610
Behavior Genes
of mutations in the amyloid precursor pro-
tein and presenilin. Interestingly, although
presenilin1 on chromosome 14 was identi-
Fed by positional cloning, presenilin2 was
discovered essentially by its homology with
presenilin1 and subsequently was demon-
strated to have an etiological role by linkage
analysis. As with the discovery of new clock
genes, we can expect the discovery of fam-
ilies of genes involved in abnormal and
normal behaviors to become more com-
monplace.
IdentiFcation of genes and gene prod-
ucts involved in psychiatric disorders will
have important implications for pharma-
cotherapy in two ways. The Frst of these is
in directing drug discovery. At present, the
drugs used in the treatment of psychiatric
or other central nervous system diseases
have their actions at a limited number of
target sites that include cell surface recep-
tors, nuclear receptors, ion channels, and
enzymes. It is likely that detecting genes
involved in the pathogenesis of psychiatric
disorders will identify new targets, some
of which fall within these categories and
some of which have not thus far been in-
cluded as target sites for drug action. In ad-
dition to targeting of treatments, advances
in genomics will allow the tailoring of treat-
ments. There is already some evidence that
the response to a typical antipsychotic such
as Clozapine is influenced by an individual
genotype at the serotonin 5HT2A receptor.
It is also well established that the rate at
which most psychoactive drugs are metab-
olized is influenced by genetic factors, in
particular, genes that code for a family of
enzymes called the cytochrome P450 sys-
tem. This may be relevant to the develop-
ment of side effects as well as to treatment
response. This whole area of pharmacoge-
nomics is still comparatively novel. It holds
enormous promise for individual tailoring
of treatments that will be a major advance
over the current trial and error approach
that the clinician is now saddled with.
There has been a degree of public con-
cern that the current pace of advance will
tend to ‘‘geneticize’’ common diseases and
encourage deterministic attitudes. In par-
ticular, worries have been expressed that
insurance companies may wish to force
DNA testing on individuals thought to be
at high genetic risk of disorder. While pre-
diction with a high degree of accuracy is
already possible for rare early-onset de-
mentia such as Huntington’s disease or
the single-gene forms of AD, this is not
possible for complex disorders. ±or exam-
ple, the apolipoprotein
¤
4 allele, despite
the conFrmed association with risk of late-
onset AD in the general population, is
of limited value as a predictor at an in-
dividual level. The situation is likely to
prove even more complicated with dis-
orders such as schizophrenia. At best,
DNA-based tests may be used to modify
the predicted risk in individuals who are
already at high risk because of having a
schizophrenic close relative. However, it is
unlikely that risk prediction will ever be
better than about 50% accurate, since ge-
netically identical individuals, MZ twins,
are discordant for schizophrenia 50% of
the time. This means that DNA-based pop-
ulation screening for complex psychiatric
disorders (including AD of late onset) will
never become a reality, but the option of
offering screening to high-risk individuals
probably will, with the caveat that such
testing will reFne risk prediction but not
give clear yes/no answers. Given that most
common diseases, and not just psychiatric
ones, will depend upon the combined ac-
tion of multiple common gene variations
together with environmental risk factors,
batteries of genetic tests will be of limited
usefulness to insurance companies and
are not likely to be widely employed.
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