Genetic Variation Might Play Role in Severe Premenstrual Depression

Marlene Busko

July 30, 2007

July 30, 2007 — A study has identified 4 substitutions in the estrogen receptor alpha gene that are associated with the likelihood of having premenstrual dysphoric disorder (PMDD). This association was seen only in women who also had a genetic variance in catechol-O-methyltransferase (COMPT), an enzyme that regulates dopamine in the prefrontal cortex.

These are the first positive (though early) genetic findings that may partly explain why some women are more likely to develop PMDD, the authors, led by Liang Huo, MD, from the National Institute of Mental Health, in Bethesda, Maryland, write. The study was published online on June 26 in Biological Psychiatry.

Study author David R. Rubinow, MD, from the University of North Carolina School of Medicine, in Chapel Hill, told Medscape: "This is the first study to identify a significant potential source of genetic variation in the susceptibility to developing this mood disorder. . . . Ideally at some point we would be able to have a profile of genes that might be useful in predicting which women would be potentially at risk for this syndrome."

PMDD, which is characterized by severe symptoms of depression and/or irritability/anxiety that are greater in the week before than in the week following a menstrual period, affects about 5% to 8% of women in their childbearing years, the group writes. Previously, they demonstrated that exposure to normal levels of steroid hormones can trigger depressed mood in women with PMDD but not in women without this history. The team sought to determine what makes women with PMDD more susceptible to this type of hormone triggering.

They performed genetic testing on blood samples from 91 women with PMDD and 56 women without PMDD to look for associations between PMDD and single-nucleotide polymorphisms, or gene building-block substitutions. The investigators focused on 24 single-nucleotide polymorphisms in the estrogen receptors alpha and beta — which have been implicated in arousal and in depression and anxiety, respectively — and a valine-methionine single-nucleotide polymorphism in COMPT.

Promising Preliminary Findings, More Study Needed

Compared with the control group, the women with PMDD were more likely to have 4 specific gene variants — differences in strings of DNA nucleotides A, G, C, or T — in the estrogen receptor alpha gene. These were observed only in women who had the valine-valine COMPT genotype. The investigators did not find an association between PMDD and estrogen receptor beta.

"These are the first positive (albeit preliminary) genetic findings in this reproductive endocrine-related mood disorder and involve the receptor for a hormone that is pathogenically relevant," the group writes. They caution that "as with all complex genetic disorders, the contribution of any single gene is likely to be quite small," and also note that their findings were done in a small sample of women and needs to be replicated. Dr. Rubinow added that the researchers also need to determine whether the genetic differences that they identified are marking susceptibility for the disorder or resilience in the controls. "It's entirely possible that the differences that we saw are protective genetic variance rather than measures of susceptibility," he noted.

Despite these caveats, the team concluded that demonstrating a relationship between genetic variations in estrogen receptor alpha and PMDD "is a significant step forward in the effort to discover the genetic underpinnings of PMDD."

The authors report no relevant financial relationships.

Biol Psychiatry. Published online June 26, 2007. Abstract


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