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Gene Variant Protects Against Depression
By Nancy Touchette

People react to stress in different ways. While one person might shrug off the loss of a job as a chance to seize new opportunities, another might become depressed. Researchers have a new clue to why people react so differently to life’s distressing events.

Beata Beatrix (1864) was inspired by the artist's wife, who committed suicide after the death of their child. Dante Gabriel Rossetti (1828 - 1882). Oil on canvas.

An international research team has found that a common variation of a gene may protect people from becoming depressed in response to stress, while another form of the gene increases the risk of depression.

The different responses are only evident, however, when people with the gene variation experience stressful events, such as the death of a loved one, financial problems, or the breakup of a relationship.

“This is a great study because it provides us with a new paradigm,” says Thomas Insel, director of the National Institute of Mental Health in Bethesda, Maryland. “It’s not enough to look for vulnerability genes. We also have to pay attention to how the environment affects those genes.”

The gene codes for a protein that clears serotonin, a brain chemical, from the spaces between nerve cells in the brain. Serotonin helps regulate mood, appetite, and sleep patterns. Low levels of serotonin have been linked to depression, anxiety, aggression, and violent behavior.

Many antidepressant drugs, including Prozac, work by blocking the protein, known as the serotonin transporter protein. Two forms of the gene for this protein, one long and one short, exist in roughly equal proportions in the general population.

Few diseases are caused by simple mutations to single genes. Instead, many problems appear to arise when people with common gene variations are exposed to different environments.

“Genetics research has been successful when focusing on rare genetic defects in rare diseases,” says Terrie E. Moffitt of the Institute of Psychiatry at King’s College in London, who led the new study. “But when researchers turned their attention to common diseases in the population such as heart disease, diabetes, and depression, the road got a lot rockier.”

The new study, published in Science, is unique because it takes into account environmental influences to identify a link between a common gene variant and a common emotional disorder: depression. Not everyone with the gene variation gets depressed, and not everyone who experiences traumatic events becomes depressed.

Results from previous studies examining the link between DNA variants and depression have been inconsistent. But most of these studies did not take the effect of the environment into account.

Moffitt and her team studied nearly 850 volunteers with no history of depression who had been followed from birth to adulthood as part of the Dunedin Health and Development Study in New Zealand. All participants were Caucasians of Scottish-Irish and English descent.

About half the volunteers had both a long and a short form of the serotonin transporter gene, while 17 percent had two copies of the short form and 31 percent had two copies of the long form. Both forms of the gene produce the same protein, but the long form results in twice as much protein as the short form.

The researchers found that the long form of the serotonin transporter gene appears to protect against stress, while the short form makes people vulnerable. Of the people who had experienced at least four stressful life events between ages 21 and 26, only 17 percent of those with two copies of the long, or protective, form of the gene developed depression, compared with 33 percent of those with one or two copies of the short, or vulnerable, form and 43 percent of those with two copies of the short form.

The researchers saw no difference in depression rates for those volunteers who did not experience a stressful life event, even if they carried only the short form of the gene. People who were maltreated as children, though, had higher rates of depression if they carried two short forms of the serotonin transporter gene.

“None of these effects would have been seen if the environment hadn’t been figured in,” says Ian W. Craig of King’s College, who participated in the study. “Only when you look at groups of people who have had particularly bad times do you see a difference in rates of depression depending on their particular gene variant.”

The results are consistent with studies in animals. For example, Stephen J. Suomi of the National Institute of Child Health and Human Development in Poolesville, Maryland, finds that rhesus macaques also harbor long and short versions of the serotonin transporter gene.

When the monkeys are raised by their mothers, Suomi observes no differences in behavior. But when they are raised in a nursery with their peers, monkeys with two copies of the short form of the gene tend to be more anxious and easily distressed, compared with those with two long forms of the gene.

“Simply having a short version of the gene doesn’t increase the risk for depression,” says Suomi. “It only occurs when there are poor early experiences.”

Suomi and Moffitt both find that depression occurs when bad genes mix with a bad environment, but they view the findings from different perspectives.

“Moffitt talks about good genes protecting against a bad environment,” says Suomi. “But we like to think in terms of a good environment protecting against the possible consequences of a bad gene. The bottom line is that we are not looking at any pure genetic or pure environmental effects. It’s the combination.”

The new—and seemingly paradoxical—findings underscore how little researchers understand about the role of serotonin in the brain and how deficits in the serotonin system can affect behavior. Many studies indicate that low levels of serotonin in certain parts of the brain may lead to depression.

Good mothering decreases the risk of depression in both monkeys and humans.

How can it be, then, that if someone has a gene that leads to lower amounts of the protein that removes serotonin from synapses, that person has a higher risk of depression?

“It’s counterintuitive,” says Craig. “We are now learning that whatever is going on at the synapse is much more complicated than we ever predicted. There are many questions that absolutely need to be studied.”

Ultimately, understanding how the serotonin transporter protein functions and how variations in a person’s genes affect their behavior may help doctors better predict who will benefit from certain medications.

Several types of antidepressants are commonly prescribed nowadays. Some drugs block the serotonin transporter protein, while others affect the production of serotonin and other brain chemicals. Doctors usually prescribe a drug and then wait and see if it improves the symptoms. If, after a month or so, it has not, the doctor cancels that treatment and prescribes another drug.

“The hope is that these kinds of studies will help us understand an individual’s variability and lead to better ways to predict drug response,” says Craig. “That is much more sensible than just throwing drugs at people and seeing what happens.”

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A. Caspi et al. Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT gene. Science 301, 386-389 (July 18, 2003).

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