David Goldman

Genetic research in alcohol dependence

The genetic evidence base for alcohol policy includes the genetic epidemiology of this clinically-defined disorder as well as an emerging understanding of the role of specific genes and gene/environment interactions. Although alcoholism and alcohol use are common phenotypes which are heterogeneous in their origins, their heritabilities are substantial. Surprisingly, a substantial portion of the genetic variance in alcoholism risk is substance-specific rather than being attributable to a shared diathesis of vulnerability to substances. The evidence for substance-specificity in alcoholism is also compatible with the functions of the genes which have so far been confirmed as having a role in inheritance of this disorder. In certain Asian populations, the aldehyde dehydrogenase2 (ALDH2) and alcohol dehydrogenase2 (ADH2) enzymes have common functional polymorphisms leading to an excess of acetaldehyde after consumption of ethanol. Acetaldehyde is toxic and aversive, discouraging alcohol intake. In particular ALDH2 Glu487/Lys487 heterozygotes -about half of Japanese- have substantially reduced vulnerability, and no Lys487/Lys/487 homozygote has yet been found to be alcoholic. The sieving of the genome has also detected several putative candidate genes and loci which may represent genes for vulnerability shared across substances. An empirical understanding of the genetic bases of alcoholism and other behaviours is still in infancy. However, the abundances of genetic variants, their modes of action, and their applications in treatment and prevention are of profound importance because appropriate approaches to alcohol will ultimately be science-based.