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 Function
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 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 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 often.

  Frequency Transmission Not Transmitted P value
P-1 0.06 36 17 0.01
P-5 0.04 23 7 0.004

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
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 genetic variance.

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.

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.