If Sherlock Holmes were a scientist, mapping the human genome might be his holy grail. If Holmes were an alcohol researcher, he would already be hot on the trail. The alcohol field has for many years been at the forefront of using genetic techniques to determine what component of alcohol-related problems might be genetic in nature. Until recently, the approach has been one of trying to find a simple genetic explanation for risk. A study/commentary in the February issue of Alcoholism: Clinical & Experimental Research clarifies the need for researchers to become more complex in their thinking and approach.
"Human alcoholism is a complex disease," said John Crabbe, director of the Portland Alcohol Center and sole author of the study. "The definition of alcoholism is based on behavioral outcomes, such as disordered relationships, biomedical events, such as symptoms experienced when drinking ceases, and psychological aspects, such as the subjective loss of control over drinking." Not only is the definition of alcoholism complex, so too is the relationship between its genetic and environmental components.
According to Crabbe, the earliest genetic studies on alcohol drinking in rats were published in the late 1940s. More serious and systematic genetic research began in the mid-1970s. By the late 1980s, researchers had clear evidence that genetic influences contributed about half of any individual's risk, but still had no idea which genes were involved.
"Simply assessing the proportion of genetic contribution to alcoholism risk is not of much practical use," said Crabbe. "We really want to know which genes are involved, and what they do. More recent gene mapping studies have identified the location of many such genes in mice and rats, and this tells us immediately and approximately where they are in the human genome." The gene mapping referred to by Crabbe began around 1990. By 1999, he said, researchers knew the location of more than 25 genes affecting alcohol or other abused substances' effects. "It will not be long before specific genes are identified," he said, "and progress toward that goal is accelerating."
Genes do not determine individual susceptibility to alcoholism, however, nor does any single gene (with the possible exception of two very rare genes found predominantly in Asian populations) exert sufficient influence to override environmental influences. Instead, it seems that specific genes confer increased or decreased risk. In other words, genes can predispose, but cannot determine, an individual’s level of risk. Furthermore, genes and the environment interact to influence susceptibility to alcohol.
"There have always been two sides to this story," said Herman H. Samson, professor of physiology and pharmacology at Wake Forest University School of Medicine and director of the Center for the Neurobehavioral Study of Alcohol. "Alcoholism runs in families. Alcoholism is a result of environmental conditions. Examples of each can be found, as can examples of the opposite. That is, in the same environment, individuals from alcoholic families may not develop alcohol problems and individuals from nonalcoholic families will develop problems. Thus, the real issue, as pointed out by Dr. Crabbe, is not choosing one or the other, but understanding how the two interact. If we do not try and study this complex interaction, we most likely will never unravel the manner in which multiple genes increase the risk to develop alcohol-related problems in given environments."
Crabbe explained that one impetus for his paper was frustration that genetic research is sometimes presented in an oversimplified fashion, "particularly in ways that promote the kind of thinking that could be paraphrased as ‘here is the gene for alcohol’s anti-anxiety effects.’ There are many, many genes for any specific behavior in rats, mice or people. There are probably even more for a behavior such as ‘alcoholism,’ which is itself a broad diagnosis."
Crabbe and Samson concurred on two key points regarding research on the genetic components of alcoholism. The first point is the difficulty, and likely impossibility, of identifying any single, specific risk-promoting or protective gene.
"Alcoholism is genetically complex," said Crabbe. "Many genes contribute to risk or protection, so each individual gene can have only a small effect. Practically, this makes the job of tracking down individual genes more difficult. Furthermore, genes interact with each other. Having four risk-promoting genes might not make a person, or a mouse, four times as likely to be affected as having a single risky gene. Genes might ‘potentiate’ or multiply each others' effects (geneticists call this ‘epistasis’) so that having four risk genes may actually increase an individual’s risk by twentyfold."
"How the genes themselves interact," said Samson, expanding on the second point, "will influence how the environmental effects of alcohol exposure will determine the development of alcohol tolerance and dependence." In sum, genes interact with each other, genes may be ‘triggered’ only by certain environments (such as a disordered family), and genes and the environment influence each other.
"The key to the future," said Crabbe, "is in understanding the interactions between genes and the environment. We have made much progress toward actually understanding the genetic risk for alcoholism, but there are no quick answers to be expected."