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Gene variants may increase risk of
anxiety disorder
Strongest genetic evidence
to date could help identify new drug targets
BOSTON - March 3, 2008 - Massachusetts General Hospital (MGH)
researchers - in collaboration with scientists at the University
of California at San Diego and Yale University - have discovered
perhaps the strongest evidence yet linking variation in a particular
gene with anxiety-related traits. In the March issue of Archives
of General Psychiatry, the team describes finding that particular
versions of a gene that affects the activity of important neurotransmitter
receptors were more common in both children and adults assessed
as being inhibited or introverted and also were associated with
increased activity of brain regions involved in emotional processing.
"We found that variations in this gene were associated with
shy, inhibited behavior in children, introverted personality in
adults and the reactivity of brain regions involved in processing
fear and anxiety," says Jordan Smoller, MD, ScD, of the MGH
Department of Psychiatry, the report's lead author. "Each of
these traits appears to be a risk factor for social anxiety disorder,
the most common type of anxiety disorder in the U.S."
It has long been recognized that the tendency to anxiety disorders
can run in families and is believed to be influenced by the interaction
of several genes. Because of the different forms of these disorders
and their complex patterns of inheritance, identifying specific
susceptibility genes has been difficult. Studies in mice have associated
an area of chromosome 1 with anxious temperament, particularly the
gene that codes for a protein called RGS2, which mediates the activity
of neurotransmitter receptors that are also the targets of many
antidepressant and antipsychotic drugs. Mice in whom RGS2 is knocked
out exhibit increased fearful behavior.
To more comprehensively investigate the role of RGS2 in humans,
the researchers conducted several experiments. They analyzed blood
samples from children from 119 families who had participated in
an earlier study assessing their reactions to unfamiliar situations
at the ages of 21 months, 4 and 6 years. The participants had been
evaluated on their levels of behavioral inhibition, a form of temperament
linked to increased risk of anxiety disorders.. Testing several
sites in the RGS2 gene identified nine variations that appeared
to be associated with inhibition.
The second experiment involved more than 700 college students who
had completed questionnaires designed to measure several personality
traits. Analyzing blood samples from this group, the research team
genotyped the four gene markers that had demonstrated the strongest
effects in the first group. They found that the versions associated
with inhibited behavior in the children were also more common in
the college students who scored high on measures of introversion,
a personality trait that also involves social inhibition.
Another group of 55 college students had functional MRI brain imaging
done after they had completed a standard interview screening for
anxiety and mood disorders. While in the MR scanner, the participants
viewed a series of faces expressing various emotions, a test that
previously was shown to influence activity in the amygdala, a brain
structure involved in emotion processing. Participants with the
inhibition/introversion-associated alleles also had increased activity
of the amygdala and the insula, another anxiety-related brain region.
"Now we need to investigate whether these RGS2 variants actually
are associated with particular disorders and how they act on a cellular
level," says Smoller, an associate professor of Psychiatry
at Harvard Medical School. "We hope that ultimately this work
will lead to new drug targets and treatment options for anxiety
disorders."
The study was supported by grants from the National Institutes of
Health, NARSAD (National Alliance for Research on Schizophrenia
and Depression), The Rose and Eugene Kleiner Family Foundation and
the U.S. Department of Veterans Affairs. Co-authors of the Archives
of General Psychiatry report are Jesen Fagerness, Shaun Purcell,
PhD, Lesley Yamaki, Dina Hirshfeld-Becker, PhD, Joseph Biederman,
MD, and Jerrold Rosenbaum, MD, MGH Psychiatry; Martin Paulus, MD,
and Murray Stein, MD, MPH, University of California at San Diego;
and Joel Gelernter, MD, Yale University School of Medicine.
Massachusetts General Hospital (www2.massgeneral.org), established
in 1811, is the original and largest teaching hospital of Harvard
Medical School. The MGH conducts the largest hospital-based research
program in the United States, with an annual research budget of
more than $500 million and major research centers in AIDS, cardiovascular
research, cancer, computational and integrative biology, cutaneous
biology, human genetics, medical imaging, neurodegenerative disorders,
regenerative medicine, systems biology, transplantation biology
and photomedicine.
Media Contacts: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
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