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One Gene Overrides Another to Prevent Brain Changes that Foster Depression

Science Update

For what appears to be the first time in humans, scientists have detected an interaction between genes that may help prevent brain changes that increase vulnerability to depression.

A variation on one gene affects how much of the brain chemical serotonin is available to brain cells.  This variation is thought to raise the risk of depression in people who carry it. But NIMH scientists found that a variation in another gene, which produces brain-derived neurotrophic factor (BDNF) – a substance that enables growth and health of brain cells – appears to prevent or offset the changes generated by the depression-fostering variant.

For now, the finding can help scientists track the biological roots of depression in the brain as they search for better treatments.  In the future, it could help clinicians identify patients who are at risk and need monitoring or treatment.

Results of the study were published online on March 12, in Molecular Psychiatry, by Lukas Pezawas, Daniel R. Weinberger, and colleagues from the National Institute of Mental Health, the Universities of Pittsburgh and Vienna, and Germany’s Central Institute of Mental Health.

Using brain imaging in a study of 111 healthy people, the researchers found that those with the depression-promoting gene variation had alterations in brain-cell networks known to regulate mood.  But those who had both the depression-promoting variation and the apparently protective variation did not have these alterations in brain-cell networks.

Not everyone who has the serotonin-related variation develops depression, a disorder thought to be caused by interactions between variations in many genes and life experiences, such as stressful events.  One variation in a single gene does not appear to cause the disorder.

In this study, the scientists examined healthy people, rather than depressed people, because the illness might have introduced factors that would have confused the results. The study was not meant to show whether people became depressed, but rather to show whether the gene variations resulted in brain changes that set the stage for depression, or protection from it, in the mood-regulating brain-cell networks.  

Further research may tell if the different variations actually translate into differences in rates of depression among their carriers.

More About the Science

Both of the variations are in genes shown by earlier studies to regulate brain functions and structures in which alterations appear to contribute to depression. 

The depression-promoting variation is in the serotonin system, which helps brain cells communicate through chemical signals.  The gene is called SLC6A4 and makes a protein that transports serotonin among brain cells.  The variation that has been associated with increased risk of depression is called the 5-HTTLPR “S” version.

The gene containing the variation that apparently overrides the negative effects of the first gene variation is called BDNF.  It makes a protein that promotes growth and maintenance of brain cells. The variation in this gene, VAL66MET, has two versions.  The one that appeared to be protective in this study is called the MET version.

Animal studies suggest that changes in serotonin signaling during brain development can lead to lifelong changes in mood.  But serotonin doesn’t act alone in brain cells; a normal function of the BDNF protein is to act as an intermediary.  When serotonin signaling occurs, BDNF mediates changes in molecular machinery that enables brain cells to send and receive chemical messages.

One possibility is that abnormalities occur in this interplay of the chemical serotonin and the BDNF protein during brain development, potentially causing mood-regulating brain circuits to go awry.  With the new finding, researchers have evidence that two genes encoding components of these systems interact in ways that affect vulnerability to depression – potentially increasing or decreasing the risk, depending on which versions of the genes are present.

As scientists map the interactions between the many gene variants and life experiences that influence the risk of depression, they identify new opportunities for prevention and treatment.


Pezawas L, Meyer-Lindenberg A, Goldman AL, Verchinski BA, Chen G, Kolachana BS, Egan MF, Mattay VS, Hariri AR, Weinberger DR. Evidence of biologic epistasis between BDNF and SLC6A4 and implications for depression . Mol Psychiatry. 2008 Jul;13(7):709-16. Epub 2008 Mar 18. PubMed PMID: 18347599.