July 2003

From University of Wisconsin-Madison
Study suggests interplay of gene, stress can predict depression
MADISON - When a loved one dies, families usually gather together to grieve. While some members cope with the loss, others sink into depression. Who will experience the telling signs of this mental illness depends in part on genetic make-up, according to new research published in the July 18 issue of the journal Science.

An international team of researchers from the University of Wisconsin-Madison, King's College London and the University of Otago in New Zealand found that variations in a gene that regulates chemical messengers in the brain could predict who was likely to develop depression after stressful life events. This finding could lead to new treatments and diagnostic techniques for a mental illness that affects millions of people each year.

The World Health Organization estimates that 121 million people worldwide currently suffer from depression, which causes them to experience periods of constant sadness, disinterest in activities once enjoyed, decreases in energy, difficulty thinking, feelings of worthlessness, recurrent thoughts of death, and changes in eating and sleeping patterns.

"The World Health Organization ranks depression as the world's fourth leading cause of disease burden - years that humans live with disability," says Terrie Moffitt, one of the paper's co-authors and a professor of psychology at UW-Madison. "If current trends continue, by the year 2020 depression will be the first cause of disease burden worldwide and, in the developed world, will be second only to heart disease."

To begin to understand this pervasive mental illness, researchers led by Moffitt and Avshalom Caspi investigated the interaction between genes and stressful events to determine if such an interaction could predict the future onset of depression. They zeroed in on the serotonin transporter gene (5-HTT). This gene regulates levels of serotonin, a neurotransmitter that sends signals between nerve cells in the brain. Variations in the 5-HTT gene, says Moffitt, have been shown to influence an animal's response to stress.

The researchers found that individuals who have a particular variation in the serotonin transporter gene were more likely to develop depression after exposure to stress.

Every human being carries two copies of the 5-HTT gene, either a short or long variant (also called an allele). This allows for three possible combinations: people can carry two copies of the short variant, two copies of the long variant or one copy of each. While both alleles are common among humans, Moffitt says nearly two-thirds of the population carries at least one copy of the short allele.

The new findings suggest that individuals carrying at least one copy of the short allele of the 5-HTT gene are more vulnerable to depression after they experience a stressful event, whereas those individuals with two copies of the long allele are more protected from it, explains Moffitt.

In the study, the researchers looked at 847 adults living in New Zealand. These individuals have been part of the longitudinal Dunedin Multidisciplinary Health and Development Study since their births between 1972 and 1973. The researchers determined the subjects' 5-HTT genotype, evaluated any signs of depression within the previous year and recorded their stressful life events over a five-year period. Life events included unemployment, financial problems, homelessness, physical illness, abuse and intimate relationship breakups.

According to the published paper, 30 percent of the subjects experienced no stressful life event, 25 percent experienced one, 20 percent experienced two, 11 percent experienced three and 15 percent experienced four or more. There was no significant difference in the number of stressful life events between the three genotypes, says Moffitt. Seventeen percent of the subjects met criteria for a recent depressive episode, and three percent had reported past-year attempts of or thoughts about suicide due to depression.

The researchers found that the interaction between the gene and past experience affected a person's likelihood of developing depression. For instance, 33 percent of the study's subjects who experienced four or more stressful life events and had at least one copy of short variant developed depression, compared to 17 percent of those carrying two copies of the long variant. Even though these individuals with the short allele and at least four stressful experiences constituted only 10 percent of the study group, Moffitt says they accounted for almost one-quarter of the 133 cases of diagnosed depression. The researchers also reported that individuals with the short allele who had experienced multiple stressful events were more likely than those with two copies of the long allele to contemplate or attempt suicide (11 versus 4 percent).

Looking back into the study subjects' childhood, the researchers found that the interaction between the short allele 5-HTT genotype and stressful life events, namely maltreatment before age 10, predicted adult depression. "Because the gene is present from conception, it would have been very suspicious if it did not affect responses to stress in childhood," says Moffitt. "The fact that it interacts with childhood maltreatment helps to demonstrate that the finding is strong."

Based on the results, the short variant of the 5-HTT gene can signal risk for depression. "The stress-sensitive genotype predicted who will get depression about as well as a bone mineral density test can predict who will get a fractured hip," says Moffitt. But she cautions that before new therapies or diagnostic tests for depression can be developed, the results of the study must be replicated.

"If replication studies confirm that genotypes can predict in advance who is vulnerable to life stresses that bring on depression," she says, "this new knowledge could advance efforts to develop a diagnostic test of vulnerability to depression."

According to the published paper, 30 percent of the subjects experienced no stressful life event, 25 percent experienced one, 20 percent experienced two, 11 percent experienced three and 15 percent experienced four or more.