Alcohol Dependence and Habitual Smoking: Risks : Part 3

by National Institute of Health

(Page 3 of 4)

A diagnosis of one type of drug dependence increased a sibling's risk of also being diagnosed with dependence on another drug. For example, alcohol-dependent siblings had more than twice the lifetime risk of being habitual smokers3 compared with non-alcohol-dependent siblings. Similarly, siblings who were habitual smokers were almost twice as likely to be alcohol dependent than were nonsmokers.

Even after controlling for the influences of individual factors, such as gender, birth cohort, and other drug dependence, however, evidence indicated a familial transmission of a drug-specific risk. Thus, habitual smoking in the probands specifically increased the risk of habitual smoking in their siblings, and alcohol dependence in the probands specifically increased the same diagnosis in their siblings. These findings are consistent with the presence of both common and drug-specific influences that are transmitted in families and combine to determine a person's risk for developing alcohol dependence or habitual smoking. These influences likely include genetic factors, which are discussed in the following sections.

Candidate Gene Studies of Alcohol Dependence and Nicotine Dependence

Researchers have used several approaches in trying to identify the genes that influence the susceptibility to a disease, such as alcoholism. One such approach is to study whether an association exists between certain genes that are suspected (based on results of other studies) to play a role in disease development (candidate genes) and actual disease development. Such association studies evaluate whether a particular form or variant of a candidate gene is more frequently observed in people with the disease than in people without the disease. This association implies that the candidate gene is directly involved in the development of the disease and is "linked" in genetic studies.

However, the association between a candidate gene and the disease may be spurious - that is, the gene actually is not genetically linked to the disease. For example, if the control population is not properly matched (with respect to ethnicity) to the population from which the affected people are drawn, spurious linkage may occur due to a phenomenon called population stratification. This means that for some genes the frequency with which different gene variants occur in a population may differ between ethnic groups. Consequently, if the samples of people with and without the disease do not have the same ethnic composition, it may appear as if certain gene variants are associated with the disease when, in fact, the frequency of those variants is determined by ethnicity and is unrelated to the disease under investigation. In the COGA study, however, researchers can study candidate genes for both alcohol dependence and habitual smoking without running the risk of spurious findings resulting from population stratification by using family-based tests, such as the Transmission Disequilibrium Test. This approach eliminates the need for a separate, matched unaffected control population. As a result, the investigators can directly test for both genetic linkage and association between a gene of interest and the presence of alcohol dependence and habitual smoking.

One candidate gene that has been studied by the COGA investigators is the dopamine D2 receptor gene. Dopamine is a brain chemical (neurotransmitter) that is used by nerve cells in the brain's "reward center" and other brain regions to transmit nerve signals among nerve cells. During this process, dopamine is released from the signal-emitting nerve cell and attaches to a protein "docking" molecule located on the outer surface of the signal-receiving nerve cells. This interaction triggers electrical and chemical changes in the signal-receiving cell, resulting in the generation of a new nerve signal in that cell. Several types of dopamine receptors exist, including the DRD2 receptor. Furthermore, several variants (polymorphisms) of the DRD2 receptor exist.

Several findings have suggested DRD2 as a potential candidate gene that might contribute to the genetic susceptibility to various types of dependence. For example, the dopamine system in general is involved in dependence on a variety of drugs. Moreover, numerous association studies have specifically implicated the DRD2 gene in the development of alcohol dependence as well as in smoking. These findings, particularly regarding the association of DRD2 with alcohol dependence, are controversial, however. Many other studies found no associations between DRD2 polymorphisms and alcohol dependence, and linkage studies of DRD2 and alcohol dependence also yielded negative results.

To address this controversy, COGA investigators studied two polymorphisms in separate regions of the DRD2 gene in the stage II COGA families using family based association study methods. Neither of those polymorphisms showed any evidence of linkage with alcohol dependence, even when the analysis was limited to more severe forms of alcoholism, where associations should be detectable more easily. Similarly, no significant linkage existed between the DRD2 gene and habitual smoking.

As mentioned earlier, alcohol dependence and smoking co-occur more often than by chance alone; moreover, twin studies have supported the role of common genetic factors in the development of both disorders. Accordingly, the COGA investigators also examined the association between the DRD2 gene and co-occurring alcohol dependence and habitual smoking. Again, those analyses found no evidence that the DRD2 gene is linked to the combined phenotype. In summary, although the dopamine neurotransmitter system clearly plays a role in alcohol and other drug use and related disorders, the COGA study detected no association between a genetic variation in the DRD2 gene and the development of alcohol dependence and/or habitual smoking. The investigators are currently using the COGA sample to examine additional candidate genes for alcohol dependence and habitual smoking.

About the Author

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