In the past year, researchers have begun to map out
a genetic basis for one of psychiatry's most baffling
conditions — bipolar disorder, a lifelong mental disease
in which people zigzag from exuberant emotional highs to
paralyzing periods of despair.
The latest findings come from UC San Diego, where doctors
plan to report today that they have identified a gene
that's linked to the disorder in up to 10% of sufferers.
The discoveries represent a significant advance in
doctors' understanding of what causes the mood swings and
pave the way for the development of a genetic test that
could help diagnose and treat the condition.
"We're getting very close to having a test that could
at least help us tell whether a person with a family
history is at a higher or lower risk" of developing
the disease, said Dr. John Kelsoe, a psychiatrist at UC
San Diego and the study's lead author. The paper appears
in the June 16 issue of Molecular Psychiatry, a medical
Bipolar disorder, or manic depression, afflicts 5 million
to 10 million Americans. The illness often begins in late
adolescence and many patients report that they suffered
symptoms for years without getting a proper diagnosis.
Although any genetic screening test would raise many
questions about patient privacy, many people with the
disorder would welcome it, said Sue Bergeson, vice
president of the Depression and Bipolar Support Alliance,
a patient advocacy organization. "Anything that helps
speed up diagnosis and improve treatment is wonderful
news," she said.
Psychiatrists have long known that bipolar
disorder runs in families: People who have a brother,
sister or parent with the illness are about seven times
more likely to develop it than those who don't have such a
family history. But there are multiple genes involved,
researchers say, and only now are scientists beginning to
narrow down the search. Dr. Pamela Sklar, a research
psychiatrist at Harvard University, said that no one has
done studies large enough to discern which genes increase
people's risk of developing the disease or to explain how
they do so. For now, she said, the new research provides "some very good leads to follow to establish genetic
Two of the genes that doctors have identified appear to
act as biological thermostats, helping the body dampen
bursts of brain chemicals during stress or excitement. One
of them, brain-derived neurotrophic factor helps
short-circuit the effect of stress hormones when it's time
to relax, studies suggest.
In the San Diego study, Kelsoe led a team of investigators
who studied genetic data in 428 families with a history of
bipolar disorder. Looking for any genes that were
especially active in the family members who had the
disorder, they focused on one called GRK3. GRK3 acts to
keep nerve cells from being overwhelmed by stimulating
brain messengers, such as dopamine, by reducing their
sensitivity to the chemicals. A mutation in the gene might
leave a person hypersensitive to dopamine, producing
precisely the sort of extended highs that manic
depressives experience. Kelsoe calculated that mutations
in this gene turned up in 3% to 10% of those with bipolar
disorder — a significant link.
"If you have a mutation and the gene can't turn on,
then you might have a baseline supersensitivity to this
stimulation," Kelsoe said. Day to day, as neural
messengers flood the system due to some excitement, the
brain would be unable to quickly blunt the sensation. The
result: a manic episode, which is then followed inevitably
by a crash, he said. "Instead of maintaining balance
in the system, you're going way up and way down."
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