title: A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences.
abstract: Using Icelandic whole-genome sequence data and an imputation approach we searched for rare sequence variants in CHRNA4 and tested them for association with nicotine dependence. We show that carriers of a rare missense variant (allele frequency=0.24%) within CHRNA4, encoding an R336C substitution, have greater risk of nicotine addiction than non-carriers as assessed by the Fagerstrom Test for Nicotine Dependence (P=1.2 × 10(-4)). The variant also confers risk of several serious smoking-related diseases previously shown to be associated with the D398N substitution in CHRNA5. We observed odds ratios (ORs) of 1.7-2.3 for lung cancer (LC; P=4.0 × 10(-4)), chronic obstructive pulmonary disease (COPD; P=9.3 × 10(-4)), peripheral artery disease (PAD; P=0.090) and abdominal aortic aneurysms (AAAs; P=0.12), and the variant associates strongly with the early-onset forms of LC (OR=4.49, P=2.2 × 10(-4)), COPD (OR=3.22, P=2.9 × 10(-4)), PAD (OR=3.47, P=9.2 × 10(-3)) and AAA (OR=6.44, P=6.3 × 10(-3)). Joint analysis of the four smoking-related diseases reveals significant association (P=6.8 × 10(-5)), particularly for early-onset cases (P=2.1 × 10(-7)). Our results are in agreement with functional studies showing that the human α4β2 isoform of the channel containing R336C has less sensitivity for its agonists than the wild-type form following nicotine incubation.
authors.affiliation: deCODE genetics/Amgen, Reykjavik, Iceland.
authors.forename: T E
authors.initials: TE
authors.lastname: Thorgeirsson
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: G W
authors.initials: GW
authors.lastname: Reginsson
authors.affiliation: deCODE genetics/Amgen, Reykjavik, Iceland.
authors.forename: G
authors.initials: G
authors.lastname: Bjornsdottir
authors.affiliation: deCODE genetics/Amgen, Reykjavik, Iceland.
authors.forename: T
authors.initials: T
authors.lastname: Rafnar
authors.affiliation: deCODE genetics/Amgen, Reykjavik, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: I
authors.identifier: http://orcid.org/0000-0001-8339-150X
authors.initials: I
authors.lastname: Jonsdottir
authors.affiliation: deCODE genetics/Amgen, Reykjavik, Iceland.
authors.forename: A
authors.initials: A
authors.lastname: Helgadottir
authors.affiliation: deCODE genetics/Amgen, Reykjavik, Iceland.
authors.forename: S
authors.initials: S
authors.lastname: Gretarsdottir
authors.affiliation: deCODE genetics/Amgen, Reykjavik, Iceland.
authors.forename: H
authors.initials: H
authors.lastname: Helgadottir
authors.affiliation: Faculty of Medicine, University of Iceland, Reykjavik, Iceland.|Department of Respiratory Medicine, Landspitali University Hospital, Reykjavik, Iceland.
authors.forename: S
authors.initials: S
authors.lastname: Jonsson
authors.affiliation: Laekning, Medical Clinics, Reykjavik, Iceland.
authors.forename: S E
authors.initials: SE
authors.lastname: Matthiasson
authors.affiliation: Faculty of Medicine, University of Iceland, Reykjavik, Iceland.|Department of Respiratory Medicine, Landspitali University Hospital, Reykjavik, Iceland.
authors.forename: T
authors.initials: T
authors.lastname: Gislason
authors.affiliation: SAA National Center of Addiction Medicine, Reykjavik, Iceland.
authors.forename: T
authors.initials: T
authors.lastname: Tyrfingsson
authors.affiliation: Faculty of Medicine, University of Iceland, Reykjavik, Iceland.|Department of Cardiothoracic Surgery, Landspitali University Hospital, Reykjavik, Iceland.
authors.forename: T
authors.initials: T
authors.lastname: Gudbjartsson
authors.affiliation: Department of Pathology, Landspitali University Hospital, Reykjavik, Iceland.
