Behavior Genes
607
a large study of Irish families, contains a
gene called dystrobrevin-binding protein-1
or dysbindin, which again contains vari-
ants that appear to be more common
in schizophrenics than in controls. Dys-
bindin is widely expressed in mouse brain,
and by binding to dystrobrevin, appears
to play a role in synapse formation and
maintenance and possibly in NMDA re-
ceptor clustering.
A region on chromosome 22q has been
implicated not just by linkage studies
but also by studies of individuals in
whom there is a micro deletion of the
region. Depending on the size of the dele-
tion, those who carry it present with an
overlapping set of syndromes of which
the central one is called velo-cardio-facial
syndrome (VCFS). About a quarter to
a third of individuals who have VCFS
also show schizophrenic-like symptoms.
Interestingly, the VCFS region contains
the
COMT
gene, but some studies of
schizophrenia, particularly the early-onset
type, have suggested an association with
variants in another gene, proline dehydro-
genase (
PRODH2
). There is again some
evidence that
PRODH2
is involved in the
modulation of glutamine transmission in
the brain at NMDA receptors.
The fact that all of these genes have an
effect on glutamate transmission seems
unlikely to be coincidental. Glutamate re-
ceptors are of two broad types – those
such as the NMDA receptor that are ion
channels (‘‘ionotropic’’) and those that are
coupled to a class of intracellular messen-
gers called g-proteins (‘‘metabotropic’’).
G-protein signaling is in turn influenced
by a class of proteins called regulators of
g-protein (RGS). One such protein, RGS4,
has been shown to have altered expres-
sion in schizophrenic brains compared
with controls. Subsequently, a haplotype,
a set of variants in the
RGS4
gene, has
been found to show differences between
patients and controls.
RGS4
is also rele-
vant to other g-protein coupled receptors
including dopamine receptors belonging
to the D2 family.
4.3
Mood Disorders
The major mood disorders belong to two
main groups, bipolar affective disorders
and unipolar depression. Bipolar disor-
der is so called because there are both,
episodes of mania (characterized by ela-
tion, over-activity, disinhibition, and often
reckless behavior) and episodes of depres-
sion (characterized by low mood often ac-
companied by sleep disturbance, appetite
and weight loss, and suicidal thoughts).
Unipolar disorder, also called depressive
disorder, consists of episodes of depres-
sion alone. Depressive disorder is very
common. Illness that is suf±ciently severe
to warrant referral to a psychiatrist has a
lifetime risk in the general population, of
around 6 to 8%. Less severe forms are even
more common. Affected women outnum-
ber men by about 2 : 1. By contrast, there
is no sex difference in the frequency of
bipolar disorder, which is a less common
condition affecting around 0.5 to 1% of the
population per lifetime.
Quantitative
genetics
of
mood
disorder
Both forms of disorder show a marked
tendency to aggregate in families. The
majority of studies show a stronger familial
effect with bipolar disorder, although some
more recent studies, particularly those
focusing on severe depression, ±nd that
unipolar disorder is almost as familial.
A major and consistent difference in all
studies is that index cases with unipolar
disorder have an excess only of unipolar
depression among their relatives, whereas
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