title: Genome-Wide Meta-Analysis of Cotinine Levels in Cigarette Smokers Identifies Locus at 4q13.2.
abstract: Genome-wide association studies (GWAS) of complex behavioural phenotypes such as cigarette smoking typically employ self-report phenotypes. However, precise biomarker phenotypes may afford greater statistical power and identify novel variants. Here we report the results of a GWAS meta-analysis of levels of cotinine, the primary metabolite of nicotine, in 4,548 daily smokers of European ancestry. We identified a locus close to UGT2B10 at 4q13.2 (minimum p = 5.89 × 10(-10) for rs114612145), which was consequently replicated. This variant is in high linkage disequilibrium with a known functional variant in the UGT2B10 gene which is associated with reduced nicotine and cotinine glucuronidation activity, but intriguingly is not associated with nicotine intake. Additionally, we observed association between multiple variants within the 15q25.1 region and cotinine levels, all located within the CHRNA5-A3-B4 gene cluster or adjacent genes, consistent with previous much larger GWAS using self-report measures of smoking quantity. These results clearly illustrate the increase in power afforded by using precise biomarker measures in GWAS. Perhaps more importantly however, they also highlight that biomarkers do not always mark the phenotype of interest. The use of metabolite data as a proxy for environmental exposures should be carefully considered in the context of individual differences in metabolic pathways.
authors.affiliation: MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, Bristol, BS8 2BN, United Kingdom.|School of Social and Community Medicine, University of Bristol, Bristol, BS8 2BN, United Kingdom.
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authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA 23298, United States.
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authors.affiliation: Department of Biological Psychology, VU University, Amsterdam, 1081 BT, Netherlands.
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authors.affiliation: Department of Public Health, University of Helsinki, Helsinki, FI-00014, Finland.
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authors.affiliation: Department of Biological Psychology, VU University, Amsterdam, 1081 BT, Netherlands.
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authors.affiliation: Department of Psychiatry and EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, 1081 HL, Netherlands.
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authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, SE1 7EH, United Kingdom.
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authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, SE1 7EH, United Kingdom.
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authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA 23298, United States.
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authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA 23298, United States.
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authors.affiliation: National Institute for Health and Welfare, Helsinki, FI-00271, Finland.|Institute for Molecular Medicine, University of Helsinki, Helsinki, FI-00014, Finland.
authors.forename: Kirsi
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authors.affiliation: Department of Clinical Chemistry, Fimlab Laboratories, Tampere, FI-33520, Finland.|Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, FI-33014, Finland.
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authors.affiliation: Department of Public Health, University of Helsinki, Helsinki, FI-00014, Finland.
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authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, BS8 2BN, United Kingdom.
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authors.affiliation: MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, Bristol, BS8 2BN, United Kingdom.|School of Social and Community Medicine, University of Bristol, Bristol, BS8 2BN, United Kingdom.
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authors.affiliation: Department of Biological Psychology, VU University, Amsterdam, 1081 BT, Netherlands.
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authors.affiliation: Department of Public Health, University of Helsinki, Helsinki, FI-00014, Finland.|National Institute for Health and Welfare, Helsinki, FI-00271, Finland.|University of Eastern Finland, Institute of Public Health and Clinical Nutrition, Kuopio, FI-70211, Finland.
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authors.affiliation: National Institute for Health and Welfare, Helsinki, FI-00271, Finland.
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authors.affiliation: National Institute for Health and Welfare, Helsinki, FI-00271, Finland.|Institute for Molecular Medicine, University of Helsinki, Helsinki, FI-00014, Finland.|Estonian Genome Center, University of Tartu, Tartu, 51010, Estonia.
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authors.affiliation: MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, Bristol, BS8 2BN, United Kingdom.|School of Social and Community Medicine, University of Bristol, Bristol, BS8 2BN, United Kingdom.
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authors.affiliation: MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, Bristol, BS8 2BN, United Kingdom.|School of Social and Community Medicine, University of Bristol, Bristol, BS8 2BN, United Kingdom.
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authors.affiliation: MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, Bristol, BS8 2BN, United Kingdom.|School of Social and Community Medicine, University of Bristol, Bristol, BS8 2BN, United Kingdom.
authors.forename: George
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authors.lastname: Davey Smith
authors.affiliation: Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, FI-20521, Finland.|Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, FI-20520, Finland.
authors.forename: Olli T
authors.initials: OT
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authors.affiliation: Department of Clinical Chemistry, Fimlab Laboratories, Tampere, FI-33520, Finland.|Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, FI-33014, Finland.
authors.forename: Terho
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authors.lastname: Lehtimäki
authors.affiliation: Department of Clinical Physiology, Tampere University Hospital, Tampere, FI-33521, Finland.|Department of Clinical Physiology, University of Tampere School of Medicine, Tampere, FI-33014, Finland.
authors.forename: Mika
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authors.affiliation: National Institute for Health and Welfare, Helsinki, FI-00271, Finland.
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authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, SE1 7EH, United Kingdom.
authors.forename: Timothy
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authors.affiliation: Department of Psychiatry and EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, 1081 HL, Netherlands.
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authors.affiliation: Department of Biological Psychology, VU University, Amsterdam, 1081 BT, Netherlands.
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authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, M5S 1A8, Canada.|Department of Psychiatry, Campbell Family Mental Health Research Institute of the Centre for Addiction and Mental Health, University of Toronto, Toronto, Canada.
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authors.affiliation: Department of Public Health, University of Helsinki, Helsinki, FI-00014, Finland.|Institute for Molecular Medicine, University of Helsinki, Helsinki, FI-00014, Finland.|National Institute for Health and Welfare, Helsinki, FI-00271, Finland.
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authors.affiliation: MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, Bristol, BS8 2BN, United Kingdom.|School of Experimental Psychology and UK Centre for Tobacco and Alcohol Studies, University of Bristol, Bristol, BS8 1TU, United Kingdom.
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mesh_terms: D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D003367:Cotinine; D005260:Female; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D012907:Smoking / Q000235:genetics*
chemical_list: C552162:UGT2B10 protein, human; D014453:Glucuronosyltransferase; D003367:Cotinine
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