authors.forename: H J
authors.initials: HJ
authors.lastname: Isaksson
authors.affiliation: Department of Respiratory Medicine, Landspitali University Hospital, Reykjavik, Iceland.
authors.forename: H
authors.initials: H
authors.lastname: Hardardottir
authors.affiliation: Department of Respiratory Medicine, Landspitali University Hospital, Reykjavik, Iceland.
authors.forename: A
authors.initials: A
authors.lastname: Sigvaldason
authors.affiliation: Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: L A
authors.initials: LA
authors.lastname: Kiemeney
authors.affiliation: Department for the Chemical and Biological Work Environment, National Institute of Occupational Health, Oslo, Norway.
authors.forename: A
authors.initials: A
authors.lastname: Haugen
authors.affiliation: Department for the Chemical and Biological Work Environment, National Institute of Occupational Health, Oslo, Norway.
authors.forename: S
authors.initials: S
authors.lastname: Zienolddiny
authors.affiliation: Community & Behavioral Health, Colorado School of Public Health, University of Colorado Denver, Aurora, CO, USA.
authors.forename: H J
authors.initials: HJ
authors.lastname: Wolf
authors.affiliation: Department of Pathology, University of Colorado Denver, Aurora, CO, USA.
authors.forename: W A
authors.initials: WA
authors.lastname: Franklin
authors.affiliation: Division of Medical Oncology, Hospital Ciudad de Coria, Coria, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Panadero
authors.affiliation: Division of Medical Oncology, University of Colorado School of Medicine, Denver, CO, USA.
authors.forename: J I
authors.initials: JI
authors.lastname: Mayordomo
authors.affiliation: Division of Respiratory Medicine, Queens Medical Centre, University of Nottingham, Nottingham, UK.
authors.forename: I P
authors.initials: IP
authors.lastname: Hall
authors.affiliation: The OLIN studies, Department of Medicine, Sunderby Central Hospital of Norrbotten, Luleå, Sweden.|Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine, Umeå University, Umeå, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Rönmark
authors.affiliation: The OLIN studies, Department of Medicine, Sunderby Central Hospital of Norrbotten, Luleå, Sweden.|Krefting Research Centre, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: B
authors.initials: B
authors.lastname: Lundbäck
authors.affiliation: Department of Respiratory Medicine, Gentofte Hospital, Copenhagen University, Hellerup, Denmark.
authors.forename: A
authors.initials: A
authors.lastname: Dirksen
authors.affiliation: Department of Respiratory Medicine, Gentofte Hospital, Copenhagen University, Hellerup, Denmark.|Centre for Diagnostic Imaging-Thoracic Section, Akershus University Hospital, Loerenskog, Norway.
authors.forename: H
authors.initials: H
authors.lastname: Ashraf
authors.affiliation: Department of Thoracic Surgery RT, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: J H
authors.initials: JH
authors.lastname: Pedersen
authors.affiliation: deCODE genetics/Amgen, Reykjavik, Iceland.
authors.forename: G
authors.initials: G
authors.lastname: Masson
authors.affiliation: deCODE genetics/Amgen, Reykjavik, Iceland.
authors.forename: P
authors.identifier: http://orcid.org/0000-0001-7123-6123
authors.initials: P
authors.lastname: Sulem
authors.affiliation: deCODE genetics/Amgen, Reykjavik, Iceland.
authors.forename: U
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.affiliation: deCODE genetics/Amgen, Reykjavik, Iceland.
authors.forename: D F
authors.initials: DF
authors.lastname: Gudbjartsson
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: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017544:Aortic Aneurysm, Abdominal / Q000209:etiology / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007055:Iceland; D008175:Lung Neoplasms / Q000209:etiology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D058729:Peripheral Arterial Disease / Q000209:etiology / Q000235:genetics; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000235:genetics; D011978:Receptors, Nicotinic / Q000235:genetics*; D012907:Smoking / Q000235:genetics*; D014029:Tobacco Use Disorder / Q000150:complications* / Q000235:genetics*; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D011978:Receptors, Nicotinic