Depression link made to gene set off by high stress

WASHINGTON -- In the first study to show a direct genetic link between emotional stress and depression, researchers found that people with a certain type of brain chemistry gene were more vulnerable to deep depression after traumatic events such as the death of a family member.

The study, appearing this week in the journal Science, focused on two forms of a gene called 5-HTT which helps regulate serotonin, a brain chemical. Researchers found that adults who carried a short form of this gene were more prone to slip into depression after experiencing serious life events than were adults who carried a long form of 5-HTT.

Experts said the study is the first to show a proven direct genetic link between emotionally distressing events and the onset of clinical depression.

"It is a very important discovery and a real advance for the field," said Dr. Thomas R. Insel, director of the National Institute of Mental Health. "The effects of stress on depression only get played out in certain individuals and those are individuals ... with a particular variation of this single gene."

Insel said the finding has no immediate clinical application, but it gives a fundamental new understanding of the linkage between genes and depression.

The World Health Organization has identified depression as the fourth leading cause of disease burden, which is defined as years patients must live with a disability. It's estimated that about 121 million people worldwide suffer from depression. The disorder is now being diagnosed more frequently and the WHO estimates that depression will become the first cause of disease burden worldwide by the year 2020.

Clinical depression can cause a constant, persistent sadness and lethargy, a sense of personal worthlessness, a loss of interest in normal activities, changes in diet and sleep, and frequent thoughts of death. Untreated, depression can lead to suicide. The condition also has been linked to a higher incidence of heart disease and death, particularly in men.

Although drugs successfully treat depression in millions of people, the precise causes and controls for the disorder remain elusive. Often patients must go through a trial-and-error period before the best treatment is identified.

In the Science study, researchers from the University of Wisconsin, Madison; King's College in London, and the University of Otago in New Zealand analyzed the type of 5-HTT gene carried by 847 adults in New Zealand who were part of a long-term health study.

There are two forms of the 5-HTT gene, the long and the short. An individual can inherit two copies of the long form, two of the short, or one of each.

The researchers focused on subjects in the study who had had traumatic life events over a five-year period. These events could include such things as a death in the family, a marriage breakup or the loss of a job.

Patients with at least one copy of the short form of 5-HTT were more at risk of depression, the study found, suggesting that this form of the gene caused a heightened sensitivity to emotional stress. Patients with only the long 5-HTT gene were more resistant to depression following serious emotional events and tolerated stress better.

Depression was diagnosed in about 33 percent of the study subjects who had at least one short 5-HTT gene copy and who had experienced four traumatic events over a five-year period. Among those with two copies of the long form of 5-HTT, only 17 percent were diagnosed with depression after four traumatic events.

Researchers said tests showed that those with even one copy of the short 5-HTT gene were almost three times more likely to think or attempt suicide than those with only the long 5-HTT.

Insel said the difference in the forms of the 5-HTT gene is not in the proteins they produce, but in the regulation of serotonin, a neurotransmitter that carries signals between nerve cells. The short version of 5-HTT is not as effective in controlling the serotonin flow as is the long version, he said.

Lead authors of the study are Dr. Avshalom Caspi of King's College London, and Dr. Terrie Moffitt of the University of Wisconsin.