title: Generational association studies of dopaminergic genes in reward deficiency syndrome (RDS) subjects: selecting appropriate phenotypes for reward dependence behaviors.
abstract: Abnormal behaviors involving dopaminergic gene polymorphisms often reflect an insufficiency of usual feelings of satisfaction, or Reward Deficiency Syndrome (RDS). RDS results from a dysfunction in the "brain reward cascade," a complex interaction among neurotransmitters (primarily dopaminergic and opioidergic). Individuals with a family history of alcoholism or other addictions may be born with a deficiency in the ability to produce or use these neurotransmitters. Exposure to prolonged periods of stress and alcohol or other substances also can lead to a corruption of the brain reward cascade function. We evaluated the potential association of four variants of dopaminergic candidate genes in RDS (dopamine D1 receptor gene [DRD1]; dopamine D2 receptor gene [DRD2]; dopamine transporter gene [DAT1]; dopamine beta-hydroxylase gene [DBH]).
  
  
  
  We genotyped an experimental group of 55 subjects derived from up to five generations of two independent multiple-affected families compared to rigorously screened control subjects (e.g., N = 30 super controls for DRD2 gene polymorphisms). Data related to RDS behaviors were collected on these subjects plus 13 deceased family members.
  
  
  
  Among the genotyped family members, the DRD2 Taq1 and the DAT1 10/10 alleles were significantly (at least p < 0.015) more often found in the RDS families vs. controls. The TaqA1 allele occurred in 100% of Family A individuals (N = 32) and 47.8% of Family B subjects (11 of 23). No significant differences were found between the experimental and control positive rates for the other variants.
  
  
  
  Although our sample size was limited, and linkage analysis is necessary, the results support the putative role of dopaminergic polymorphisms in RDS behaviors. This study shows the importance of a nonspecific RDS phenotype and informs an understanding of how evaluating single subset behaviors of RDS may lead to spurious results. Utilization of a nonspecific "reward" phenotype may be a paradigm shift in future association and linkage studies involving dopaminergic polymorphisms and other neurotransmitter gene candidates.
authors.affiliation: Department of Psychiatry, School of Medicine and McKnight Brain Institute, University of Florida, Gainesville, FL 32601, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Blum
authors.forename: Amanda L C
authors.initials: AL
authors.lastname: Chen
authors.forename: Marlene
authors.initials: M
authors.lastname: Oscar-Berman
authors.forename: Thomas J H
authors.initials: TJ
authors.lastname: Chen
authors.forename: Joel
authors.initials: J
authors.lastname: Lubar
authors.forename: Nancy
authors.initials: N
authors.lastname: White
authors.forename: Judith
authors.initials: J
authors.lastname: Lubar
authors.forename: Abdalla
authors.initials: A
authors.lastname: Bowirrat
authors.forename: Eric
authors.initials: E
authors.lastname: Braverman
authors.forename: John
authors.initials: J
authors.lastname: Schoolfield
authors.forename: Roger L
authors.initials: RL
authors.lastname: Waite
authors.forename: Bernard W
authors.initials: BW
authors.lastname: Downs
authors.forename: Margaret
authors.initials: M
authors.lastname: Madigan
authors.forename: David E
authors.initials: DE
authors.lastname: Comings
authors.forename: Caroline
authors.initials: C
authors.lastname: Davis
authors.forename: Mallory M
authors.initials: MM
authors.lastname: Kerner
authors.forename: Jennifer
authors.initials: J
authors.lastname: Knopf
authors.forename: Tomas
authors.initials: T
authors.lastname: Palomo
authors.forename: John J
authors.initials: JJ
authors.lastname: Giordano
authors.forename: Siobhan A
authors.initials: SA
authors.lastname: Morse
authors.forename: Frank
authors.initials: F
authors.lastname: Fornari
authors.forename: Debmalya
authors.initials: D
authors.lastname: Barh
authors.forename: John
authors.initials: J
authors.lastname: Femino
authors.forename: John A
authors.initials: JA
authors.lastname: Bailey
mesh_terms: D000483:Alleles; D016739:Behavior, Addictive / Q000235:genetics*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics*; D004299:Dopamine beta-Hydroxylase / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D010375:Pedigree; D010641:Phenotype; D011110:Polymorphism, Genetic; D017447:Receptors, Dopamine D1 / Q000235:genetics*; D017448:Receptors, Dopamine D2 / Q000235:genetics*; D012201:Reward
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D004299:Dopamine beta-Hydroxylase