The serotonin transporter promoter polymorphism 5-HTTLPR region of gene SLC6A4, one of the over 1,000 genes located on human chromosome 17, has been positively identified as the moderator of the relationship between stress and depression. A new, extensive analysis of 54 studies of more than 40,000 individuals was recently completed at the University of Wurzburg, Germany, finding “strong evidence that 5-HTTLPR moderates the relationship between stress and depression, with the s [short] allele associated with an increased risk of developing depression under stress.”
The meta-analysis of the 54 studies looked at 40,749 individuals stratified into subgroups according to specific types of stressors. They found a statistically significant relationship between the presence of the short allele of 5-HTTLPR in the individual’s gene and increased stress sensitivity in two of the subgroups: the subgroup of individuals who had suffered childhood maltreatment and the subgroup of individuals who developed a specific stress-related medical condition.
Despite some analytical limitations due to the variety of sources and methods within the 54 original studies, the authors of the meta-analysis conclude that, “the present study suggests that there is cumulative and replicable evidence that 5-HTTLPR moderates the relationship between stress and depression. Our evidence, particularly the identification of important study characteristics that influence study outcome (stressor type and stress assessment method), can provide guidance for the design of future gene x environment interaction studies.”
This new study, already published online and scheduled to appear in the January 2011 edition of the Archives of General Psychiatry, disconfirms the findings of 2 earlier and much less extensive studies, which had found no evidence of the interaction. The authors of the new study speculate that the earlier negative findings may have been due to the small number of cases analyzed, the authors’ inability to obtain primary data for many of the studies, and the inclusion only of studies that looked at stressful life events (SLEs), and not other stressors such as childhood maltreatment.
More On 5-HTTLPR and Serotonin
Since its discovery in the 1990s, polymorphic region 5-HTTLPR located on SLC6A4, the gene that codes for the serotonin transporter, has received intense investigation for its possible role in stress and other mental health issues, especially mood disorders. A 2000 study uncovered evidence that 5-HTTLPR may be involved in the appearance of certain anxiety-related personality traits, and a 2003 study presented evidence that 5-HTTLPR may also be involved in the development of childhood anxiety and shyness.
Serotonin is a small-molecule indoleamine neurotransmitter that plays an important role in mood, depression and anxiety, and is also implicated in the sleep/wake cycle. Serotonin, after being released in the raphe nuclei of the brain stem and other parts of the body and having its effect on mood, is routinely removed from the synaptic cleft by the reuptake of the transmitter with the serotonin transporter. It is the blocking of this reuptake that results in the therapeutic effect of SSRI (selective serotonin reuptake inhibitor) antidepressant medications, such as Lexapro, Paxil, Zoloft, and Prozac.