title: Role of nicotine dependence in the association between the dopamine receptor gene DRD3 and major depressive disorder.
abstract: BACKGROUND
  The aims of this study were to analyze associations of dopamine receptor genes (DRD1-5) with Major Depressive Disorder (MDD) and nicotine dependence (ND), and to investigate whether ND moderates genetic influences on MDD.
  
  
  METHODS
  The sample was ascertained from the Finnish Twin Cohort. Twin pairs concordant for smoking history were recruited along with their family members, as part of the multisite Nicotine Addiction Genetics consortium. Genetic association analyses were based on 1428 adults. Total of 70 tagging single nucleotide polymorphisms within the dopamine receptor genes were genotyped and analyzed for association with MDD, ND, and MD-ND co-morbidity. Individual level logistic regression analyses were based on 1296 adults with data on ND and MDD diagnoses, as well as on dopamine receptor genotypes adjusted for sex, age, and alcohol use. Four independent samples, such as population-based and case-control samples, were used for replication.
  
  
  RESULTS
  Rs2399496, located 1.5 kb downstream of DRD3, showed suggestive association for MDD (p = 0.00076) and significant association for MDD-ND co-morbidity (p = 0.000079). Suggestive gene-(rs2399496) by-ND-interaction justified analyses by genetic risk variant and ND status. Individuals with ND and two minor alleles (AA) of rs2399496 had almost six-fold risk for MDD (OR 5.74, 95%CI 3.12-10.5, p = 9.010e-09) compared to individuals without ND and with two major alleles (TT).
  
  
  CONCLUSIONS
  Significant association between a variant downstream of DRD3 and a co-morbid MDD-ND phenotype was detected. Our results further suggest that nicotine dependence may potentiate the influence of the DRD3 genetic variant on MDD.
authors.affiliation: Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland; Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland; Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
authors.forename: Tellervo
authors.initials: T
authors.lastname: Korhonen
authors.affiliation: Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland; Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Anu
authors.initials: A
authors.lastname: Loukola
authors.affiliation: Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Juho
authors.initials: J
authors.lastname: Wedenoja
authors.affiliation: Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland; Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland.
authors.forename: Emma
authors.initials: E
authors.lastname: Nyman
authors.affiliation: Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland; Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Antti
authors.initials: A
authors.lastname: Latvala
authors.affiliation: Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland; Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Ulla
authors.initials: U
authors.lastname: Broms
authors.affiliation: Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Anja
authors.initials: A
authors.lastname: Häppölä
authors.affiliation: Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland; Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland; Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Tiina
authors.initials: T
authors.lastname: Paunio
authors.affiliation: Washington University School of Medicine, Department of Psychiatry, Saint Louis, Michigan, United States of America.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Schrage
authors.affiliation: Department of Biological Psychology/Netherlands Twin Register, VU University, Amsterdam, The Netherlands.
authors.forename: Jaqueline M
authors.initials: JM
authors.lastname: Vink
authors.affiliation: Department of Biological Psychology/Netherlands Twin Register, VU University, Amsterdam, The Netherlands.
authors.forename: Hamdi
authors.initials: H
authors.lastname: Mbarek
authors.affiliation: Department of Biological Psychology/Netherlands Twin Register, VU University, Amsterdam, The Netherlands.
authors.forename: Dorret I
authors.initials: DI
authors.lastname: Boomsma
authors.affiliation: Department of Psychiatry, VU University Medical Center/GGZ InGeest, Amsterdam, The Netherlands.
authors.forename: Brenda W J H
authors.initials: BW
authors.lastname: Penninx
authors.affiliation: Washington University School of Medicine, Department of Psychiatry, Saint Louis, Michigan, United States of America.
authors.forename: Michele L
authors.initials: ML
authors.lastname: Pergadia
authors.affiliation: Washington University School of Medicine, Department of Psychiatry, Saint Louis, Michigan, United States of America.
authors.forename: Pamela A F
authors.initials: PA
authors.lastname: Madden
authors.affiliation: Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland; Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland; Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland.
authors.forename: Jaakko
authors.initials: J
authors.lastname: Kaprio
mesh_terms: D000328:Adult; D000437:Alcoholism / Q000235:genetics; D016022:Case-Control Studies; D015331:Cohort Studies; D015897:Comorbidity; D003865:Major Depressive Disorder / Q000453:epidemiology* / Q000235:genetics*; D005387:Finland; D056726:Genetic Association Studies; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D050637:Receptors, Dopamine D3 / Q000235:genetics*; D014029:Tobacco Use Disorder / Q000453:epidemiology* / Q000235:genetics*; D014427:Twins
chemical_list: C493593:DRD3 protein, human; D050637:Receptors, Dopamine D3