title: Increased alcohol consumption as a cause of alcoholism, without similar evidence for depression: a Mendelian randomization study.
abstract: BACKGROUND
  Increased alcohol consumption has been associated with depression and alcoholism, but whether these associations are causal remains unclear. We tested whether alcohol consumption is causally associated with depression and alcoholism.
  
  
  METHODS
  We included 78,154 men and women aged 20-100 years randomly selected in 1991-2010 from the general population of Copenhagen, Denmark, and genotyped 68,486 participants for two genetic variants in two alcohol dehydrogenase (ADH) genes, ADH-1B (rs1229984) and ADH-1C (rs698). We performed observational and causal analyses using a Mendelian randomization design with antidepressant medication use and hospitalization/death, with depression and alcoholism as outcomes.
  
  
  RESULTS
  In prospective analyses, the multifactorially adjusted hazard ratio for participants reporting >6 drinks/day vs participants reporting 0.1-1 drinks/day was 1.28 (95% confidence interval, 1.00-1.65) for prescription antidepressant use, with a corresponding hazard ratio of 0.80 (0.45-1.45) for hospitalization/death with depression and of 11.7 (8.77-15.6) for hospitalization/death with alcoholism. For hospitalization/death with alcoholism, instrumental variable analysis yielded a causal odds ratio of 28.6 (95 % confidence interval 6.47-126) for an increase of 1 drink/day estimated from the combined genotype combination, whereas the corresponding multifactorially adjusted observational odds ratio was 1.28 (1.25-1.31). Corresponding odds ratios were 1.11 (0.67-1.83) causal and 1.04 (1.03-1.06) observational for prescription antidepressant use, and 4.52 (0.99-20.5) causal and 0.98 (0.94-1.03) observational for hospitalization/death with depression.
  
  
  CONCLUSIONS
  These data indicate that the association between increased alcohol consumption and alcoholism is causal, without similar strong evidence for depression.
authors.affiliation: Department of Clinical Biochemistry, and Copenhagen General Population Study, Copenhagen University Hospital, Herlev, Denmark, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark, National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark and Copenhagen City Heart Study, Copenhagen University Hospital, Frederiksberg, Denmark Department of Clinical Biochemistry, and Copenhagen General Population Study, Copenhagen University Hospital, Herlev, Denmark, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark, National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark and Copenhagen City Heart Study, Copenhagen University Hospital, Frederiksberg, Denmark Department of Clinical Biochemistry, and Copenhagen General Population Study, Copenhagen University Hospital, Herlev, Denmark, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark, National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark and Copenhagen City Heart Study, Copenhagen University Hospital, Frederiksberg, Denmark.
authors.forename: Marie Kim
authors.initials: MK
authors.lastname: Wium-Andersen
authors.affiliation: Department of Clinical Biochemistry, and Copenhagen General Population Study, Copenhagen University Hospital, Herlev, Denmark, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark, National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark and Copenhagen City Heart Study, Copenhagen University Hospital, Frederiksberg, Denmark Department of Clinical Biochemistry, and Copenhagen General Population Study, Copenhagen University Hospital, Herlev, Denmark, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark, National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark and Copenhagen City Heart Study, Copenhagen University Hospital, Frederiksberg, Denmark Department of Clinical Biochemistry, and Copenhagen General Population Study, Copenhagen University Hospital, Herlev, Denmark, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark, National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark and Copenhagen City Heart Study, Copenhagen University Hospital, Frederiksberg, Denmark.
authors.forename: David Dynnes
authors.initials: DD
authors.lastname: Ørsted
authors.affiliation: Department of Clinical Biochemistry, and Copenhagen General Population Study, Copenhagen University Hospital, Herlev, Denmark, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark, National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark and Copenhagen City Heart Study, Copenhagen University Hospital, Frederiksberg, Denmark.
authors.forename: Janne Schurmann
authors.initials: JS
authors.lastname: Tolstrup
authors.affiliation: Department of Clinical Biochemistry, and Copenhagen General Population Study, Copenhagen University Hospital, Herlev, Denmark, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark, National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark and Copenhagen City Heart Study, Copenhagen University Hospital, Frederiksberg, Denmark Department of Clinical Biochemistry, and Copenhagen General Population Study, Copenhagen University Hospital, Herlev, Denmark, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark, National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark and Copenhagen City Heart Study, Copenhagen University Hospital, Frederiksberg, Denmark Department of Clinical Biochemistry, and Copenhagen General Population Study, Copenhagen University Hospital, Herlev, Denmark, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark, National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark and Copenhagen City Heart Study, Copenhagen University Hospital, Frederiksberg, Denmark Department of Clinical Biochemistry, and Copenhagen General Population Study, Copenhagen University Hospital, Herlev, Denmark, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark, National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark and Copenhagen City Heart Study, 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; D000426:Alcohol Dehydrogenase / Q000235:genetics; D000428:Alcohol Drinking / Q000009:adverse effects / Q000453:epidemiology / Q000235:genetics*; D000437:Alcoholism / Q000453:epidemiology / Q000235:genetics*; D000928:Antidepressive Agents / Q000627:therapeutic use; D003430:Cross-Sectional Studies; D003718:Denmark / Q000453:epidemiology; D003866:Depressive Disorder / Q000453:epidemiology* / Q000235:genetics; D005260:Female; D005838:Genotype; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D013315:Stress, Psychological / Q000453:epidemiology / Q000235:genetics; D055815:Young Adult
chemical_list: D000928:Antidepressive Agents; D000426:Alcohol Dehydrogenase
keywords: Alcohol; Mendelian randomization; alcohol dehydrogenase gene; alcoholism; antidepressant medication; depression; general population