Alcoholism is a complex, multifaceted disorder that has long been recognized to run in families. There is substantial evidence from twin research and adoption studies that a major genetic component operates in the development of alcoholism. In this study, we investigated the association between alcoholism and the genetic polymorphisms of the GABAA
receptor genes, and the association between the genetic polymorphisms and the clinical characteristics of alcoholics. We found that genetic polymorphisms of the GABAA
α1 and α6 receptor genes were associated with alcoholism, but the GABAA
β2 and γ2 receptor genes were not. A number of groups have investigated the role of the GABAA
receptor genes polymorphisms that are located on chromosome 5, and these studies have reported mixed results. In research on several populations, revealed a possible association between alcoholism and the genetic polymorphisms of the GABAA
α1 or α6 receptor genes (11
). Although there was some evidence for association, previous studies also showed no association of the GABAA
α6, β2 and γ2 receptor genes polymorphisms with alcoholism or familial alcoholism (13
). These controversial results from other studies might be due to either ethnic differences in the allele frequencies or the difference of the phenotype definition. Because Koreans are a unitary race that is genetically homogeneous (19
), the subjects in this study have the merit of minimizing the stratification bias that can originate from association studies when the subjects of these studies consist of diverse races. Therefore, our results support the evidence that genetic polymorphisms of the GABAA
α1 and α6 receptor genes may have crucial roles for the development of alcoholism in Koreans.
The GG genotype of the GABAA
α1 receptor gene was significantly associated with the early onset of alcoholism and the alcohol withdrawal symptoms. Furthermore, the GG genotype was associated with a high mean ADS score, which suggests a tendency toward severe alcoholism. Typology studies have suggested a way of reducing the etiological heterogeneity. The best known of these typologies is the Type 1/Type 2 distinction developed by Cloninger from the studies that were done on the adopted sons of Swedish alcoholics (2
). Type 1 alcoholics are characterized by the late onset of problem drinking, few childhood risk factors, a prominence of guilt and anxiety related to drinking, relatively mild dependence, few alcohol related problems and little psychopathology. In contrast, type 2 alcoholics are characterized by the early onset of alcoholism, many childhood risk factors, significant psychopathology, a strong family history of alcohol abuse and the absence of guilt and fear concerning drinking (20
). An adoption study based on Cloninger's typology reported that the lifetime risk of severe alcoholism was increased sixfold for the adopted sons having the type 2 genetic background compared with type 1 subjects, regardless of their postnatal environment (21
). In contrast, neither the genetic nor environmental risk factors for type 1 alcoholism were sufficient enough to cause alcoholism. These finding indicate that the age of onset and the antisocial behavior represent two characteristics that are susceptible to the genetic components of alcoholism. Our results support possibility that the GG genotype of the GABAA
α1 receptor gene may be associated with Cloninger's type 2 alcoholics. However, further evaluations for the antisocial behavior and the family history of alcoholics will be required to elucidate a positive association between Cloninger's type 2 alcoholics and the genetic polymorphisms of the GABAA
α1 receptor gene.
A possible limitation in case-control association studies is the risk of spurious associations as a result of population admixture. However, this objection is less likely in the present study, as our study group was composed of subjects of Korean descent for generations and because the Italian population is relatively homogeneous. In addition, the size of our sample is relatively small and replication of our results on a larger and independent sample is required. Moreover, another limitation was that this study lacked a structured diagnostic interview. Finally, only male patients were genotyped. Therefore, the generalization of the results to all alcoholics is limited.
In conclusion, there was a significant association between the genetic polymorphisms of the GABAA α1 and α6 receptor genes and alcoholism. The GG genotype of the GABAA α1 receptor gene was associated with not only the onset age of alcoholism and the alcohol withdrawal symptom, but also the ADS score in Korean population. These results indicate that genetic polymorphisms of the GABAA α1 and α6 receptor genes may have a crucial role in the development of alcoholism. In particular, the GG genotype of the GABAA α1 receptor gene may play an important role in the development of early onset drinking and the more severe alcoholism in Korean population.