The collaborative study on the genetics of alcoholism: an update

Alcohol Research & Health, Fall, 2002 by Howard J. Edenberg

DNA Regions Associated with Co-Occurring Disorders. Many people in the COGA families of alcoholics also met the DSM-III-R diagnostic criteria for major depressive disorder or depressive syndrome (Nurnberger et al. 2001). Depression alone showed modest evidence of linkage to a region on chromosome 7. The phenotype characterized by co-occurring alcoholism and depression showed evidence of linkage to a region on chromosome 2, primarily in the replication sample. The most interesting finding was for the broad "alcoholism or depression" phenotype, with very strong evidence for linkage to the same region of chromosome 1 that was linked to alcoholism alone (Nurnberger et al. 2001). This suggests that a gene or genes within this chromosomal region increase the risk for both alcoholism and depression. (For more information on these analyses, see the article by Nurnberger and colleagues, pp. 233-240, in this issue.)

DNA Regions Linked with Electrophysiological Measures. The COGA investigators also evaluated electrophysiological variables, such as EEGs and ERPs, from study participants. EEGs measure overall brain activity, whereas ERPs are brain waves elicited in response to specific stimuli (e.g., a light or sound). Analysis of such electrophysiological data may reveal a subset of genes that affect these quantitative, biological phenotypes related to alcoholism (Porjesz et al. 1998, 2002). One component of an ERP is a brain wave called P300, which typically occurs 300 milliseconds after a stimulus. Previous studies had found that a reduced amplitude of the P300 wave is a heritable phenotype that correlates with alcohol dependence and other psychiatric disorders (Porjesz et al. 1998). The genetic analyses of the COGA participants identified four regions, on chromosomes 2, 5, 6, and 13, that appear to contain genes affecting the amplitude of the P300 (Begleiter et al. 1998).

In addition to these findings, recent analyses demonstrate strong evidence for a locus that affects brain wave oscillations as measured by electroencephalography (Porjesz et al. 2002). Thus, a gene or genes that affect brain rhythms lies in a region of chromosome 4 that contains a cluster of genes encoding proteins (i.e., receptors) which interact with the brain chemical gamma-aminobutyric acid (GABA).

Candidate Genes. COGA researchers have also analyzed candidate genes--genes suspected to play a role in the development of alcoholism based on other studies. Some of these candidate genes encode components of various brain chemical systems that allow communication among nerve cells. Two of these genes are the dopamine [D.sub.2] receptor gene (DR[D.sub.2]) and a serotonin transporter gene (HTT). However, the analyses found no evidence that DR[D.sub.2] affected the risk for alcoholism (Edenberg et al. 1998a) or that HTT was linked to either alcoholism in general or to a more severe form of alcoholism (Edenberg et al. 1998b).

Perspective

Where does the COGA study go from here? The increasing availability of the DNA sequence of the entire human genome and knowledge of variations in that sequence among people are greatly aiding the current phase of the research. Particularly important to the current work is the use of the sequence data to identify which genes are located within the regions that have shown linkage with alcoholism and the other phenotypes examined in the COGA analyses and to identify variations (i.e., polymorphisms) within those genes. Where the available data are incomplete or insufficient, COGA researchers are seeking these polymorphisms themselves. Of particular value are single-nucleotide polymorphisms (SNPs)--sites at which people differ in a single base pair--in or near genes within the regions of interest. COGA investigators are doing additional genotyping of SNPs in and near candidate genes in the regions of linkage for further analysis of linkage and linkage disequilibrium (i.e., the nonrandom association of alleles). This should allow the investigators to greatly narrow the regions and to identify individual genes in which variations affect the risk for alcoholism and the other phenotypes they are studying.