These findings may account for the difficulty many researchers have faced in attempting to replicate the 2003 study. 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.

"Identifying gene-environment interactions is most successful when studies can focus on a single gene with a major effect, or when the environmental exposure has a strong effect," said lead author Neil Risch, Ph.D., University of California, San Francisco and Kaiser Permanente Northern California. "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."

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. "Future progress will require thoughtful integration of the tools of genetics, epidemiology, and clinical and behavioral sciences."

The authors on the paper include Neil Risch, Ph.D., University of California at San Francisco and Kaiser Permanente Northern California; Richard Herrell, Ph.D., NIMH; Thomas Lehner, Ph.D., NIMH; Kung-Yee Liang, Ph.D., Johns Hopkins University; Lindon Eaves, Ph.D., Virginia Commonwealth University; Josephine Hoh, Ph.D., Yale University; Andrea Griem, NIMH; Maria Kovacs, Ph.D., University of Pittsburgh; Jurg Ott, Ph.D., Rockefeller University; Kathleen Ries Merikangas, Ph.D., NIMH.

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