Serotonin Gene, Even When Combined With Life Events, Has No Effect on Depression

Barbara Boughton

June 17, 2009

June 17, 2009 ( Updated June 25 with commentary ) — A gene variation that has long been thought to increase the risk for depression in combination with stressful life events may have no effect after all, according to a new meta-analysis published in the June 17 issue of the Journal of the American Medical Association (JAMA).

The serotonin-transporter gene has been the focus of genetics research on depression for years, because it results in decreased transport of serotonin into cells. While a 2003 study by Caspi et al, hailed as a breakthrough at the time, showed that a genetic variation in the promoter region of the gene increased risk for depression among those who had stressful life events over a 5-year period (Caspi A et al. Science. 2003;301:386-389), the new meta-analysis failed to find any association.

"The findings remind us that if we strictly look for genes involved in mental illness, without appreciating how complex the pathways are to these disorders, we may not have something at the end of the road that we can translate into prevention or treatment for illnesses such as depression," said Kathleen Ries Merikangas, PhD, senior investigator and chief of the genetic epidemiology research branch at the National Institute of Mental Health (NIMH).

Dr. Merikangas noted that this meta-analysis was performed by world-renowned experts in statistics, epidemiology, and genetics and rigorously examined data from 14 studies published from 2003 to 2009, but the research team was unable to replicate the findings of the previous study.

Authors of that previous study, however, have some push-back on these findings that would contradict their conclusions. Lead author Avshalom Caspi, PhD, who currently has appointments at Duke University, in Durham, North Carolina, and King's College London, in the United Kingdom, said that the new meta-analysis ignores the complete body of evidence linking these entities, including animal and clinical research, and the studies included were widely various in their quality.

"What is needed is not less research into gene-environment interaction, as Risch et al recommend, but more research of better quality and a more thorough and thoughtful evaluation of it," Dr. Caspi told Medscape Psychiatry.

Replication "Crucial"

The meta-analysis was the result of a workshop held by the NIMH after it began receiving thousands of applications to try to replicate the Caspi study and apply its approach to a range of other disorders, Dr. Merikangas said. While many studies had failed to find a link between the serotonin-transporter gene variation and depression, the Caspi study was the first to find it had an effect when stressful life events were also considered.

Yet since 2003, the scientific literature had failed to clearly validate these findings. While some studies supported the gene-environment interaction and its relationship to depression, others could not replicate the results. Since considerable resources were being devoted to studies on the serotonin-transporter gene, and some researchers had proposed marketing a test for it to the public, the question of whether the Caspi findings could be verified was crucial, Dr. Merikangas said.

In the meta-analysis, the researchers analyzed data on 14,250 participants in 14 studies. From among these, the researchers also reanalyzed original data on 10,943 participants in 10 studies.

The researchers did find an association between stressful life events and depression (odds ratio, 1.41; 95% CI, 1.25–1.57). However, they found no association between the serotonin-transporter gene variation (5-HTTLPR) and the mental disorder (OR, 1.05; 95% CI, 0.98–1.13) or any increased risk for depression when the genetic polymorphism and stressful life events were combined (OR, 1.01; 95% CI, 0.94–1.10).

Further, no link between the serotonin-transporter gene variation, stressful life events, and depression was found when data were analyzed for women, men, or both sexes combined.

"The strength of the meta-analysis is that it was very inclusive — we considered studies whether they claimed they had replicated the original findings of the Caspi study or not. We also went back and got the original data and reanalyzed them in exactly the same fashion as the Caspi study was done," said Neil Risch, PhD, lead author and director of the Institute for Human Genetics at the University of California, San Francisco. The meta-analysis applied the same definitions of study variables and used the same data-analysis methods used in the Caspi study, he added.

The research team did note that the meta-analysis had some limitations. Recoding of the data according to the methods used in the Caspi study may have led to findings different from those originally reported, they write. They were also able to obtain original data on only 10 of the studies. However, they note that data from the remaining studies would not have changed the report's conclusions, since the participants made up only 10% of the population studied.

While the study does seem to disprove theories about the serotonin-transporter gene, stressful life events, and depression, it confirms the importance of verifying genetic findings about mental disorders, Dr. Risch said. "It is critical that health practitioners and scientists in other disciplines recognize the importance of replicating such [genetic] findings before they can serve as valid indicators of disease risk or have utility for translation into clinical and public-health practice," the researchers write.

