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."

For interviews with Dr. Enoch or Dr. Goldman, please call the NIAAA press office at 301-443-3860. The paper, "Genetic origins of anxiety in women: a role for a functional catechol-O-methyltransferase polymorphism," appears in the March 1 issue of Psychiatric Genetics , 2003; 13:33-41 (Website: http://www.psychgenetics.com/ ).

The National Center on Minority Health and Health Disparities supported the study in part with funding for the work with the American Indian community.

Additional alcohol research information, including publications from NIAAA’s genetics research program, are available at www.niaaa.nih.gov.