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Depression May Alter Genes that Protect Neurons

By Edward R. Winstead

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Depression and Bipolar Disorder

Halfway through a project to document how the brain changes in response to mental illness, researchers have identified a family of genes that is consistently less active in the brains of depressed individuals compared to mentally healthy men and women.

The genes comprise a “complex and powerful” family of genes that normally helps build the brain early in life and maintains connections between neurons later in life. But the genes, known as fibroblast growth factors, or FGFs, appear to be less active in at least some individuals who experienced recurrent episodes of major depression.

The reason for the decreased activity is not yet known, nor is it known whether the misbehavior of these genes contributes to the development of depression or occurs because of the disease. In any case, the researchers have begun to study the genes in rats to see whether pharmacological approaches might be a way to affect the genes.

“This particular family of genes had not previously been implicated in any psychiatric disorder, but it’s not a big leap to see how they play a role in the development of depression,” says Simon J. Evans, one of the researchers on the project from the University of Michigan in Ann Arbor.

Evans is part of the Pritzker Neuropsychiatric Disorders Research Consortium, which includes scientists from four universities— Michigan, Stanford University in California, the University of California Irvine, and the University of California Davis. The Pritzker family of Chicago is funding the consortium, which has been doing research for about four years.

Microarrays are the new kid on the block when it comes to searching for genes in psychiatric disorders. --Kenneth Kendler
Eventually the group will study about 25 different brain regions to develop a comprehensive picture of the brain as it looks in individuals with depression, bipolar disorder, and schizophrenia. The tissue is collected at autopsy, and the group plans to study more than 200 individuals, including some who had these disorders and some who didn’t. Records are kept on each individual’s health history and the nature of his or her death.

The consortium will “profile” the activity of genes in this tissue using DNA microarrays, which are glass slides or microchips spotted with DNA. They are also known as gene chips.

In this study, the team used microarrays containing about 20,000 genes to profile two regions of the brain known to be affected by depression. Writing in Proceedings of National Academy of Sciences, the researchers say this family of genes “emerged as the most significantly altered ensemble of genes” in the two regions.

“This finding is significant because it was made by studying patients with depression and because it points toward an area of biology that neuroscientists think is important in this illness,” says Stanley J. Watson of the University of Michigan, another researcher on the team.

The fact that the researchers got “a bunch of hits in related genes” is intriguing, says Kenneth Kendler, who directs the Psychiatric Genetics Research Program at Virginia Commonwealth University in Richmond and was not involved in the project. But he says it’s impossible to know at this point whether the genes have anything to do with depression in people.

Although microarrays have been used to identify genetic changes related to cancers, brain diseases may be another matter, Kendler says. The challenge, he adds, of comparing brain tissues from autopsy that may have undergone dramatic changes before they were collected is daunting.

“Microarrays are the new kid on the block when it comes to searching for genes in psychiatric disorders,” he says. “But the science is good, and someone ought to try to follow this up.”

Despite the efforts of many researchers around the world who have studied the DNA of people who develop mood disorders, no single gene has yet been shown to be responsible for causing clinical depression in a group of people. Perhaps this isn’t surprising given that depression is thought to occur most often when life takes a turn for the worse.

To be sure, a small number of genes, such as those involved in transporting the chemical serotonin in the brain, have been linked to changes in mood. But the search is still on for genes that may predispose individuals to have potentially fatal mood swings if they experience certain events in their lives.

Last year a study reported that people who had a particular form of a gene and who experienced certain adverse events in their lives were more likely to develop major depression than people who experienced similar challenges but had a different form of the gene. The gene was involved in transporting serotonin in the brain, and the study compared people who have the “long” and the “short” forms of the gene.

This finding was possible because researchers had access to a remarkable long-term study in which people have been tracked over many years and records are kept about their mental health histories and relevant experiences. But such resources are rare.

Another strategy for finding these genes has been to search the DNA of families with a history of depression for common genes and mutations. Known as genome scans, this approach has been used widely, but most of the results have not been replicated by other scientists studying other groups of people.

Like genome scans, microarray studies such as this one do not focus on a gene that may be important in depression. Instead, the researchers start with no preconceived notions of what they might find and instead run the experiment and let the data talk, if you will.

But when the data are based on tissue from many individuals of different ages who died of a variety of causes, the results are meaningful only if confounding factors are taken into account. The consortium has spent much of the last four years identifying such factors and figuring out how to compare tissues that have such different origins.

When comparing autopsy tissue from different individuals one has to take into account the medications the person was taking at the time of death and other factors that might influence the results. The most important factor is the cause of death.

The team does not use tissue from people who died prolonged deaths in the hospital because the brain undergoes such change during this period. Other factors such as the person’s gender and medications at the time of death can more easily be taken into account in the analysis, according to the researchers.

“The brain is a dynamic organ that makes a lot of internal modifications on demand,” says Watson. “When we started the project we began to realize that the way someone dies can cause the brain to shift into survival mode and we find that survival mode involves a very different set of genes than is normally active.”

Although it’s not clear why the genes were less active in some individuals, it does not appear to be because of antidepressant medications such as Prozac. Indeed, the genes seemed more active in people taking antidepressants, which led the researchers to hypothesize that the drugs may somehow affect the activity of these genes.

From obtaining the brain tissue at autopsy to using statistical tools to sort the data, the study presents numerous challenges and requires diverse expertise. “The project has required an enormous effort and no one place can do this—it’s expensive and it’s complex, and it’s taken almost four years,” says Watson.

“We have great respect for the families who are willing to do this,” he continues. “We have to ask family members at the time of death to participate in the research or else the brain deteriorates and that is a difficult thing to ask at such a time.”

Other members of the research team included Edward G. Jones at the University of California at Davis, William E. Bunney, Jr., at the University of California Irvine, Huda Akil at Michigan, and Richard M. Myers and Alan Schatzberg at Stanford.

Later this month at the Society of Neuroscience meeting in San Diego, the team will report on two other brain regions, the hippocampus and the amygdala.

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