Stress as a mediating factor in the association between the DRD2 TaqI polymorphism and alcoholism
Introduction
Marked variability in the outcome of association studies has become an important issue in psychiatric genetics. Moreover, while such variability in results has been observed with all psychiatrically relevant polymorphisms that have been extensively studied, none have generated the level of debate and controversy that has been attached to studies of the association between the DRD2 TaqI polymorphism and alcoholism. To date, more than 20 DRD2/alcoholism association studies have been reported, with about half supporting and half not supporting the association. Noble (1998) published the most recent meta-analysis of DRD2/alcoholism studies, evaluating the results of 15 US and international reports, consisting of 1,015 alcoholics and 898 controls. Noble reported that, overall, alcoholics had a higher prevalence of the A1 allele than controls (P<10−6). Additionally, the prevalence of the A1 allele was 1.5-fold higher in more severe than in less severe alcoholics (P<10−4) and the prevalence was two-fold higher in unassessed than in Michigan Alcoholism Screening Test (MAST)-assessed controls (P<10−4). These findings suggest that study-to-study variability in the type of alcoholics and the nature of controls used by different investigators would probably alter the outcome of DRD2 TaqI association studies of alcoholism.
Despite the appeal of Noble's (1998) conclusions as an explanation for variability in the outcome of DRD2 studies, a recent study by Gelernter and Kranzler (1999) suggested that neither differences in alcoholism severity nor use of unassessed vs. MAST-assessed controls were, at least in their hands, viable mediators of outcome. In a study of 160 alcohol-dependent subjects, segregated by severity, and 136 screened control subjects, they found no differences in DRD2 TaqI allelic frequencies between cases and controls, and analysis based on severity of alcohol dependence also yielded no significant association. Indeed, Gelernter et al. (1993) suggested that, in view of the marked differences in DRD2 TaqI allelic frequencies between ethnic groups, those DRD2 studies that report positive findings may be flawed by hidden ethnic stratification sampling biases. However, although there is certainly merit to the notion that subtle differences in ethnic background may contaminate the veracity of outcome in these studies, this concept alone is an insufficient explanation for the observed variability in all studies. For one thing, there have been separate reports of a positive association between the DRD2 A1 allele and alcoholism in Japanese samples Arinami et al., 1993, Ishiguro et al., 1997, Kono et al., 1997, as well as in Finnish (Hietala et al., 1997) and French (Amadeo et al., 1993) samples, where both cases and controls are presumably ethnically homogeneous.
An alternative view, put forth by Comings (1998) proposes that study-to-study variability in the outcome of psychiatric association studies is to be expected because these are polygenic disorders, involving many different risk-associated genetic markers, each accounting for only 1%–3% of the variance in the phenotype. As a result, a given phenotype, such as alcoholism, may in one individual or group tend to be linked to one set of gene variations, whereas in the next individual the phenotype may derive from a different set of gene variations. Therefore, within such a polygenic context, true risk may only be reliably assessed by the cumulative number of risk alleles carried by individuals.
A fourth explanatory model for understanding variability in genotype–phenotype associations is provided by studies that have demonstrated gene–environment interactions. The potential relevance of this argument to the DRD2/alcoholism debate resides in the established role of the dopaminergic system in the mediation of stress and, conversely, the ability of stress to modify dopaminergic response. The dopaminergic system has been implicated in reactivity to perturbation in environmental conditions and for general emotional responses (Pani et al., 2000). Stress of social subordination in female cynomolgus monkeys has been shown to be associated with decreased D2 receptor function, and stress exposure has been found to decrease D2 receptor mRNA in the nucleus accumbens, substantia nigra, and ventral tegmental areas (Shively, 1998). Collectively, these studies suggest the possibility that stress exposure may act to modify the nature of the association between DRD2 genotype and any or all dopamine D2 receptor-related phenotypic expressions. Thus, in a little referenced but theoretically important study, Berman and Noble (1997) examined the role of childhood stress exposure in the mediation of the association between the DRD2 TaqI polymorphism and two measures that have been linked to alcoholism: impairments in the Line Orientation score (a measure of visuospatial ability) (Berman & Noble, 1995) and reductions in the amplitude of the P300 EEG-evoked potential (Hill et al., 2000). In their study of preadolescent boys, Berman and Noble (1997) divided subjects into low vs. high childhood family stress exposure and found that among low stress subjects there were no differences in performance scores between A1+ subjects (A1A1 and A1A2) and A1− subjects (A2A2). However, they also found that in the presence of the DRD2 A1 allele, the Family Stress score was negatively correlated both with reductions in visuospatial ability and P300 amplitude, whereas in A2A2 boys Family Stress was not correlated with either measure.
The findings reported by Berman and Noble (1997) suggest that stress exposure has no discernible effect on alcoholism-risk measures in A1− subjects, but is associated with significant performance decrements in A1+ subjects. It is therefore reasonable to assume that carriers of the DRD2 A1 allele may be more stress sensitive or reactive, than A2A2 individuals, at least with respect to the expression of alcoholism-related phenotypes. Furthermore, if Berman and Noble's observations in preadolescent boys have relevance for adult behavior, we should be able to expect that variability in stress exposure may interact with the DRD2 TaqI genotypes in predicting risk of developing alcoholism. In order to test this hypothesis, we sought to examine the gene–stress interactional model in a sample of ethnically homogeneous adult male Mayan descendants resident in the Olancho district of Honduras.
Section snippets
The setting
The present study was undertaken in Catacamas, located in the Olancho district in the Eastern part of Honduras. The majority of the population in Catacamas are descendants of the indigenous Mayan population and Spanish conquistadors. The average educational level is 5.2 years, and the majority of the population are engaged in agriculture (beans, corn, and rice). The unemployment rate is commonly 40%, and underemployment is even higher (Pan American Health Organization [PAHO], 1998). In 1994,
Results
The age range of participants was 18 to 87 years, with a mean age of 37.8 years. Subjects had an average of 5.9 people living in the household, an average of 2.9 children, and an average of 5.2 years of education. The demographic characteristics for categorical variables are shown in Table 1.
DRD2 TaqI genotyping revealed that in this sample 23 subjects (7.6%) were A1A1, 128 (42.1%) were A1A2, and 153 (49.5%) were A2A2, generating an overall prevalence of A1+ carriers at 49.7%. Thus, the
Discussion
The findings of the present study support the gene–stress interactional model first proposed by Berman and Noble (1997). Moreover, while demonstrating that DRD2 A1+ individuals may only have an increased risk of alcoholism when exposed to a “culturally salient” stressor (in this case, occupational/economic stress), these results also suggest that in unstressed subjects (or groups) rates of alcoholism may actually be higher in A1− individuals. This gene–stress interactional phenomenon may help
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