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NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

2000; Crabbe, 2002). Many psychiatric disorders are likely to be caused by
multiple genes that interact with each other (Cooper, 2001). This suggests
that having one predisposing allele does not imply high risk; in fact, the
majority of carriers are not expected to express the disorder (Stoltenberg
&Burmeister, 2000). Issues of genetic heterogeneity create complexity for
linkage studies, as well as for studies that examine only one gene, or allelic
variant at a time (Wahlsten, 1999).

Phenotype
At least some genetic defects appear to predispose populations to forms of
dependence that do not fall into the neatly defined categories in DSM-IV or
ICD-10 (Boxes 1.2 and 1.3). This is certainly the case for tobacco dependence
where other ways of determining dependence have been proposed and used
(e.g. Fagerstrom & Schneider, 1989; Heatherton et al., 1991). Likewise, it was
found that different symptoms of alcohol dependence yielded heritability
estimates ranging from 3% to 53% (Slutske et al., 1999), and the same has
been observed with alternative diagnostic tools for alcohol dependence (van
den Bree et al., 1998a). These findings indicate the need to clearly define the
phenotype of interest. In other words, clearly defining the endpoint (e.g.
relative risk for drinking over 8 drinks per day, alcohol withdrawal, relative
risk for initiation of smoking, initial tolerance) may improve the ability to
identify specific genes involved.

Comorbidity
Many psychiatric disorders co-occur with substance dependence (see
Chapter 6). Comorbidity among disorders will be understood only with
increased knowledge of the underlying neurobiology of the disorders.
Behavioural genetic approaches will allow investigators to directly test causes
of each disorder as well as the comorbidity, and to estimate the size of the
effect of each contributing factor.

Methodological issues
Candidate gene studies have often found conflicting results. The reasons for
differences in findings include:
— inconsistencies in the definitions of “smokers” (i.e. ever vs. never,
former, >100 cigarettes in lifetime, dependence) and “smoking
behaviour” (i.e. initiation, maintenance, quitting, cessation, relapse);

— issues concerning functionless polymorphisms, methodology (e.g.
erroneous genotyping techniques) and statistical power;
— ethnic ancestry.

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