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5. GENETIC BASIS OF SUBSTANCE DEPENDENCE

& Goldman, 2001). Heritability estimates were 66% in women and 42–75% in
men for frequency of alcohol consumption (Heath et al., 1991; Heath
&Martin, 1994) and 57% in women and 24–61% in men for average quantity
consumed when drinking (Heath et al., 1991).
It is not clear if genetic risk is a major factor in the initiation of drinking or
drinking during adolescence (Han et al., 1999a; Maes et al., 1999; Stallings et
al., 1999). It may be that environmental effects explain most of the variation
in initiation of drinking but genetic factors are more important in explaining
the frequency of intoxication (Viken et al., 1999). Genetic factors contribute
to the stability over time (68–80%) in frequency and in the quantity of alcohol
consumed per drinking occasion (Kaprio et al., 1992; Carmelli et al., 1993).
Twin studies can also be used to examine other aspects of alcohol
dependence. Estimated heritability of early alcohol use was significantly
greater in boys (55%) than girls (11%) (Rose et al., 2001). Men (but not women)
who are at increased genetic risk of alcohol dependence exhibited reduced
sensitivity to alcohol (Heath et al., 1999b). The genetic risk for alcohol
dependence was increased in those reporting a history of conduct disorder
or major depression and in those with high neuroticism, social non-
conformity, “tough-mindedness”, novelty-seeking or (in women only)
extraversion scores (Heath et al., 1997). Specific genes are also likely to
influence the heritability for alcohol withdrawal syndrome (reviewed in
Schuckit, 2000). In addition, genetic influences also alter treatment seeking
(41%) for alcohol dependence, with shared environment explaining a further
40% of the variance (True et al., 1996).
These findings indicate further that there are genetic influences at many
stages in the development of substance dependence, and indeed factors that
influence treatment-seeking behaviour. The defining criteria of the
phenotype in question can have major effects on the results of the study.
Although it is clear that there is a genetic component to many aspects of
alcohol drinking (e.g. initiation, frequency, quantity and response to alcohol),
the relationship between genes and alcohol drinking behaviour is not a simple
one.

Alcohol dependence and linkage studies
On chromosome 4q, one location identified was very close to the region of
the alcohol dehydrogenase (ADH) genes (Long et al., 1998; Reich et al., 1998;
Saccone et al., 2000); these genes have been associated with protective effects
in Asians, as will be discussed later in this chapter (Reich et al., 1998). The
finding of a linkage to 4q in a southwestern American Indian tribe and in
Americans of European descent strongly supports a role for genes in this
location in alcohol dependence. Linkage to chromosome 4p has also been
seen near the β GABA receptor gene (Long et al., 1998).
1
In a study of paired siblings (sib-pairs) in Finland, alcohol dependence
showed weak evidence of linkage with a location on chromosome 6 and

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