of Iowa, Iowa City, Iowa, United States of America
Rasika A Mathias - Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America
Daniel W McNeil - Department of Psychology and Dental Practice and Rural Health, West Virginia University, Morgantown, West Virginia, United States of America
Sarah E Medland - Department of Epidemiology, Queensland Institute of Medical Research, Brisbane, Queensland, Australia
Grant W Montgomery - Department of Epidemiology, Queensland Institute of Medical Research, Brisbane, Queensland, Australia
Tanda Murray - Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America
Matthias Nauck - University Medicine Greifswald, University of Greifswald, Greifswald, Germany
Kari E North - Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, United States of America
Peter D Paré - Department of Medicine, University of British Columbia, Vancouver, Canada
Michele Pergadia - Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, United States of America
Ingo Ruczinski - Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America
Veikko Salomaa - Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland
Jorma Viikari - Department of Medicine, Turku University Hospital, Turku, Finland
Gonneke Willemsen - Department of Biological Psychology, VU University, Amsterdam, Amsterdam, The Netherlands
Kathleen C Barnes - Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America
Eric Boerwinkle - Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America
Dorret I Boomsma - Department of Biological Psychology, VU University, Amsterdam, Amsterdam, The Netherlands
Neil Caporaso - Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America
Howard J Edenberg - Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
Clyde Francks - Department of the MPI Psycholinguistics, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands
Joel Gelernter - Departments of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, United States of America
Hans Jörgen Grabe - University Medicine Greifswald, University of Greifswald, Greifswald, Germany
Hyman Hops - Oregon Research Institute, Eugene, Oregon, United States of America
Marjo-Riitta Jarvelin - Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPA) Centre for Environment and Health School of Public Health, Imperial College London, United Kingdom; Institute of Health Sciences and Biocenter Oulu, University of Oulu, Finland; Unit of Primary Care, Oulu University Hospital, Oulu, Finland; Department of Children and Young People and Families, National Institute for Health and Welfare, Oulu, Finland
Magnus Johannesson - Department of Economics, Stockholm School of Economics, Stockholm, Sweden
Kenneth S Kendler - Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, United States of America
Terho Lehtimäki - Department of Clinical Chemistry, Fimlab Laboratories, Tampere University Hospital and University of Tampere School of Medicine, Tampere, Finland
Patrik K.E Magnusson - Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
Mary L Marazita - Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
Jonathan Marchini - Department of Statistics, University of Oxford, Oxford, United Kingdom
Braxton D Mitchell - Department of Epidemiology and Public Health, University of Maryland, Baltimore, Maryland, United States of America
Markus M Nöthen - Department of Genomics, Life and Brain Center, Life and Brain Center, Institute of Human Genetics, University of Bonn, Bonn, Germany
Brenda W Penninx - Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands
Olli Raitakari - Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital; Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
Marcella Rietschel - Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Clinical Faculty Mannheim / Heidelberg University, Mannheim, Germany
Dan Rujescu - Department of Psychiatry, University of Munich (LMU), Munich, Germany
Nilesh J Samani - Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom
Ann G Schwartz - Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, United States of America
Sanjay Shete - Department of Epidemiology, MD Anderson, Houston, Texas, United States of America
Margaret Spitz - Department of Epidemiology, MD Anderson, Houston, Texas, United States of America
Gary E Swan - Center for Health Sciences, SRI International, Menlo Park, California, United States of America
Henry Völzke - University Medicine Greifswald, University of Greifswald, Greifswald, Germany
Juha Veijola - Institute of Health Sciences and Biocenter Oulu, University of Oulu, Finland
Qingyi Wei - Department of Epidemiology, MD Anderson, Houston, Texas, United States of America
Chris Amos - Department of Epidemiology, MD Anderson, Houston, Texas, United States of America
Dale S Cannon - Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, Utah, United States of America
Richard Grucza - Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, United States of America
Dorothy Hatsukami - Department of Psychiatry, University of Minnesota, Minneapolis, Minnesota, United States of America
Andrew Heath - Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, United States of America
Eric O Johnson - Department of Behavioral Health Epidemiology, RTI International, Research Triangle Park, North Carolina, United States of America
Jaakko Kaprio - Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland
Pamela Madden - Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, United States of America
Nicholas G Martin - Department of Epidemiology, Queensland Institute of Medical Research, Brisbane, Queensland, Australia
Victoria L Stevens - Department of Epidemiology Research, American Cancer Society, Atlanta, Georgia, United States of America
Robert B Weiss - Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, Utah, United States of America
Peter Kraft - Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America
Laura J Bierut - Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, United States of America
Marissa A Ehringer - Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado, United States of America
Publication Details: Genetic epidemiology, Vol.37(8), pp.846-859
Academic Unit: Miller School of Medicine; John P. Hussman Institute for Human Genomics
Language: English
Resource Type: Journal article
PMID: 24186853
PMCID: PMC3947535
Record Identifier: 991031600638602976