BioWorld International Correspondent
LONDON - A gene that plays a key role in neurotransmitter metabolism can influence someone's risk of developing depression - but only if that person has been exposed to stressful life events such as unemployment, financial problems or bereavement.
The researchers who carried out the study predict that it could open up a new avenue of research, allowing the identification of many more genes that affect the risk of disease when combined with environmental stresses.
Terrie Moffitt, professor of psychiatry at the Medical Research Council Social, Genetic and Developmental Psychiatry Research Centre at King's College London, and one of the authors of the study, told BioWorld International: "We are not reporting a gene that causes a disease. Instead, we believe the gene helps influence whether people are resistant to the negative psychological effects of the unavoidable stresses of life."
Once people get the idea that studying environmental risks is a powerful research tool, she added, there ought to be more success in finding relationships between genes and all kinds of diseases that have so far not been detected. "We recommend that researchers should measure nongenetic environmental causes of diseases in genetic studies. These could be infections or toxins, as well as other types of stress," Moffitt said.
An account of the study appears in the July 18, 2003, Science in a paper titled "Influence of Life Stress on Depression: Moderation by a Polymorphism in the 5-HTT Gene."
Moffitt, working with Avshalom Caspi and others at the same research center, and collaborators at the University of Wisconsin in Madison and at the University of Otago in Dunedin, New Zealand, wanted to find out why some people who suffer stressful life events are vulnerable to depression whereas others cope well.
Their search for candidate genes for depression began with the brain neurotransmitter serotonin and associated metabolic pathways. They knew, for example, that some drugs that are effective treatments for depression work by selectively inhibiting the reuptake of serotonin at brain synapses.
The serotonin transporter, which is encoded by a gene called 5-HTT, is responsible for preventing the buildup of too much serotonin in the synaptic space. Earlier work by others had shown that a polymorphism in the gene encoding the promoter region of the serotonin transporter influenced the efficiency with which the promoter was transcribed. The short (s) allele of this gene resulted in less efficient transcription of the serotonin transporter, while the long (l) allele transcribed it more efficiently.
Experiments in animals had suggested that polymorphism could alter how they respond to stressful events.
The team therefore set out to evaluate whether people with two ss alleles of the 5-HTT promoter were more likely to suffer from depression than those with two ll alleles.
Their study population was a subgroup of 847 Caucasian non-Maori people belonging to the Dunedin Multidisciplinary Health and Development Study, who had been studied from the age of 3 and were now 26.
Some 147 (17 percent) were ss in their 5-HTT promoter gene, 435 (51 percent) were sl and 265 (31 percent) were ll. The researchers investigated how many had experienced stressful life events between the ages of 21 and 26.
Thirty percent of the group had experienced no stressful life events, 25 percent had experienced one event, 20 percent two events, 11 percent three events and 15 percent four or more events. There was no significant difference between genotype and the number of events people suffered, suggesting that ss, sl or ll genotype did not influence their exposure to stressful life events.
The researchers then determined who had suffered depression during the year up to their 26th birthday. Seventeen percent had suffered a major depressive episode, and 3 percent had either tried to commit suicide or experienced recurrent thoughts about suicide during the previous year.
Analysis showed that anyone carrying an s allele was significantly more likely to report symptoms of depression than those who were ll (p= 0.02). While 43 percent of those who were ss or sl who suffered multiple life events developed depression, only 17 percent who had the protective ll genotype did so, despite suffering multiple life events.
People who had experienced multiple life events who had the ss or sl genotype were also more likely to have thought about or attempted suicide (11 percent) than those who were ll (4 percent).
Moffitt and her co-authors also showed that whether those who had been maltreated as children grew up to become depressed adults also depended on whether they carried the protective version of the gene.
Studies into why the l allele of the 5-HTT gene seems to have a protective effect could lead to new strategies for treating depression, Moffitt said. But she does not believe that the 5-HTT promoter gene could be used to develop a test to predict who will get depression if they suffer stressful life events.
"First, our data need to be replicated by others," she said. "Second, this particular polymorphism is too common in the general population to allow doctors to decide whom to treat. However, if future studies reveal several other genes related to depression, then it may be possible one day to offer a diagnostic test for high risk of depression based on an array of these genes," she concluded.