Interactive Effects of Genetics on Depression

It is well known that depression results from the combination of many different factors. Environmental effects, such as stressful life events, are a trigger in many patients for the development of major depressive disorder (MDD) and the milder disorder, dysthymia. It is also true that the same major stressors will not produce depressive symptoms in some, pointing to underlying risk factors that make some more susceptible to depression than others. Researchers have attempted to identify a single gene that can be linked to MDD, and while familial clustering of depressive disorders is a common finding, single-gene inheritance patterns are not seen. Instead, patterns suggested that several genes are involved in depression, and a recent research study demonstrated the interactive effects of these genes on the disease.

SLC6A4 is one allele for the serotonin transporter protein, and individuals who inherit this gene are at a 4-times greater risk of developing depression following major life stressors. It clearly plays a role in depression susceptibility, but inheritance mapping does not demonstrate a clear, one-to-one ratio of this gene and the presence of depression. Other factors are clearly required. A second gene, BDNF, is also linked to mood disorders. Several different alleles for this protein exist, and patients who inherit a specific combination of the BDNF allele in combination with the SLC6A4 allele are at a significantly increased risk of depression.

The interaction of these two genes helps to explain why scientists have failed to find a clear genetic link in major depression. Instead of depending upon a single mutated gene, depression results from a multifactorial combination of several genes and environmental factors. Thus, depression cannot be predicted by single gene mutations, but increased susceptibility to MDD may one day be detectable by molecular testing for a combination of genes.

The effects of the SLC6A4 allele are thought to occur during brain development, affecting the way negative environmental events are interpreted. This sets the stage for an exaggerated negative response to life stressors. The protein produced by the BDNF gene may affect the way the serotonin receptor interacts with the cell, extracellular proteins or both.

Further elucidation of genes that play a role in mood disorders stand to have an important impact on mental health treatment. By detecting specific alleles associated with depression, molecular therapeutics can be developed that directly target the affected protein with minimal side effects. Genetic testing of at-risk individuals may allow for early detection and prevention of major depression. The ability to clearly identify and treat patients at a high risk for major depression will allow physicians to intervene before the disease reaches it’s full-blown form, instead diagnosing patients at an early stage and providing pharmacological and psychological treatment to prevent progression.

Reference

Pezawas, L., Meyer-Lindenberg, A., Goldman, A.L., Verchinski, B.A., Chen, G., Kolachana, B.S., Egan, M.F., Mattay, V.S., Hariri, A.R., Weinberger, D.R. (2008). Evidence of biologic epistasis between BDNF and SLC6A4 and implications for depression. Molecular Psychiatry DOI: 10.1038/mp.2008.32