June 16 (HealthDay News) -- A new analysis upends a previous, highly acclaimed study that had concluded that a particular gene variation was associated with an increased risk of major depression.

The new analysis did, however, verify the portion of the earlier finding that showed more stressful life events translate into a substantially higher risk for depression.

"Mental disorders are the most complex of all diseases," said study senior author Kathleen Ries Merikangas, a senior investigator and branch chief of genetic epidemiology research in the Intramural Research Program at the U.S. National Institute of Mental Health. "We're learning more about how genes can control the different biologic pathways in the brain but, more importantly, how that brain is wired to respond to environmental factors. We're at the very primitive stages of knowledge."

According to the authors of the current paper, published in the June 17 issue of the Journal of the American Medical Association, the new findings call into question how research -- especially research in the mental health field -- is conducted and received.

Scientists have had an unusually tough time linking specific genes with different psychiatric illnesses, such as depression, bipolar disorder and schizophrenia. The likely reason: The genetic and environmental interactions are both more subtle and more complex than in many other diseases, said Keith A. Young, vice chair of research at the Texas A&M Health Science Center College of Medicine Department of Psychiatry and Behavioral Science.

A 2003 study published in the journal Science reported that a mutation on a gene involved in the transport of the neurochemical serotonin increased the risk of depression, but only in people who had suffered numerous stressful events.

Serotonin is a neurotransmitter known to be involved in depression and other mental illnesses. According to Merikangas, there may be as many as 40 genes governing serotonin activity.

The 2003 findings were heralded far and wide, despite the fact that they had not been verified by other research.

"For an initial study that hadn't been replicated, it was published to much acclaim," Merikangas said. "If it had been replicated, it was an important finding [but] geneticists have been uniformly skeptical from the beginning."

Mental health professionals have been less skeptical, maybe because, Young pointed out, "it was really the first time that people had seen a gene-environment interaction."

Merikangas and her team conducted a "meta-analysis" of 14 existing studies involving 14,250 participants, 1,769 with depression and 12,481 without the disease.

People with previous stressful life events had a 41 percent increased chance of developing depression, but the analysis turned up no association between stressful events and this gene mutation, either in men or women.

"I was surprised by this [but] I haven't give up yet on this particular allele [mutation] as having an effect. It just may be that it's not as big an effect as we thought," said Young, who's also with the VA Center of Excellence for Research on Returning War Veterans at Central Texas Veterans Health Care System.

Young has conducted two experiments, both of which showed that this mutation had an effect on brain structure. But it's still difficult to untangle how this effect arose.

The authors of the new study warned that a research strategy that tries to tie genes with environmental factors may be fraught with danger, but that scientists should be looking at both environmental and genetic factors in trying to account for mental illness.

"We have to work in both directions," Merikangas said.

More information

The U.S. National Institute of Mental Health has more on depression.

SOURCES: Kathleen Ries Merikangas, Ph.D., senior investigator and chief, genetic epidemiology research branch, U.S. National Institute of Mental Health Intramural Research Program; Keith A. Young, Ph.D., vice chair, research, Texas A&M Health Science Center College of Medicine Department of Psychiatry and Behavioral Science, and neuroimaging and genetics core leader, VA Center of Excellence for Research on Returning War Veterans, Central Texas Veterans Health Care System; June 17, 2009, Journal of the American Medical Association