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Gene is identified that causes bipolar in some: finding is 'a double, not a home run'. (Families of Northern European Descent).

A research team at the University of California, San Diego, has identified a single mutation in a single gene that might play a key role in as much as 10% of bipolar disorder.

The gene, G protein receptor kinase 3 (GRK3), controls a homeostatic mechanism that modulates the neuron response to dopamine and other neurotransmitters.

An inability to downregulate receptors resulting from the mutation could create the mood instability characteristic of the disorder, said Dr. John R. Kelsoe, senior author and professor of psychiatry at the university.

The study, which used data from sets of 153 and 275 families, found a significant association between one of six single nucleotide polymorphisms (SNPs) in the promoter region of GRK3 and the presence of bipolar disorder (Mol. Psychiatry 8[5]:546-57, 2003).

This research represents a refinement of ongoing work that has focused on the chromosome region 22q12, one of several implicated in bipolar disorder by linkage studies conducted by Dr. Kelsoe's group and others. Data from the human genome project placed GRK3 in this region.

GRK3 is one of six known genes that regulate the expression of G protein receptor kinase, an enzyme responsible for homologous desensitization in the presence of high concentrations of neurotransmitters. It is widely distributed in the brain, including the limbic system.

An earlier microarray study of 8,000 rat genes, conducted by the Kelsoe group, found that GRK3 was "turned on very dramatically more than any other gene on the chip" by exposure to amphetamine, a widely used animal model of mania. This supports its role in regulation of response to dopamine, and possibly other neurotransmitters as well, Dr. Kelsoe said.

For the current study investigators sequenced the GRK3 gene in 14 bipolar patients from 12 families, and identified six SNPs in its promoter region--the part of the gene that switches expression on and off.

Investigators then screened DNA samples from the whole group to compare the frequency of variants in individuals with bipolar disorder and other family members. In the 153-family set, one of the six (P-5) was significantly associated with susceptibility to the disorder; these findings were replicated in the second set of 275 families.

Pooled data from the two sets found 26 transmissions of disease and 7.7 nontransmissions, in the presence of the variant.

Both family sets were ethnically diverse, and the association between bipolar disorder and P-5 appeared only in those of Northern European origin.

The findings were limited by the relative infrequency of the P-5 mutation: It was only found in 3% of affected individuals in the study Dr. Kelsoe suggested that it may in fact play a role in transmission in 3%10% of the overall bipolar population.

When P-5 does occur, its impact seems substantial, Dr. Kelsoe said: Among members of families with bipolar disorder, its presence appears to triple the risk of illness. Combined with the sevenfold increase associated with membership in such a family "the variant could explain half of genetic causation in those who carry it," he said.

That excess transmission was seen m families of Northern European descent rather than in those of other ethnicities suggests that P-5 might operate differently against certain genetic backgrounds.

Dr. James Potash of Johns Hopkins University, Baltimore, called the GRK3 finding very promising," and praised its methodology as "state of the art." His own recent study focused on the same region, 22q12, in families with psychotic bipolar disorder (Am. J. Psychiatry 160[4]:680-86, 2003).

Linkage studies such as his, which tell you "what neighborhood you're likely to find a disease gene," have provided useful bipolar data for 16 years, "but only in the last year have promising association studies ... a more fine-grained approach that allows you to pinpoint genes involved in the disease" emerged, he said.

"There are several reasons to like this finding," Dr. Potash said of the UCSD paper. "The gene is in the linkage region, it's a good candidate on biological grounds, and the association data are there."

But "it's a double, not a home run" because the rarity of the variant limits the study's statistical power, he said.

The involvement of GRK3 in dopamine response, if confirmed, might suggest an overlap between the genetics of bipolar disorder and schizophrenia, he said--a theme of his own and other recent papers ("Schizophrenia, Bipolar Link Found," CLINICAL PSYCHIATRY NEWS, June 2003, p. 1).

Dr. Kelsoe suggested that such research could have implications for drug discovery: "Current bipolar treatments that work through a handful of mechanisms identifying genes for susceptibility to illness might point to new targets for novel pharmaceuticals."

A panel of such genes, once determined, could also facilitate earlier bipolar diagnosis and treatment, he said.
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Author:Sherman, Carl
Publication:Clinical Psychiatry News
Geographic Code:1USA
Date:Jul 1, 2003
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