July 18, 2003, Pg. A01

Variation in One Gene Linked to Depression; Contrast Emerges in Response to Stress

By Shankar Vedantam

People with a genetic vulnerability to stress are more than twice as likely to develop depression after a traumatic event, such as divorce, as those with a version of the same gene that appears to confer protection, scientists have found.

Leaders in the field said the work marks the first time that scientists have traced the roots of a complex mental disorder to a specific interaction of genes and the environment: In effect, they said, traumatic experiences are like falling off a bicycle, but genes determine whether the person is wearing a helmet.

"What they have done is going to change the paradigm for how we think about genes and psychiatric disorders," said Thomas R. Insel, the federal government's top researcher of mental illness and the director of the National Institute of Mental Health (NIMH).

Many previous attempts to pin down genes that cause depression and other mental illnesses have proven fruitless, said the researchers who did the new study, because they were based on the wrong assumption that there were "direct paths" from genes to mental illnesses.

The new work points to an entirely different mechanism, at least in the case of depression: Genetic variations affect how people respond to stress -- making some vulnerable and others resilient.

"Nature works via nurture," said Terrie Moffitt, a psychologist at King's College in London and the University of Wisconsin who conducted the study with a team of researchers.

Moffitt's study helps explain why only a minority of people who go through emotional crises develop depression -- a disorder defined by long periods of sadness; impaired work performance and personal relationships; feelings of hopelessness and lassitude; and even suicidal behavior.

It also helps explain why most who go through such crises emerge unscathed. About a third of Moffitt's sample had the protective version of the gene, while about one in six had the high-risk version. The rest -- about half the sample -- had both versions, apparently putting them in a middle category of risk.

The new study tracked 847 people for five years as they lived through emotional crises such as a death in the family, loss of a job or the breakup of a relationship, and found that the crises resulted in depression in 43 percent of people who had a short form of the serotonin transporter gene.

Among those with the long form of the gene, only 17 percent developed depression after experiencing similar traumas, Moffitt found.

"The environmental factors were far and away the more significant factors," said Daniel R. Weinberger, who heads the division at the NIMH that studies mental illnesses using brain imaging, molecular and genetic techniques.

"The gene was only significant in its interaction with the environment," he said. "It's like cancer and smoking. Genes have something to do with who gets lung cancer, but if you want to have a public health impact in cancer, you would have a much greater impact by targeting smoking than targeting genes."

Other genes may yet be identified that could explain why 57 percent of people with the riskier version of the gene did not succumb to depression, while 17 percent of the people with the safer form of the gene did fall sick, Weinberger said. Other research has also shown that cultural and social factors may confer protections against mental illness.

Moffitt's study, being published today in the journal Science, involved Caucasian patients, specifically a group of New Zealanders of mainly English, Scottish and Irish descent. There has been limited study of such genetic variations in other ethnic groups, Moffitt said, although preliminary studies indicated that groups in West Africa, as well as African Americans, were more likely to have the protective form of the gene. Small studies in Japan, Korea and China found a higher frequency of the gene that increases vulnerability, she said. Neither Moffitt nor Weinberger knew of any studies examining the question in Hispanics or Native Americans.

Moffitt and her colleagues focused on the serotonin transporter gene because antidepressant drugs such as Prozac -- called selective serotonin reuptake inhibitors (SSRI) -- are known to boost levels of the neurotransmitter serotonin in the spaces between nerve cells, called synapses.

But to the surprise of many, the results from the gene study proved to be "counter-intuitive," said Insel at NIMH.

Said Moffitt: "The short version [of the gene] is associated with more serotonin in the synapse and more risk of depression. The SSRI drugs increase serotonin in the synapse but are used to treat depression. So the short-term effect of the drug seems opposite to what the gene does."

That finding will spur new research into the drugs' mechanism of action, Insel, Moffitt and Weinberger said, because it suggests that the initial increase in serotonin is probably not the reason why the medicines have an antidepressant effect.

Steven Hollon, a psychologist at Vanderbilt University, said Moffitt's study also opened the possibility of identifying people with the vulnerable form of the gene and using prevention techniques.

"So much of what we do is focusing on treating people, but the horse is already out of the barn," he said. Prevention, he said, might draw on psychotherapy techniques to help people come up with multiple approaches to life problems and to reevaluate their assumptions.

"Having a relationship break up doesn't mean it's the end of the world," Hollon said. "It doesn't mean no one is ever going to love you."

§ § §