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Genome-wide association study on detailed profiles of smoking behavior and nicotine dependence in a twin sample

Molecular Psychiatry volume 19, pages 615–624 (2014)Cite this article

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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.

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Acknowledgements

We warmly thank the participating twin pairs and their family members for their contribution. We would like to express our appreciation to the skilled study interviewers A-M Iivonen, K Karhu, H-M Kuha, U Kulmala-Gråhn, M Mantere, K Saanakorpi, M Saarinen, R Sipilä, L Viljanen and E Voipio. E Hämäläinen and M Sauramo are acknowledged for their skilful technical assistance. Dr E Vuoksimaa and Dr A Latvala are thanked for collaboration in FT12 traits related to cognitive functions and schizotypy. Professor A Palotie is acknowledged for his advice and expertise in whole-genome genotyping. We are ever grateful to the late Academician Leena Peltonen-Palotie for her indispensable contribution throughout the years of the study. This work was supported for data collection by Academy of Finland grants (JK) and a NIH Grant DA12854 (PAFM). Genome-wide genotyping in the Finnish sample was funded by Global Research Award for Nicotine Dependence/Pfizer Inc. (JK), and Wellcome Trust Sanger Institute, UK. Genome-wide genotyping in the Australian sample was funded by NIH Grants AA013320, AA013321, AA013326, AA011998 and AA017688. This work was further supported by the Sigrid Juselius Foundation (JK), Doctoral Programs of Public Health (UB), the Yrjö Jahnsson Foundation (UB), the Jenny and Antti Wihuri Foundation (JK), the Juho Vainio Foundation for Post-Doctoral research (UB), Finnish Cultural Foundation (TK), a NIH Grant DA019951 (MLP) and by the Academy of Finland Center of Excellence in Complex Disease Genetics (Grant numbers: 213506, 129680 to JK).

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Authors and Affiliations

  1. Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland

    A Loukola, J Wedenoja, K Keskitalo-Vuokko, U Broms, T Korhonen, J Pitkäniemi, L He, A Häppölä, K Heikkilä & J Kaprio

  2. National Institute for Health and Welfare, Helsinki, Finland

    U Broms, T Korhonen, S Ripatti, A-P Sarin & J Kaprio

  3. Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland

    S Ripatti, A-P Sarin & J Kaprio

  4. Wellcome Trust Sanger Institute, Cambridge, UK

    S Ripatti

  5. Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA

    Y-L Chou, M L Pergadia, A C Heath & P A F Madden

  6. Queensland Institute of Medical Research, Brisbane, QLD, Australia

    G W Montgomery & N G Martin

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Correspondence to J Kaprio.

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Competing interests

JK has served as a consultant to Pfizer in 2008, 2011 and 2012. UB has served as a consultant to Pfizer in 2008. TK has served as a consultant to Pfizer in 2011 and 2012. The other authors declare no conflict of interest.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website

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Loukola, A., Wedenoja, J., Keskitalo-Vuokko, K. et al. Genome-wide association study on detailed profiles of smoking behavior and nicotine dependence in a twin sample. Mol Psychiatry 19, 615–624 (2014). https://doi.org/10.1038/mp.2013.72

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  • DOI: https://doi.org/10.1038/mp.2013.72

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