Stress as a mediating factor in the association between the DRD2 TaqI polymorphism and alcoholism.

Results of earlier studies have shown that rating of prior stress exposure in preadolescent boys influenced the association between DRD2 genotypes and alcoholism risk factors, suggesting that variability in stress exposure, either in patient or control samples, could readily account for at least part of the confusion in DRD2 study outcomes. In order to test the hypothesis that the DRD2 A1 allele is only associated with alcoholism in subjects with elevated stress exposure, we examined the gene-stress interactional model in a sample of males of Mayan descent in the Olancho district of Honduras. Ascertainment was based on an epidemiologic, observational cross-sectional design, and the study was approved by the Institutional Review Board. A total of 309 adult males (age range 18-87 years) were interviewed by a physician or a public health nurse, blood samples were obtained for genetic studies, and participants were administered the short version of the Michigan Alcoholism Screening Test (S-MAST) and the Hispanic Stress Inventory (HSI). Three explanatory models were evaluated. The first model tested the effect of the demographic variables alone as predictors of MAST scores, the second tested the effects of stress and DRD2 genotypes separately, and the third tested the effect of the interaction between stress and the DRD2 genotypes. Neither model 1 nor model 2 yielded significant results; neither MAST scores nor HSI scores were found to be associated with DRD2 genotypes. However, Model 3 was confirmed reflecting a significant (P<.05) interaction between DRD2 genotype and stress score as a predictor of MAST score. Additionally, this difference was found to be largely accounted by the HSI occupational/economic stress score, which had a highly significant (P=.003) interaction with DRD2 genotype as a predictor of MAST score. This stress score was the only one of four that showed levels of stress as high as HSI scores in a US population. The MAST scores of A2A2 genotype participants were found to be nearly identical in low stress and high stress participants, whereas the MAST scores of A1A2 participants increased modestly with stress (P=.01) and that of A1A1 participants increased markedly with stress (P=.001). These findings support the hypothesis that DRD2 genotype-phenotype associations depend on the magnitude of stress exposure, and they lend support to the view that variability in DRD2 study outcomes may in part be explained by this gene-environment interaction.

[1]  M. Itokawa,et al.  Association between severity of alcoholism and the A1 allele of the dopamine D2 receptor gene TaqI A RFLP in Japanese , 1993, Biological Psychiatry.

[2]  D. Comings,et al.  Polygenic inheritance of Tourette syndrome, stuttering, attention deficit hyperactivity, conduct, and oppositional defiant disorder: the additive and subtractive effect of the three dopaminergic genes--DRD2, D beta H, and DAT1. , 1996, American journal of medical genetics.

[3]  E. Oord,et al.  The DRD2 TaqI polymorphism and symptoms of attention deficit hyperactivity disorder , 1999, Molecular Psychiatry.

[4]  Amado M. Padilla,et al.  The Hispanic Stress Inventory: A culturally relevant approach to psychosocial assessment. , 1991 .

[5]  S. Hill,et al.  Factors predicting the onset of adolescent drinking in families at high risk for developing alcoholism , 2000, Biological Psychiatry.

[6]  S. Berman,et al.  Reduced visuospatial performance in children with the D2 dopamine receptor A1 allele , 1995, Behavior genetics.

[7]  G. Gessa,et al.  The role of stress in the pathophysiology of the dopaminergic system , 2000, Molecular Psychiatry.

[8]  D. Comings.  Why different rules are required for polygenic inheritance: lessons from studies of the DRD2 gene. , 1998, Alcohol.

[9]  C. Shively,et al.  Social subordination stress, behavior, and central monoaminergic function in female cynomolgus monkeys , 1998, Biological Psychiatry.

[10]  D. Coombs,et al.  Alcohol use and alcoholism in Latin America: changing patterns and sociocultural explanations. , 1986, The International journal of the addictions.

[11]  J. Gelernter,et al.  D2 Dopamine Receptor Gene (DRD2) Allele and Haplotype Frequencies in Alcohol Dependent and Control Subjects: No Association with Phenotype or Severity of Phenotype , 1999, Neuropsychopharmacology.

[12]  H. Yoneda,et al.  Association between early-onset alcoholism and the dopamine D2 receptor gene. , 1997, American journal of medical genetics.

[13]  E P Noble,et al.  The D2 Dopamine Receptor (DRD2) Gene and Family Stress; Interactive Effects on Cognitive Functions in Children , 1997, Behavior genetics.

[14]  J. Hietala,et al.  Allelic association between D2 but not D1 dopamine receptor gene and alcoholism in Finland , 1997, Psychiatric genetics.

[15]  T. Arinami,et al.  Association study between the -141C Ins/Del and TaqI A polymorphisms of the dopamine D2 receptor gene and alcoholism. , 1998, Alcoholism, clinical and experimental research.

[16]  M. Abbar,et al.  D2 dopamine receptor gene and alcoholism. , 1993, Journal of psychiatric research.

[17]  M. Papp,et al.  Changes in dopamine receptor mRNA expression following chronic mild stress and chronic antidepressant treatment , 1997, Behavioural pharmacology.

[18]  D. Grandy,et al.  The human dopamine D2 receptor gene is located on chromosome 11 at q22-q23 and identifies a TaqI RFLP. , 1989, American journal of human genetics.

[19]  T. Arinami,et al.  Association study between the -141C Ins/Del and TaqI A polymorphisms of the dopamine D2 receptor gene and alcoholism. , 1998, Alcoholism, clinical and experimental research.

[20]  E. Noble,et al.  The D2 dopamine receptor gene: a review of association studies in alcoholism and phenotypes. , 1998, Alcohol.

[21]  N Risch,et al.  The A1 allele at the D2 dopamine receptor gene and alcoholism. A reappraisal. , 1993, JAMA.