title: Investigating the possible causal association of smoking with depression and anxiety using Mendelian randomisation meta-analysis: the CARTA consortium.
abstract: OBJECTIVE
  To investigate whether associations of smoking with depression and anxiety are likely to be causal, using a Mendelian randomisation approach.
  
  
  METHODS
  Mendelian randomisation meta-analyses using a genetic variant (rs16969968/rs1051730) as a proxy for smoking heaviness, and observational meta-analyses of the associations of smoking status and smoking heaviness with depression, anxiety and psychological distress.
  
  
  METHODS
  Current, former and never smokers of European ancestry aged ≥16 years from 25 studies in the Consortium for Causal Analysis Research in Tobacco and Alcohol (CARTA).
  
  
  METHODS
  Binary definitions of depression, anxiety and psychological distress assessed by clinical interview, symptom scales or self-reported recall of clinician diagnosis.
  
  
  RESULTS
  The analytic sample included up to 58 176 never smokers, 37 428 former smokers and 32 028 current smokers (total N=127 632). In observational analyses, current smokers had 1.85 times greater odds of depression (95% CI 1.65 to 2.07), 1.71 times greater odds of anxiety (95% CI 1.54 to 1.90) and 1.69 times greater odds of psychological distress (95% CI 1.56 to 1.83) than never smokers. Former smokers also had greater odds of depression, anxiety and psychological distress than never smokers. There was evidence for positive associations of smoking heaviness with depression, anxiety and psychological distress (ORs per cigarette per day: 1.03 (95% CI 1.02 to 1.04), 1.03 (95% CI 1.02 to 1.04) and 1.02 (95% CI 1.02 to 1.03) respectively). In Mendelian randomisation analyses, there was no strong evidence that the minor allele of rs16969968/rs1051730 was associated with depression (OR=1.00, 95% CI 0.95 to 1.05), anxiety (OR=1.02, 95% CI 0.97 to 1.07) or psychological distress (OR=1.02, 95% CI 0.98 to 1.06) in current smokers. Results were similar for former smokers.
  
  
  CONCLUSIONS
  Findings from Mendelian randomisation analyses do not support a causal role of smoking heaviness in the development of depression and anxiety.
authors.affiliation: MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, UK.|UK Centre for Tobacco and Alcohol Studies, School of Experimental Psychology, University of Bristol, Bristol, UK.
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authors.initials: AE
authors.lastname: Taylor
authors.affiliation: MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, UK.|UK Centre for Tobacco and Alcohol Studies, School of Experimental Psychology, University of Bristol, Bristol, UK.
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authors.forename: Johan H
authors.initials: JH
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authors.affiliation: Faculty of Medicine, Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Maiken Elvestad
authors.initials: ME
authors.lastname: Gabrielsen
authors.affiliation: Faculty of Medicine, Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway.
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authors.affiliation: Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
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authors.affiliation: Department of Epidemiology and Public Health, University College London, London, UK.
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authors.affiliation: University of Helsinki, Hjelt institute, Helsinki, Finland.
authors.forename: Anu
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authors.affiliation: University of Eastern Finland, Institute of Public Health & Clinical Nutrition, Kuopio, Finland.|Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.|Hospital District of North Karelia, Joensuu, Finland.
authors.forename: Tiina
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authors.affiliation: South West London and St George's Mental Health Trust, London, UK.
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authors.affiliation: Metabolic Genetics Section, Faculty of Health and Medical Sciences, Novo Nordisk Foundation Centre for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.|Copenhagen Prospective Studies on Asthma in Childhood, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.|Danish Pediatric Asthma Center, Gentofte Hospital, The Capital Region, Copenhagen, Denmark.
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authors.affiliation: Research Centre for Prevention and Health, the Capital Region of Denmark, Denmark.
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authors.affiliation: Research Centre for Prevention and Health, the Capital Region of Denmark, Denmark.
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authors.affiliation: Research Centre for Prevention and Health, the Capital Region of Denmark, Denmark.
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authors.affiliation: Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, UK.
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authors.affiliation: Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, UK.
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authors.affiliation: Department of Primary Care & Population Health, UCL, London, UK.
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authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.|The Medical and Population Genomics Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland.
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authors.affiliation: Folkhälsan Research Centre, Helsinki, Finland.
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authors.affiliation: MRC Unit for Lifelong Health, Ageing at UCL, UK.
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authors.initials: L
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authors.affiliation: Department of Psychology, University of Toronto, Toronto, Canada.|Rotman Research Institute, Toronto, Canada.
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authors.affiliation: Department of Psychological Medicine, University of Otago, Christchurch, New Zealand.
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authors.initials: LJ
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authors.affiliation: Departments of Physiology and Nutritional Sciences, University of Toronto, Toronto, Canada.|Hospital for Sick Children, Toronto, Canada.
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authors.initials: Z
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authors.affiliation: Rotman Research Institute, Toronto, Canada.|Departments of Psychology and Psychiatry, University of Toronto, Toronto, Canada.
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authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
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authors.initials: EA
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authors.affiliation: Department of Epidemiology and Public Health, University College London, London, UK.
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authors.lastname: Kivimaki
authors.affiliation: Folkhälsan Research Centre, Helsinki, Finland.|Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, Finland.|National Institute for Health and Welfare, Finland.|Department of General Practice and Primary health Care, University of Helsinki, Finland.|Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland.|Vasa Central Hospital, Vasa, Finland.
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authors.initials: JG
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authors.affiliation: Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, UK.|Institute of Cardiovascular Science, University College London, UK.
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authors.initials: DI
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authors.affiliation: Research Centre for Prevention and Health, the Capital Region of Denmark, Denmark.|Department of Clinical Experimental Research, Glostrup University Hospital, Denmark.|Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Denmark.
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authors.affiliation: Institute of Health Sciences, FI-90014 University of Oulu, Finland.|Biocenter Oulu, FI-90014 University of Oulu, Finland.|Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPA) Centre for Environment and Health, School of Public Health, Imperial College London, UK.|Unit of Primary Care, Oulu University Hospital, Oulu, Finland.|Department of Children and Young People and Families, National Institute for Health and Welfare, Oulu, Finland.
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authors.initials: MR
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authors.affiliation: University of Helsinki, Hjelt institute, Helsinki, Finland.|University of Eastern Finland, Institute of Public Health & Clinical Nutrition, Kuopio, Finland.|Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland.
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authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.|Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
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authors.initials: DJ
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authors.affiliation: Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
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authors.initials: C
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authors.initials: PR
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authors.affiliation: MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, UK.|School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: George Davey
authors.initials: GD
authors.lastname: Smith
authors.affiliation: MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, UK.|UK Centre for Tobacco and Alcohol Studies, School of Experimental Psychology, University of Bristol, Bristol, UK.
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mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001007:Anxiety / Q000453:epidemiology*; D001008:Anxiety Disorders / Q000453:epidemiology*; D015984:Causality; D003863:Depression / Q000453:epidemiology*; D003866:Depressive Disorder / Q000453:epidemiology*; D005260:Female; D006801:Humans; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D011978:Receptors, Nicotinic / Q000235:genetics; D012907:Smoking / Q000453:epidemiology* / Q000235:genetics; D013315:Stress, Psychological / Q000453:epidemiology*; D055815:Young Adult
chemical_list: D009419:Nerve Tissue Proteins; D011978:Receptors, Nicotinic; C447158:CHRNA5 protein, human; C447159:CHRNB4 protein, human
keywords: Anxiety; Depression; Mendelian randomisation; Smoking