Dr. Risch also noted that studying candidate genes that may enhance risk for medical disorders, including psychiatric disorders, may not be as promising an approach as whole genomewide analysis, in which many genes with modest effects on an illness may be unearthed. "The technology for this analysis has really come down in price and is so much more efficient now. Most studies in the future will concentrate on this approach," he said.

Funding "Miniscule" for Gene-Environment Studies

Dr. Caspi took issue with this latter point. "In fact, the funding devoted to gene-environment studies has been miniscule in comparison with the funding devoted to genomewide association studies. It has not escaped our notice that the loudest objections to gene-environment research generally come from research teams that have collected only DNA but neglected to collect any data on environmental causes of disease," he told Medscape Psychiatry.

With regard to the specific findings reported by Risch et al, Dr. Caspi made several points in response to their report.

First, he said, the JAMA article "ignores the complete body of scientific evidence. In the past 6 years, extensive research in experimental neuroscience using both animals and humans has validated the original report by showing that 5-HTTLPR short-allele carriers are excessively vulnerable to stress," he said. "Environmental studies that expose human participants to stressors in the laboratory show that individuals having the 5-HTTLPR short genotype have greater stress responses on measures of cognitive reactivity, hormonal reactivity, physiological reactivity, and reactivity in the brain's emotional circuitry," he added, "findings that have also been confirmed in animal research."

Further validation comes from studies that have shown carriers of this allele are vulnerable not only to depression but to other mental-health problems, including posttraumatic stress disorder and anxiety.

Second, "this article misrepresents the body of observational studies," Dr. Caspi said. "The article not only opted not to analyze but also failed to mention the existence of well-designed studies that compared individuals exposed to stress" with and without the high-risk allele. For example, studies of children who are victims of abuse and patients suffering from hip fractures, strokes, and coronary heart disease have shown that people exposed to these stressors who also carry the short allele of the 5-HTTLR gene are more vulnerable to mental health problems, he noted. "Several other positive replications from studies with very strong research designs were omitted from the meta-analysis as well," he added.

Within the subset of studies that were included in the current meta-analysis, there is wide variation in the findings, with some reporting replication of their results and others that did not, Dr. Caspi continued. "Whenever an inconsistent pattern of results like this is observed across studies, the next step in science is to try to understand why some studies report a positive finding and others do not," he said. In the article, an attempt was made to test whether this variation across studies was significant enough to warrant investigation, he noted, and the authors concluded it was not statistically significant.

"However, we have learned that the test fell just short of statistical significance," Dr. Caspi asserts. "This means that it is essential for the researchers to now look for commonalities among the studies that do vs do not replicate the original finding."

Finally, Dr. Caspi pointed to what he feels is a wide variation in the quality of the studies that were included. A meta-analysis gives more mathematical weight to studies with the largest samples, he said, "but in this case, the studies with the largest number of participants were not the best-quality studies. The big studies had to collect their data through telephone calls or self-complete postal questionnaires, which are known to be weak methods of measuring life events and assessing mental-health problems such as depression."

Of the more than 14,000 individuals were included in the studies, more than 8000 reported their stress and depression over the phone or through the mail, he concluded. "Not surprisingly, these big studies with weak measures did not find positive results, and this tilted the meta-analysis toward a null finding."

Doors Left Open

Whatever methods are used to study the interactions among genes, environment, and depression, the debate about the serotonin-transporter gene may still continue. While the new meta-analysis and its conclusions are significant, it probably will not settle questions about the effects of the serotonin-transporter gene variation and its interactions with life events in increasing risk for depression, according to Steven Hamilton, MD, PhD, a researcher in the genetics of psychiatric disorders and associate professor of psychiatry at the University of California, San Francisco.

"It's not the definitive answer, and there were some doors left open," he said. For instance, while the largest studies considered in the meta-analysis did not support the original Caspi findings, the smaller studies did verify its conclusions. "Some might argue that there's something different about these small studies that can't be picked up in a meta-analysis. Some studies were also performed more rigorously than others, and that wasn't taken into account," he said.

"There's still much that people can argue about on this issue," Dr. Hamilton noted. However, he added that the study does show that it is crucial for genetic studies, particularly those that study the interaction between genes and environmental factors, to be as consistent with one another and as rigorous as possible. "Gene-environment interaction studies require a heightened level of consensus in the field," he said.

The study was supported in part by the National Institutes of Health, National Institute of Mental Health, Intramural Research Program, Division of Developmental Translational Research, and Division of Neuroscience and Basic Behavioral Science. Drs. Merikangas, Risch, and Hamilton report no relevant financial disclosures.

JAMA. 2009;301:2462-2471.

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