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5. GENETIC BASIS OF SUBSTANCE DEPENDENCE

Differences in definitions of “smokers”, “drinkers” and “ethnic ancestry”
are likely to contribute substantially to the differing outcomes of studies.
Another issue is that “attractive” candidate genes will be studied in many
laboratories, and there is often a bias towards reporting positive findings.
A further issue is the practice of examining one gene and sometimes one
allele at a time. While this is simpler and requires smaller sample sizes,
examples exist which indicate that only when two or more genetically variable
genes (e.g. ALDH2 and ALD) are examined together, will meaningful results
be found. Another limitation of the candidate gene approach is the amount
of knowledge of the biology of the disorder being studied. This issue further
supports integrating research approaches, using chromosomal locations
identified by linkage or QTL studies, as well as candidate genes identified in
model systems such as Drosophila, to identify other potential candidate
genes. To understand the genetic contributions to smoking and drinking
behaviours, many aspects of the behaviour need to be assessed, as different
genes may affect the various behaviours differentially. Large studies of
multiple gene variants and clearly-defined phenotypes will lead to clearer
understanding of the specific genes and mechanisms involved.

Future directions
The genetic approaches and findings outlined in this chapter provide an
indication of the promise that genetic research offers. These genetic data can
be, and have been, used to improve our understanding of the etiology of
substance dependence and variation in risk between individuals. Once genes
are identified which alter the predisposition to dependence, a major challenge
will be to understand how the functions of these genes interact with the
environmental influences on dependence (Swan, 1999). Analysis of specific
genes will allow a rational exploration of biochemical underpinnings of the
actions of nicotine, alcohol and other substances, and makes possible a link
between behavioural change, genetic predisposition and biochemical action.
Such genes, and the proteins they encode, will become primary targets for
creating novel diagnostic tools as well as the basis of novel behavioural and
pharmacological treatments.
Genetic information may be useful for identifying individuals at increased
risk for substance dependence (and thus for refining prevention approaches),
and for predicting the health consequences of substance dependence (e.g.
hepatic toxicity). By gaining a better understanding of genes that are involved
in initiation, maintenance and cessation of substance dependence, novel
pharmacological and behavioural treatment approaches may be created
(Swan, 1999; Sellers & Tyndale, 2000; Marteau & Lerman, 2001; Johnstone,
York & Walton, 2002). This research field also offers great potential for using a
person’s genetic information to personalize treatment approaches (i.e.
choosing the appropriate treatment, drug and dose) and for minimizing
adverse reactions. Again, it is important to emphasize that a certain genetic

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