Researchers have identified a genetic factor that appears
to influence anxiety in women. Combining DNA analysis,
recordings of brain activity, and psychological tests,
investigators at the National Institute on Alcohol Abuse
and Alcoholism (NIAAA) found that Caucasian and American
Indian women with the same gene variant had similarly high
scores on tests that measure anxiety. These women also had
similar electroencephelograms (EEG) -- recordings of brain
electrical activity as unique as an individual's
fingerprints -- that showed characteristics of anxious
temperament, further strengthening the association of this
shared genetic factor with anxiety. The study appears in
the current issue of the journal "Psychiatric Genetics".
"These results shed more light on the genetic origins of
anxiety, which can sometimes be a warning sign for
developing alcoholism," says NIAAA Director T.K. Li, M.D.
"Such multidimensional studies that integrate
neurogenetics, behavioral science, and the study of the
brain are vital to increasing our fundamental knowledge of
the genes related to complex psychiatric disorders."
Research physician Mary-Anne Enoch, M.D., and colleagues in
the Laboratory of Neurogenetics in NIAAA's Division of
Intramural Clinical and Biological Research in Bethesda,
Maryland, conducted the study. The team investigated a gene
that encodes catechol-'O'-methyltranferase, or COMT, a
major enzyme responsible for the metabolism of certain
neurotransmitters -- the nervous system's chemical
messengers -- including norepinephrine, which affects
anxiety. People can inherit various possible forms, or
polymorphisms, of the COMT gene, which in turn can affect
the metabolism of their neurotransmitters. Dr. Enoch's
team hypothesized that a particular genetic polymorphism
identified as COMT Val158Met might be associated with
anxiety as measured by a personality dimension test and EEG
records.
"We set out to investigate the relationship of COMT gene
variants with general anxiety, the normal range of anxiety
experienced by people in the community every day, not the
more severe clinical disorders," says Dr. Enoch. "We chose
to conduct this study in two communities very different
from each other." The study participants included 92 women
and 57 men, most of whom identified themselves as
Caucasian, living in suburban Bethesda, Maryland, and a
group of Plains American Indians in rural Oklahoma that
comprised 149 women and 103 men.
The researchers had the study volunteers respond to
psychological questionnaires that use harm avoidance as a
measure of the dimensions of anxiety. As another measure
of anxiety, they also recorded the volunteers' EEG
readings, which are known to display highly inherited
characteristic patterns. In addition to these tests, the
study team analyzed DNA from blood samples to determine the
variants of the COMT gene among the study group
participants.
As expected, the women from both groups scored higher than
the men on the harm avoidance measurements, indicating they
experienced a higher state of general anxiety.
Significantly, regardless of their ethnic background, the
women from either group who shared a particular genetic
makeup, or genotype, identified as COMT Met158/Met 158 were
among those who tested highest for anxiety -- higher than
other women who lacked that particular genotype. In
addition, the women with COMT Met158/Met158 also exhibited
a low-voltage alpha EEG, a specific brain-wave pattern
associated with anxiety disorders and alcoholism.
"Other studies have shown that women have lower COMT levels
than men. In addition the COMT Met158/Met158 genotype is
associated with a threefold to fourfold decrease in COMT
enzyme levels," says Dr. Enoch. "Therefore our study
suggests that women with this genotype may be more
vulnerable to anxiety because their COMT levels fall below
a minimum threshold."
The men in the study who had the COMT Met158/Met 158
genotype did not rank as high on anxiety tests as the
women, and their scores were similar to the test results of
men with other genotypes. They also did not have the low-
voltage alpha EEG. "Men naturally tend to have lower
anxiety scores," says Dr. Enoch, "but it's possible that
there may be a caveat here that a larger sample population
may be necessary to study the association in men."
A recent study of COMT gene activity in both men and women
conducted by the same laboratory was consistent with the
findings of Dr. Enoch's study. David Goldman, M.D., Chief
of the Laboratory of Neurogenetics at NIAAA and colleagues
from the University of Michigan found that the same genetic
variant is associated with a higher level of brain response
to pain and stress. (See "Science" 299: 1240, 2003, and
the accompanying NIAAA news release of February 20, 2003).
Noting that other studies from NIAAA and elsewhere indicate
a role for COMT in cognition, Dr. Goldman says, "The COMT
polymorphism is a common genetic variant which leads to
differences in both anxiety and cognition, both domains of
normal behavior. The COMT variant's different effects also
implicate it as a risk factor in diverse and clinically
very distinct psychiatric diseases, including alcoholism,
schizophrenia, and anxiety disorders. The evidence so far
indicates that people with the Met158 variant, especially
women, are more likely to be worriers, but on the other
hand they benefit from effects of this variant on
cognition."
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