title: Genome-wide association study on detailed profiles of smoking behavior and nicotine dependence in a twin sample.
abstract: Smoking is a major risk factor for several somatic diseases and is also emerging as a causal factor for neuropsychiatric disorders. Genome-wide association (GWA) and candidate gene studies for smoking behavior and nicotine dependence (ND) have disclosed too few predisposing variants to account for the high estimated heritability. Previous large-scale GWA studies have had very limited phenotypic definitions of relevance to smoking-related behavior, which has likely impeded the discovery of genetic effects. We performed GWA analyses on 1114 adult twins ascertained for ever smoking from the population-based Finnish Twin Cohort study. The availability of 17 smoking-related phenotypes allowed us to comprehensively portray the dimensions of smoking behavior, clustered into the domains of smoking initiation, amount smoked and ND. Our results highlight a locus on 16p12.3, with several single-nucleotide polymorphisms (SNPs) in the vicinity of CLEC19A showing association (P<1 × 10(-6)) with smoking quantity. Interestingly, CLEC19A is located close to a previously reported attention-deficit hyperactivity disorder (ADHD) linkage locus and an evident link between ADHD and smoking has been established. Intriguing preliminary association (P<1 × 10(-5)) was detected between DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) ND diagnosis and several SNPs in ERBB4, coding for a Neuregulin receptor, on 2q33. The association between ERBB4 and DSM-IV ND diagnosis was replicated in an independent Australian sample. Recently, a significant increase in ErbB4 and Neuregulin 3 (Nrg3) expression was revealed following chronic nicotine exposure and withdrawal in mice and an association between NRG3 SNPs and smoking cessation success was detected in a clinical trial. ERBB4 has previously been associated with schizophrenia; further, it is located within an established schizophrenia linkage locus and within a linkage locus for a smoker phenotype identified in this sample. In conclusion, we disclose novel tentative evidence for the involvement of ERBB4 in ND, suggesting the involvement of the Neuregulin/ErbB signalling pathway in addictions and providing a plausible link between the high co-morbidity of schizophrenia and ND.
authors.affiliation: Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland.
authors.forename: A
authors.initials: A
authors.lastname: Loukola
authors.affiliation: Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Wedenoja
authors.affiliation: Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland.
authors.forename: K
authors.initials: K
authors.lastname: Keskitalo-Vuokko
authors.affiliation: 1] Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland [2] National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: U
authors.initials: U
authors.lastname: Broms
authors.affiliation: 1] Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland [2] National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: T
authors.initials: T
authors.lastname: Korhonen
authors.affiliation: 1] National Institute for Health and Welfare, Helsinki, Finland [2] Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland [3] Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: S
authors.initials: S
authors.lastname: Ripatti
authors.affiliation: 1] National Institute for Health and Welfare, Helsinki, Finland [2] Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland.
authors.forename: A-P
authors.initials: AP
authors.lastname: Sarin
authors.affiliation: Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Pitkäniemi
authors.affiliation: Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland.
authors.forename: L
authors.initials: L
authors.lastname: He
authors.affiliation: Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland.
authors.forename: A
authors.initials: A
authors.lastname: Häppölä
authors.affiliation: Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland.
authors.forename: K
authors.initials: K
authors.lastname: Heikkilä
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA.
authors.forename: Y-L
authors.initials: YL
authors.lastname: Chou
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Pergadia
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Heath
authors.affiliation: Queensland Institute of Medical Research, Brisbane, QLD, Australia.
authors.forename: G W
authors.initials: GW
authors.lastname: Montgomery
authors.affiliation: Queensland Institute of Medical Research, Brisbane, QLD, Australia.
authors.forename: N G
authors.initials: NG
authors.lastname: Martin
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA.
authors.forename: P A F
authors.initials: PA
authors.lastname: Madden
authors.affiliation: 1] Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland [2] National Institute for Health and Welfare, Helsinki, Finland [3] Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Kaprio
mesh_terms: D015331:Cohort Studies; D058999:Drug-Seeking Behavior; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D066247:Receptor, ErbB-4 / Q000235:genetics; D012907:Smoking / Q000235:genetics* / Q000523:psychology*; D014029:Tobacco Use Disorder / Q000235:genetics* / Q000523:psychology*; D014429:Twins, Dizygotic / Q000235:genetics; D014430:Twins, Monozygotic / Q000235:genetics
chemical_list: C587689:ERBB4 protein, human; D066247:Receptor, ErbB-4