Alcohol Dependence and Habitual Smoking: Risks

Genomic Screening by Linkage Analysis
by National Institute of Health

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In addition to pursuing the candidate gene approach when searching for susceptibility genes for alcohol dependence, researchers have undertaken a more comprehensive search of the entire genome. In the cell, the DNA is packaged into segments, or chromosomes. Each human cell contains 23 pairs of chromosomes,5 one set inherited from the mother and one from the father. To screen the entire genome for DNA sequences related to a disease, scientists first identify numerous DNA sequences (which may or may not contain genes) whose locations on the chromosomes are known and which can serve as genetic markers. The goal is to identify enough markers to cover several regions on each chromosome. Subsequently, the researchers test how commonly these markers are shared by siblings who are both affected with alcohol dependence or habitual smoking. If a certain marker is shared more often by affected siblings than can be expected by chance alone, the marker is said to be "linked" with the disease.

The COGA investigators divided their samples into two groups - an initial study sample and a larger replication sample - and conducted independent genomic screens with both groups. The initial sample entailed a complete genome survey of 987 members of 105 multigenerational families that were severely affected with alcohol dependence. The investigators then analyzed 292 genetic markers located across the genome in 382 affected sibling pairs. This analysis found evidence that specific markers located on chromosomes 1, 2, and 7 were linked with alcohol dependence, thereby suggesting multiple DNA regions that then could be searched in more detail to identify specific candidate genes for the development of alcohol dependence.

To confirm these findings, the investigators conducted a genome survey in the replication sample, which included 1,219 people from 152 families, using 351 genetic markers. This analysis found the following results.

Consistent with the data from the initial sample, there was evidence of linkage (increased sharing in sibling pairs) of several markers on chromosome 1 with alcohol dependence in the replication sample. This linkage can be expressed in the form of a so-called logarithmof- the-odds-of-linkage score. Higher values of that score indicate stronger evidence for genetic linkage. Thus, the maximum LOD score for these markers was 2.5 in the initial sample and 1.6 in the replication sample, suggestive of genetic linkage.

In contrast with the initial sample, which had shown increased sharing in affected siblings of certain markers on chromosome 2, no evidence of linkage of those markers with alcohol dependence existed in the replication sample.

In the initial sample, there was evidence of genetic linkage between a large area of chromosome 7 and alcohol dependence. A smaller part of chromosome 7 also appeared to be linked with alcohol dependence in the replication sample, suggestive of genetic linkage.

Certain markers on chromosome 3, which showed no evidence of linkage in the initial sample, showed strong linkage with alcohol dependence in the replication sample.

In summary, the COGA study provided evidence that certain regions of chromosomes 1 and 7 were linked with alcohol dependence in both the initial and replicate samples. Other DNA regions, however, may have contained susceptibility genes that were present in only one of the samples (a region on chromosome 2 in the initial sample and a region on chromosome 3 in the replication sample).

It is still unclear why these differences in susceptibility genes exist, particularly because there are no prominent differences between the initial sample and the replication sample. One can speculate that many genes of modest effect influence the development of alcohol dependence. Because such genes will be difficult to detect consistently, it is possible that one gene may be identified in the initial sample and a different gene may be identified in the replication sample.

The COGA genome screen data were also used in the Genetic Analysis Workshop (GAW), conducted in Aracachon, France, in September 1998. During that workshop, the researchers compared the genome data with the COGA participants' lifetime histories of smoking and alcohol dependence. This analysis identified several DNA regions that appeared to show shared linkage with both disorders. The genetic study of cooccurring habitual smoking and alcohol dependence is ongoing.

In summary, the COGA investigators have completed a comprehensive search for the genetic linkage of certain DNA regions with alcohol dependence and habitual smoking. These analyses support the hypothesis that some common genetic factors are involved in the susceptibility for developing both disorders. Additionally, these data provide evidence that specific genetic factors may be involved in the development of alcohol dependence and habitual smoking.

Future Directions

Numerous developments, such as the increasing identification of human genes and their functions, the sequencing of the entire human genome, and the development of new analytic techniques to detect linkage, have resulted in a surge in genetic studies. These advances provide the tools that allow researchers to study the genetic basis of common, complex disorders, such as smoking and alcohol dependence. In addition to these ongoing genetic analyses, researchers are exploring other characteristics thought to be related to the susceptibility for developing alcohol-related problems, including personality traits and various measures of the brain's electrical activity (electroencephalograms and event-related potentials). An integration of these results from multiple correlated domains, along with further genetic findings, will improve researchers' understanding of the mechanisms and risk factors underlying the development of alcohol dependence and habitual smoking.

About the Author

NIH is the nation's medical research agency - making important medical discoveries that improve health and save lives. The National Institutes of Health (NIH), a part of the U.S. Department of Health and Human Services, is the primary Federal agency for conducting and supporting medical research.