The collaborative study on the genetics of alcoholism: an update

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

Foroud and colleagues (2000) also analyzed the combined data set from the initial and replication samples using a more restricted definition of alcoholism as specified in the ICD-10. This restriction greatly reduced the number of sibling pairs in the comparison. The region on chromosome 1 provided the strongest evidence for a susceptibility gene in the combined sample. In addition, this new evaluation detected a region on chromosome 8 that was linked with the risk for alcoholism.

DNA Regions with Protective Genes. Interestingly, analyses of nonalcoholic sibling pairs in the initial sample produced evidence for a protective region on chromosome 4, in the general vicinity of the alcohol dehydrogenase (ADH) genes. (2) A related analysis, using a technique that treats alcoholism as the extreme of a distribution of an underlying quantitative trait, (3) showed evidence for linkage to this same region (Williams et al. 1999). This finding suggests that variants of a gene or genes within this region reduced the risk of becoming alcoholic. ADH alleles are known to affect the risk for alcoholism; however, the known protective alleles occur at high frequency in Asian populations but are rare in the Caucasian population that makes up most of the COGA sample (Edenberg 2000). Therefore, these analyses may have identified a new protective ADH allele or another protective gene located nearby. The number of unaffected sibling pairs genotyped in the replication sample was too small to analyze. Another phenotype that may reflect a protective influence against alcoholism is the maximum number of drinks a person has consumed in a 24-hour period (MAXDRINKS). This phenotype is quantitative and heritable, and a low number of drinks consumed in a 24-hour period may reflect a reduced tolerance for high levels of alcohol. An advantage of a quantitative phenotype is that everyone in a study can contribute to the genetic analysis, not just people who meet diagnostic criteria. Analysis of the MAXDRINK phenotype in both the initial and replication data sets (and in the combined sample) showed the strongest evidence for linkage in the same region of chromosome 4 where the ADH genes reside (Saccone et al. 2000). This finding suggests that the gene or genes influencing the MAXDRINKS phenotype may be related to the protective region identified in the unaffected sibling pairs and to protective effects of certain ADH alleles (Edenberg 2000).

DNA Regions Related to Symptoms of Alcoholism. The symptoms used to establish a diagnosis of alcoholism are highly diverse, ranging from more biological symptoms (e.g., tolerance and withdrawal) to more social symptoms (e.g., social and legal problems). Each person diagnosed with alcoholism exhibits a unique mix of those symptoms; therefore, a diagnosis of alcoholism does not reflect a uniform phenotype. This lack of uniformity complicates genetic analyses. Consequently, researchers have constructed other, more defined phenotypes from the data obtained in the COGA interviews. These include an analysis of symptoms related to alcoholism that produced phenotypes which appeared to reflect the severity of alcohol problems. Analysis of these phenotypes provided evidence for a DNA region on chromosome 16 that was associated with an increased risk for more severe alcohol problems (Foroud et al. 1998).