Using the above concepts and methods scientists at the University
of California, San Diego (UCSD) have identified one of the first
genes for bipolar disorder, G protein receptor kinase 3 (GRK3).
Bipolar Disorder and Chromosome 22
Chromosome 22 has long been a focus of genetic studies
of psychiatric illness. This stemmed initially from the observation
of psychotic symptoms in adolescents with the dysmorphism syndrome,
Velocardiofacial syndrome (VCFS). VCFS results from a one megabase
deletion on 22q11. However, subsequent studies of chromosome 22
in schizophrenia and bipolar disorder pointed to other regions
on 22q quite removed from the VCFS region. Presently, several genes
and regions have implicated on chromosome 22. UCSD scientists conducted
a linkage study of bipolar disorder in 20 large families (Kelsoe
2001). They found evidence of two possible genes on chromosome
22. One of these two regions mapped exactly at an interesting candidate
gene, G protein receptor kinase 3 (GRK3).
GRK3 therefore, plays a key role in maintaining balance in neurotransmitter
systems. This leads logically to the hypothesis that a defect in GRK3 functioning
could lead to a failure in homeostasis in critical brain neurotransmitter
systems. This could lead to a hypersensitivity to dopamine, thereby, predisposing
to mania or psychosis. Alternative, a failure in such a homeostatic mechanism
could lead to oscillation such as those seen in bipolar disorder.
GRK3 is involved in the desensitization of
a variety of receptors in the brain including those for dopamine, norepinephrine
and corticotrophin releasing factor (CRF). It is a key component of adaptive
mechanisms in the brain that maintains homeotasis in the presence of
increased signaling in these systems. For illustration, under stress
or other stimulation, dopamine release increases in the brain. Normally,
the brain will adapt by decreasing the sensitivity to dopamine. This
has been shown to be mediated by GRK3, which is turned on in response
to such signaling. GRK3 then migrates to the cell surface where it phosphorylates
the receptor. This leads to the binding of another protein, β arrestin,
which decreases the efficiency of binding of the receptor to the G protein
complex. This reduces the amount of cAMP or other second messenger
that is generated and thereby decreases the signaling at the post synaptic
intracellular level. Later, the process leads to the receptors being
removed from the cell surface through endocytosis.
GRK3 mutation and association
Proof of this hypothesis came from studies of the sequence of
the GRK3 gene and association studies in bipolar patients. If GRK3 were
a susceptibility gene for bipolar disorder, then a mutation or SNP must
exist that affects the function of the gene, a functional mutation. These
functional mutations must then be associated with illness, or occur in
patients with bipolar disorder more often than controls.
The sequence of the GRK3 gene was studied in 24 subjects with bipolar
disorder who came from families linked to this region of chromosome 22.
No mutation was discovered that affect sequence coding for protein. However,
a mutation, P-5, was found that occurred in the promoter of the gene,
that region that regulates when the gene is turned on or off.
Studies of this P-5 mutation have shown that it in fact does affect
the regulation of GRK3 gene expression in mouse brain cells. To show its
association to bipolar disorder, the P-5 mutation was genotyped in a set
of 398 bipolar families. These studies showed that P-5 occurred in only
about 4% of patients, but in those patients it occurred about 3 times more
P-1 is another SNP near P-5 that likely reflects the effect
of P-5. A test of association was conducted termed the TDT, that employs
families and compares how often an allele is transmitted vs. not transmitted.
These data suggest that P-5 occurs in about 4% of patients and in
those patients it conveys an approximate 3 fold increase in risk.
However, P-5 did not seem to explain all of the involvement
of GRK3 in bipolar disorder, so a search was conducted for another mutation
in the gene. Though the precise second mutation has not yet been discovered,
several SNP markers have been found that mark its presence. The markers
for this second mutation occur in about 10% of patients and in those
subjects it conveys an approximate 2.4 fold increase in risk. Therefore,
together these marker in GRK3 occur in about 14% of patients and in
those patients convey between a between 2.4 – 3 fold increase
in risk. These results for the P-5 mutation or the second marker have
now been replicated in four independent samples of subjects.
Clinical Use and Interpretation
Testing using GRK3 will be useful in patients whose
diagnosis is unclear, but bipolar disorder is suspected either because
of clinical presentation or because of a family history of bipolar disorder.
In such cases, the presence of one of the GRK3 markers will indicate
that bipolar disorder is more likely. Approximately 15% of bipolar patients
will test positive in for GRK3 markers. Positive results in those
patients will indicate 200-300% increased likelihood of bipolar disorder
compared to the general population.
GRK3 represents one of the first genes for bipolar disorder
identified and the first to be made available for clinical use. Bipolar
likely results from many genes and their interaction with environment.
GRK3 is only one of these genes and explains only a part of the total
It is important to note that these results were obtained in
a population of Caucasians largely of northern European ancestry.
Its meaning in other ethnic and racial populations has not yet been
tested and is not known.
The frequency of these GRK3 markers has not been established in other
diagnostic groups such as schizophrenia or ADHD. Therefore, the GRK3
test should not be used to rule out these or other diagnostic alternatives.
The test indicates likelihood of bipolar disorder in comparison to
the general population only. As indicated above, it is best applied
where there is some reason clinically to suspect bipolar disorder,
such as clinical presentation or family history.
A negative test for GRK3 does not rule out bipolar disorder.
Many genes likely are involved in the genetic vulnerability to bipolar
disorder; GRK3 is just one of them. Other genes may be operating in
a patient negative for GRK3 who has bipolar disorder.