Behavior Genes
609
overlap in the genes contributing to all
three disorders as well as the existence of
speciFc genes contributing to the liability
of either schizophrenia or bipolar disor-
der. The Fndings are therefore consistent
with linkage study Fndings pointing to
an overlap in the genomic regions that
contain schizophrenic and bipolar genes.
As we write, no studies have yet been
published on bipolar disorder and
G72
or
DAAO
, the genes on chromosome 13q dis-
cussed earlier in relation to schizophrenia.
Nor have there been any published stud-
ies on PR0DH2 and bipolar disorder on
the chromosome 22q genes implicated in
schizophrenia. However,
COMT
variants
have been implicated in bipolar disorder,
particularly inpatients who show rapid cy-
cling, that is, those having four or more
episodes per year.
Molecular genetic studies are much less
advanced in unipolar disorder, although
several large-scale linkage and association
studies are currently under way. To date,
the most provocative results have been
based on the serotonin transporter gene.
One of the ways in which serotonin is
cleared from the synapse is by reuptake
into the presynaptic neuron. This is the site
of action of the antidepressant drugs called
selective serotonin reuptake inhibitors
of which fluoxetine (Prozac) is probably
the best-known example. The serotonin
transporter gene contains a common
variable number tandem repeat (VNTR)
polymorphism within one of its introns, as
well as a common variant in the promoter
region that has been shown to effect levels
of gene expression. Both variants have
been implicated in association studies
of mood disorders and the promoter
polymorphism may also be associated
with the personality trait of neuroticism,
which may in turn be associated with
vulnerability to depression.
5
Future Directions
Behavioral genetics is now moving into an
era of behavioral genomics, offering an im-
proved understanding of the neurobiology
of disease. Not only is the complete human
genome sequence known but there are
also complete genome sequences or draft
sequences available on over 60 species.
Comparing genomes across species and
noting differences in those genes that have
been conserved will show the major varia-
tions between species and offer an under-
standing of the basis for neurobiological
and hence behavioral evolution. Knowing
the structure and function of all human
genes has been compared with the discov-
ery of a ‘‘periodic table of life.’’ It paves the
way for a series of paradigm shifts where
the emphasis moves from the structure of
the genome to functional genomics and
to proteomics, the study of proteins, at a
functional level. A striking example of how
one complex aspect of human behavior,
circadian rhythms, can be dissected and
its basis understood at a molecular level is
given by the recent discovery of new ‘‘clock
genes,’’ simply by the analysis of the draft
sequence of the human genome that was
discovered when searching for genes with
a high similarity to known clock genes
originally discovered in mice or fruit flies.
Even before the publication of the draft
sequence of the human genome, discov-
eries arrived at by positional cloning in
Alzheimer’s disease (AD) have begun to
provide important new understandings
of the neuropathological mechanism. Al-
though Alzheimer’s disease has a charac-
teristic neuropathology that was described
at the beginning of the twentieth century,
the problem of discovering its pathogen-
esis did not appear to have a tractable
solution until the discovery of the role
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