Touted “Depression Risk Gene” May Not Add to Risk After All

A gene variation long thought to increase a person's risk for major depression when paired with stressful life events may actually have no effect, according to a new analysis. The result challenges a common approach to studying depression risk factors.

Most mental disorders are thought to be caused by a combination of many genetic risk factors interacting with environmental triggers. Finding the exact combinations of factors, however, has been a significant challenge. Advances during the past decade have led to powerful tools for studying how genes and the environment interact to affect the risk for disease. In 2003, these advances allowed scientists to show that variation in a gene called the serotonin transporter gene affected the risk of major depression in people who had a number of stressful life events over a 5-year period.

Serotonin is a chemical messenger that helps brain cells communicate. The serotonin transporter directs serotonin from the space between brain cells back into the cell for reuse. Since the most widely prescribed class of medication for treating major depression acts by blocking this protein, it's been a prime suspect in mood and anxiety disorders.

Considerable resources have been invested in studies that built on the transporter gene discovery. Some researchers even proposed marketing a gene test to the public to predict a person's risk for depression. However, efforts to replicate the 2003 study's findings—a key step to ensure a finding isn't a chance event—yielded inconsistent results.

Scientists from NIH's National Institute of Mental Health (NIMH) and 6 universities set out to review the relevant research that's been done. Led by NIMH's Dr. Kathleen Merikangas, the team had expertise in epidemiology, biostatistics, genetics and psychiatry. In an approach called a meta-analysis, they re-analyzed data on over 14,000 participants in 14 studies published from 2003 through March 2009. The researchers were also able to obtain original data on almost 11,000 participants in 10 of the studies. They used the data to see whether they could find any gender differences.

In the June 17, 2009, issue of the Journal of the American Medical Association, the researchers reported a strong association between the number of stressful life events and the risk of depression. However, variations in the serotonin transporter gene didn't affect the risk for major depression, alone or in interaction with stressful life events. An analysis of original data found the same results, in both men and women.

This analysis supports some earlier reviews that questioned the validity of the gene's effect on depression risk. “In the case of modest gene effects or environmental impacts, the statistical power to detect an interaction will be low, and thus weak positive results should be interpreted carefully,” said first author Dr. Neil Risch of the University of California, San Francisco and Kaiser Permanente Northern California.

“Rigorous re-evaluations of published studies provide the checks and balances necessary for scientific progress,” said Dr. Thomas R. Insel, director of NIMH. “We are still in the early days of understanding how genes and environment interact to increase the risk for depression.”