Stressful life events are strongly associated with a person’s risk for major depression, but a certain gene variation long thought to increase risk in conjunction with stressful life events actually may have no effect.
The study published in the Journal of the American Medical Association, challenges a widely accepted approach to studying risk factors for depression.
Most mental disorders are thought to be caused by a combination of many genetic risk factors interacting with environmental triggers. However, finding the exact combinations continues to present significant challenges to research.
Advances in scientific understanding and technologies during the past decade have led to powerful tools for studying how genetic and environmental factors can affect a person’s risk for disease. Such advances allowed mental health researchers in 2003 to show that a gene involved in serotonin activity increased the risk of major depression in people who had a number of stressful life events over a five-year period.
Coming at a time of heightened research interest in these gene-environment interactions and the relative lack of progress in the field for mental disorders, this study received wide acclaim and had a far-reaching influence. Not only have considerable resources been invested in subsequent studies that built on this finding, but also some researchers have proposed marketing the gene test to the public, claiming to be able to predict a person’s risk for depression.
However, efforts to replicate the 2003 study’s findings-a key step in scientific progress that helps show whether a particular finding was a chance event-have had inconsistent results.
To examine whether the 2003 study’s finding had been confirmed, a workgroup of scientists from NIMH and six universities with expertise in epidemiology, biostatistics, genetics, and psychiatry reviewed the status of relevant replication studies.
The workgroup analyzed these original data to see whether there were gender differences in the associations between the serotonin genotype, stressful life events, and depression.
By applying the same definitions of study variables and data analysis methods used in the 2003 study, the workgroup found a strong association between the number of stressful life events and risk of depression across the studies. However, the presumed high-risk version of the serotonin transporter gene did not show a relationship to increased risk for major depression, alone or in interaction with stressful life events, in the analysis of the 14 studies. Their findings were the same in men and women alone in the analysis of original data from 10 studies.
This analysis confirms some earlier reviews that had also questioned the validity of the gene’s effect on depression risk. However, the workgroup emphasized that the intent of its analysis was not to deter research on gene-environment interactions for mental disorders.
The authors concluded that incorporating environmental exposures in candidate gene studies (those that study a particular gene) may be as likely to yield false positive findings as the candidate gene studies themselves. Therefore, the results of other studies using the same approach as the 2003 study also deserve thorough review and meta-analysis.
“Even though our re-analysis did not confirm an association between the serotonin gene and depression, the finding that the environmental factor was strongly associated with depression in several studies reminds us that environmental factors are also involved in the complex pathways leading to mental disorders,” noted Merikangas of NIMH Intramural Research Program.
Source: National Institute of Mental Health, USA