The collaborative study on the genetics of alcoholism: an update

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

The methods used in these genetic analyses and other aspects of the COGA study are described in more detail in the article by Bierut and colleagues, pp. 208-213, in this issue.

Results of Genetic Analyses

DNA Regions with Susceptibility Genes. Genetic analyses using the diagnostic criteria for alcohol dependence as the phenotype have revealed regions on several chromosomes that appear to contain genes affecting the risk for alcoholism. The primary analyses were based upon determining the extent of allele sharing among siblings who meet diagnostic criteria for alcoholism. The primary COGA definition of being affected with alcoholism requires a person to meet both DSM-III-R criteria for alcohol dependence and the Feighner criteria (Feighner et al. 1972) for definite alcoholism. If siblings who are alcoholic share more alleles at a marker than would be expected based on chance, this suggests that genes within the chromosomal region containing the marker contribute to the risk of alcoholism.

Analyses of 987 people from 105 families in the initial sample provided evidence that regions on 3 chromosomes contained genes that increase the risk for alcoholism (Reich et al. 1998). The strongest evidence was for regions on chromosomes 1 and 7, with more modest evidence for a region on chromosome 2. The DNA regions identified through these analyses were broad, as is typical for studies of complex genetic diseases, and therefore are likely to contain numerous genes. Much additional work is required to narrow the regions and attempt to determine which specific gene or genes play a role in affecting the risk for alcoholism. Therefore, additional markers within these regions of interest were analyzed in the same people. Subsequent analyses that included the additional markers supported the initial findings (Foroud et al. 2000) but did not narrow the chromosomal regions in which genes influencing alcoholism susceptibility are likely to lie.

The data from the second part of the split sample--the replication sample, which comprised 1,295 people from 157 families--generally supported the initial findings (Foroud et al. 2000). Thus, the replication sample again provided evidence that genes increasing the risk of alcoholism were located in the same regions of chromosomes 1 and 7, albeit with less statistical support. When the initial and replication samples were combined, these chromosomal regions remained the strongest candidates for containing genes influencing the risk of alcoholism. Evidence for the region on chromosome 2 increased with the additional markers in the initial sample, but the replication sample provided no additional evidence for alcoholism susceptibility genes in this chromosomal region. Conversely, the strongest evidence in the replication sample for a region containing genes affecting the risk for alcoholism was on chromosome 3, which had shown no evidence of being linked with alcoholism in the initial sample. Because of the large number of genes that may contribute to the risk for a complex genetic disease such as alcoholism, however, it is not surprising that an independent sample, even one collected by the same group of researchers, might replicate some previously identified genes and also identify some novel alcoholism susceptibility loci.