title: Genome-wide meta-analysis reveals common splice site acceptor variant in CHRNA4 associated with nicotine dependence.
abstract: We conducted a 1000 Genomes-imputed genome-wide association study (GWAS) meta-analysis for nicotine dependence, defined by the Fagerström Test for Nicotine Dependence in 17 074 ever smokers from five European-ancestry samples. We followed up novel variants in 7469 ever smokers from five independent European-ancestry samples. We identified genome-wide significant association in the alpha-4 nicotinic receptor subunit (CHRNA4) gene on chromosome 20q13: lowest P=8.0 × 10(-9) across all the samples for rs2273500-C (frequency=0.15; odds ratio=1.12 and 95% confidence interval=1.08-1.17 for severe vs mild dependence). rs2273500-C, a splice site acceptor variant resulting in an alternate CHRNA4 transcript predicted to be targeted for nonsense-mediated decay, was associated with decreased CHRNA4 expression in physiologically normal human brains (lowest P=7.3 × 10(-4)). Importantly, rs2273500-C was associated with increased lung cancer risk (N=28 998, odds ratio=1.06 and 95% confidence interval=1.00-1.12), likely through its effect on smoking, as rs2273500-C was no longer associated with lung cancer after adjustment for smoking. Using criteria for smoking behavior that encompass more than the single 'cigarettes per day' item, we identified a common CHRNA4 variant with important regulatory properties that contributes to nicotine dependence and smoking-related consequences.
authors.affiliation: Behavioral and Urban Health Program, Behavioral Health and Criminal Justice Research Division, Research Triangle Institute International, Research Triangle Park, NC, USA.
authors.forename: D B
authors.initials: DB
authors.lastname: Hancock
authors.affiliation: deCODE Genetics/Amgen, Reykjavik, Iceland.
authors.forename: G W
authors.initials: GW
authors.lastname: Reginsson
authors.affiliation: Research Computing Division, Research Triangle Institute International, Research Triangle Park, NC, USA.
authors.forename: N C
authors.initials: NC
authors.lastname: Gaddis
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA.|Nevada Institute of Personalized Medicine and Department of Psychology, University of Nevada, Las Vegas, NV, USA.
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Genetics, Washington University in St. Louis, St. Louis, MO, USA.
authors.forename: N L
authors.initials: NL
authors.lastname: Saccone
authors.affiliation: Department of Biostatistics and Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Lutz
authors.affiliation: Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: B
authors.initials: B
authors.lastname: Qaiser
authors.affiliation: Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Sherva
authors.affiliation: deCODE Genetics/Amgen, Reykjavik, Iceland.
authors.forename: S
authors.initials: S
authors.lastname: Steinberg
authors.affiliation: deCODE Genetics/Amgen, Reykjavik, Iceland.
authors.forename: F
authors.initials: F
authors.lastname: Zink
authors.affiliation: deCODE Genetics/Amgen, Reykjavik, Iceland.
authors.forename: S N
authors.initials: SN
authors.lastname: Stacey
authors.affiliation: Behavioral and Urban Health Program, Behavioral Health and Criminal Justice Research Division, Research Triangle Institute International, Research Triangle Park, NC, USA.
authors.forename: C
authors.initials: C
authors.lastname: Glasheen
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, USA.
authors.forename: F
authors.initials: F
authors.lastname: Gu
authors.affiliation: Iowa Department of Public Health, Des Moines, IA, USA.
authors.forename: B N
authors.initials: BN
authors.lastname: Frederiksen
authors.affiliation: Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: A
authors.initials: A
authors.lastname: Loukola
authors.affiliation: deCODE Genetics/Amgen, Reykjavik, Iceland.
authors.forename: D F
authors.initials: DF
authors.lastname: Gudbjartsson
authors.affiliation: Institute of Epidemiology I, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Brüske
authors.affiliation: Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, USA.
authors.forename: M T
authors.initials: MT
authors.lastname: Landi
authors.affiliation: Department of Genetic Epidemiology, University of Göttingen-Georg-August University Göttingen, Göttingen, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Bickeböller
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: P
authors.initials: P
authors.lastname: Madden
authors.affiliation: Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.|Department of Neurology, Boston University School of Medicine, Boston, MA, USA.|Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA.|Department of Genetics and Genomics, Boston University School of Medicine, Boston, MA, USA.|Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.|Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Farrer
authors.affiliation: Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland.|National Institute for Health and Welfare, Helsinki, Finland.|Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Kaprio
authors.affiliation: Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.|VISN 4 Mental Illness Research, Education and Clinical Center, Philadelphia VA Medical Center, Philadelphia, PA, USA.
authors.forename: H R
authors.initials: HR
authors.lastname: Kranzler
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.|Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.|Department of Neurobiology, Yale University School of Medicine, New Haven, CT, USA.|VA CT Healthcare Center, Department of Psychiatry, West Haven, CT, USA.
authors.forename: J
authors.initials: J
authors.lastname: Gelernter
authors.affiliation: Center for Tobacco Research and Intervention, University of Wisconsin, Madison, WI, USA.
authors.forename: T B
authors.initials: TB
authors.lastname: Baker
authors.affiliation: Department of Epidemiology, Harvard University School of Public Health, Boston, MA, USA.|Department of Biostatistics, Harvard University School of Public Health, Boston, MA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Kraft
authors.affiliation: Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.|Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.|Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanoven, NH, USA.
authors.forename: C I
authors.initials: CI
authors.lastname: Amos
authors.affiliation: Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, USA.
authors.forename: N E
authors.initials: NE
authors.lastname: Caporaso
authors.affiliation: Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Hokanson
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: L J
authors.initials: LJ
authors.lastname: Bierut
authors.affiliation: deCODE Genetics/Amgen, Reykjavik, Iceland.
authors.forename: T E
authors.initials: TE
authors.lastname: Thorgeirsson
authors.affiliation: Fellow Program and Behavioral Health and Criminal Justice Research Division, Research Triangle Institute International, Research Triangle Park, NC, USA.
authors.forename: E O
authors.initials: EO
authors.lastname: Johnson
authors.affiliation: deCODE Genetics/Amgen, Reykjavik, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: K
authors.initials: K
authors.lastname: Stefansson
mesh_terms: D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D022821:RNA Splice Sites; D011978:Receptors, Nicotinic / Q000235:genetics*; D014029:Tobacco Use Disorder / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D022821:RNA Splice Sites; D011978:Receptors, Nicotinic