title: Tobacco smoking is causally associated with antipsychotic medication use and schizophrenia, but not with antidepressant medication use or depression.
abstract: BACKGROUND
  Tobacco smoking is more common among patients with schizophrenia and depression than among healthy individuals. We tested the hypothesis that high tobacco smoking intensity is causally associated with antipsychotic medication use, schizophrenia, antidepressant medication use and/or depression in the general population, and compared results with those for chronic obstructive pulmonary disease.
  
  
  METHODS
  We used self-reported smoking intensity in cigarettes/day and a polymorphism in the CHRNA3 gene cluster (rs1051730) associated with smoking intensity, on 63,296 20-100-year-old individuals from the Danish general population; 23,282 were never-smokers and 40,014 ever-smokers. For schizophrenia, we compared our results with those in the Psychiatric Genomics Consortium.
  
  
  RESULTS
  In smokers, heterozygotes (CT) and homozygotes (TT) for rs1051730 genotype had higher smoking intensity compared with non-carriers (CC). Furthermore, in ever-smokers homozygotes had increased risk of antipsychotic medication with an odds ratio (OR) of 1.16 [95% confidence interval (CI) 1.02-1.31] compared with non-carriers, whereas in never-smokers the corresponding OR was 1.07 (0.87-1.31) (P-interaction: 0.60). Correspondingly, ORs were 1.60 (0.74-3.47) and 1.02 (0.11-9.10) for schizophrenia (P-interaction: 0.85), 1.02 (0.93-1.13) and 0.99 (0.85-1.15) for antidepressant medication (P-interaction: 0.87), 0.85 (0.66-1.10) and 1.26 (0.87-1.83) for depression (P-interaction: 0.30) and 1.31 (1.16-1.47) and 0.89 (0.58-1.36) for chronic obstructive pulmonary disease (P-interaction: 0.16). Odds ratios per rs1051730 allele for schizophrenia and antipsychotic medication use in ever-smokers in the general population were 1.22 (95% CI: 0.84-1.79) and 1.06 (1.00-1.12). In the Psychiatric Genomics Consortium, the corresponding OR for schizophrenia was 1.06 (1.04-1.08) in ever- and never-smokers combined.
  
  
  CONCLUSIONS
  Our data suggest that tobacco smoking could influence the development of psychotic conditions causally, whereas an influence on depression seems unlikely.
authors.affiliation: Department of Clinical Biochemistry, Herlev Hospital, Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark and Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Frederiksberg, Denmark Department of Clinical Biochemistry, Herlev Hospital, Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark and Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Frederiksberg, Denmark Department of Clinical Biochemistry, Herlev Hospital, Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark and Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Frederiksberg, Denmark.
authors.forename: Marie Kim
authors.initials: MK
authors.lastname: Wium-Andersen
authors.affiliation: Department of Clinical Biochemistry, Herlev Hospital, Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark and Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Frederiksberg, Denmark Department of Clinical Biochemistry, Herlev Hospital, Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark and Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Frederiksberg, Denmark.
authors.forename: David Dynnes
authors.initials: DD
authors.lastname: Ørsted
authors.affiliation: Department of Clinical Biochemistry, Herlev Hospital, Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark and Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Frederiksberg, Denmark Department of Clinical Biochemistry, Herlev Hospital, Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark and Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Frederiksberg, Denmark Department of Clinical Biochemistry, Herlev Hospital, Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark and Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Frederiksberg, Denmark Department of Clinical Biochemistry, Herlev Hospital, Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark and Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Frederiksberg, Denmark Boerge.Nordestgaard@regionh.dk.
authors.forename: Børge Grønne
authors.initials: BG
authors.lastname: Nordestgaard
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000928:Antidepressive Agents / Q000627:therapeutic use; D014150:Antipsychotic Agents / Q000627:therapeutic use; D003866:Depressive Disorder / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000453:epidemiology / Q000235:genetics; D011978:Receptors, Nicotinic / Q000235:genetics; D012559:Schizophrenia / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics*; D012907:Smoking / Q000009:adverse effects / Q000453:epidemiology / Q000235:genetics*; D055815:Young Adult
chemical_list: D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D011978:Receptors, Nicotinic
keywords: CHRNA3; Mendelian randomization; general population; genetic variant; rs1051730; schizophrenia