Review Trait Markers for Alcoholism: Clinical Utility

Because alcoholism is a multi-factorial psychiatric disorder, with both psychosocial and biochemical/genetic factors leading to its manifestation in any one individual, the presence of biochemical/ genetic factors alone may not lead to the manifestation of the disorder. There are numerous difficulties associated with identification of a trait abnormality in a disorder that requires suitable socio-cultural permissiveness with distinct behavioural characteristics to manifest a disorder that may not require that predisposing trait abnormality in order to develop. Numerous studies have been performed in the past to potentially identify a biochemical or genetic trait abnormality in alcoholism, and not all of them have addressed significant methodological flaws in this type of research. This review addresses some of the difficulties inherent in this research, and aims for a comprehensive review of the highlights of the search for a clinically useful trait abnormality. Some series of investigations hold promise that a trait marker for a particular subset of alcoholics may be developed, e.g. severe alcoholism and the dopamine D2 receptor gene; the level of reaction to alcoholism in family history-positive alcoholics; β-endorphin abnormalities in specific family groups of alcoholics; reduced P3 wave event-related potentials as markers and predictors of development of substance abuse in predisposed youths; reduced growth hormone response to apomorphine as a predictor of relapse to alcoholism in early abstinence; abnormal adenylyl cyclase activity in certain defined subgroups of alcoholics; and abnormal platelet monoamine oxidase levels in subjects with a behavioural predisposition to addictive disorders. The review concludes that while there has not yet been an identification of a comprehensive trait marker for alcoholism, there is hope for identification subgroups of alcoholics with consistent biological markers within that subgroup that may well prove fruitful over time. It will then be up to a future generation of clinicians to take that information and develop prevention programmes that can incorporate this information to help the predisposed individual avoid alcohol problems. © 1999 Medical Council on Alcoholism 649 *Author to whom correspondence should be addressed. to differentiate a potential genetic marker for the development of alcoholism from a potential marker for the development of alcohol-related disease or tissue damage, a separate matter which is not encompassed within this review. To preserve the clinical focus of this review, we will also confine it to the discussion of human studies, rather than the much broader literature of basic research. Investigations of non-alcoholic family members of genetically ‘loaded’ families can help identify predisposing factors. However, the extent of family history may have significant impact on whether a trait can be defined. Trait studies conducted in families with highly significant family histories may simply identify those traits in particular families that may not be applicable to traits of alcoholism in general. Trait studies conducted in families with more modest genetic loading run the risk of non-detection of a potential trait, because of dilution of that identifying factor. There is also no guarantee that any individual with a significant family history is actually going to develop the disorder, and thus spot studies on ‘those at risk’ may just present interesting associations that bear no relation to actual risk. Indeed, some individuals with significant family histories may be regarded as being at less risk of development of the disorder by virtue of becoming ‘teetotalers’ in response to this family experience of alcoholism. Ideally an alcoholic trait marker would be identified by the following types of studies: identification in a population of alcoholics, preferably abstinent; reliability within the population of alcoholics; an absence of any significant confounder that renders the marker redundant; identification in a group of ‘at risk’ i.e. in those non-alcoholics with strong family histories of alcoholism; persistence of that trait in this population over time; and prediction of development of alcoholism or substance abuse by presence of the trait. Such an approach will avoid the possible confusion that may arise from a failure to distinguish between consumption or state markers, such as carbohydrate-deficient transferrin (Stibler and Borg, 1986), 5-hydroxytryptophol excretion (Beck et al., 1982), or haemoglobin modification (Lindross, 1989), from genuine markers of susceptibility to alcoholism. By identifying not just the positive findings of various scientific groups, but by delineating the potential limitations of each line of investigation, we hope to clarify the current confusing scene and to help identify the most positive potential lines of investigation for the future. It is perhaps unlikely that the holy grail of a single genetic/biochemical marker for alcoholism, defining those predisposed to alcoholism before the development of the disorder, and also delineating those who are currently alcoholic, or who have suffered from it in the past, will ever be found. It is far more likely that various markers defining trait biochemical abnormalities or personality characteristics predisposing to alcoholism may be found, but these are unlikely in themselves to produce the complete disorder. It is far more likely that a number of trait markers will be identified that individually or in tandem may help predict genuine risk in those with a significant family history, or even those who may be at risk of alcoholism even without a significant family history. It will then be up to a future generation of clinicians to take that information and develop prevention programmes that can incorporate this information to help the predisposed individual avoid alcohol problems. The following is an account of important studies on trait markers for alcoholism, which are also outlined in Table 1.