606
Behavior Genes
DRD3
receptor gene. There has also been
renewed interest in another gene involved
in dopamine neurotransmission, catechol-
O-methyltransferase
(
COMT
).
COMT
inactivates
catecholamines,
including
dopamine,
by
methylating
their
m-
hydroxy group. A functional
COMT
gene
polymorphism has been described that
influences enzyme activities and the high-
activity allele (
val
-108) has been found
to be associated with schizophrenia in
some studies. This is of particular interest
because schizophrenics, compared with
controls,
on
average
show
reduced
metabolism in the prefrontal lobe of
the brain and do less well on cognitive
tests that are designed to test prefrontal
function. Otherwise healthy subjects who
have the high-activity allele fair less well
in such tests and have less efFcient
prefrontal physiology than those who
have only the low-activity (
met
-108) allele.
Unfortunately, the
val/met
polymorphism
association with schizophrenia has not
proved consistent across studies. The
largest single study to focus on
COMT
suggests that there is a weak but highly
signiFcant association with schizophrenia,
but this results from a set of variants in a
haplotype in a different part of the gene.
Perhaps of even greater interest, sev-
eral new positional candidates, genes that
are involved in neurochemical pathways
and/or neurodevelopmental processes that
are of relevance to schizophrenia, have
been implicated in linkage regions. One
of these, neuregulin-1 (
NRG1
), maps to
chromosome 8p, a region of the genome
implicated in schizophrenia in a number
of studies including one based on Ice-
landic families. The Icelandic researchers
performed an association analysis across
the region that gave signiFcant evidence of
an effect of a variant in
NRG1.
The
NRG1
association with schizophrenia was subse-
quently replicated in Scottish patients and
controls. Mice in which one copy of
NRG1
or of the gene for its receptor
ErbB4
have
been ‘‘knocked out’’ show some behaviors
that occur in schizophrenic patients, in-
cluding a response to simple stimuli called
prepulse inhibition. These changes can be
partially reversed in the mice with the an-
tipsychotic drug Clozapine. The mutant
mice also have fewer functional receptors
for the excitatory amino acid glutamine of
theNMDAtypethandowild-typemice.
A completely novel gene encoding for a
protein called G72 also appears to have a
role in NMDA receptor function. The
G72
gene maps to chromosome 13q to a region
that again has been implicated in several
linkage studies. In a study involving Cana-
dian patients, which was then replicated
in cases from Russia, the region was again
narrowed down by linkage disequilibrium
mapping. Potential genes in the narrowed
region were then identiFed by searching
computer databases. After experimental
annotation using RT-PCR, two genes were
identiFed, one of which,
G72
,wasfoundto
be expressed in the human brain. It is also
of interest that given the quintessentially
human and language-based character of
schizophrenic symptoms,
G72
appears to
be found only in primates. ±urthermore,
the longest transcript of the gene in the
chimpanzee brain is only about half that
of its human counterpart, perhaps sug-
gesting rapid evolutionary change. Using
a way of identifying interacting proteins
called the yeast 2 hybrid method, an in-
teraction with the enzyme D-amino acid
oxidase (DAAO) was found. DAAO is also
expressed in the brain and oxidizes D-
serine, which in turn has an activating
effect at an NMDA receptor.
A third linkage region, this time on
chromosome 6p originally identiFed by
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