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5. GENETIC BASIS OF SUBSTANCE DEPENDENCE

Smoking has been shown to be a significant risk factor for promoting the
progression of alcohol dependence (Bucholz, Heath & Madden, 2000). This
effect may occur by diminishing the effects of alcohol, because nicotine can
increase the activity of the alcohol-metabolizing enzyme CYP2E1 (Madden
et al., 1995). However, alcohol dependence is associated with more serious
nicotine withdrawal (Madden et al., 1997). This indicates that tobacco and
alcohol dependence share a considerable proportion of genes (Carmelli et
al., 1990; Hettema, Corey & Kendler, 1999; Vanyukov & Tarter, 2000). This
common genetic influence may partially explain the clinical and
epidemiological observations that people who are dependent on alcohol are
also often dependent on tobacco.
Family studies show strong familial aggregation of substance dependence
(Meller et al., 1988; Mirin et al., 1991; Kendler, Davis & Kessler, 1997; Bierut et
al., 1998; Merikangas et al., 1998). One estimate is that there is an eight-fold
increased risk of substance dependence amongst relatives of dependent
people compared to controls, which applied to a wide range of substances
including opioids, cannabis, sedatives and cocaine (Bierut et al., 1998;
Merikangas et al., 1998).
A major population-based twin study has been used to examine the role of
genes in the familial transmission of substance dependence (Kendler &
Prescott, 1998). This large-scale study showed that genetic factors substantially
influence vulnerability to substance dependence. Family environment is also
important, but family environment predominantly influences initiation,
whereas genetic factors have a stronger influence on heavy use and dependence
(van den Bree et al., 1998b; Kendler 2001). These studies place heritability
estimates for substance dependence at between 50% and 80%.
Few studies specifically address the interrelationship or overlap of
heritability between opioid dependence and alcohol dependence. There is
evidence of both common and specific additive factors transmitted in families
(Beirut et al., 1998). Overall the evidence suggests that independent causative
factors mainly operate for alcohol and opioid dependence, although there
may be some common genetic factors related to dependence in general.

Linkage studies of substance dependence
The well-established links between alcohol dependence and smoking have
been recently reviewed (Narahashi et al., 2001). Approximately one-third of
the loci that showed evidence for linkage to smoking behaviour also showed
evidence for linkage to alcohol dependence (Bergen et al., 1999). Strong
evidence for linkage to chromosome 15 was observed in a family study
involving people with alcohol dependence and heavy smokers (Merette et
al., 1999). Of note, linkage with alcohol was found on chromosome 19q12-
13, which may be due to linkage with smoking and the polymorphic CYP2A6
enzyme (19q13.2) which can inactivate nicotine (Messina, Tyndale & Sellers,
1997).

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