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Stanford-led study closes in on genes that may predispose some people to severe depression

Some people appear to be genetically predisposed to developing severe depression, but researchers have yet to pin down the genes responsible. Now, a specific region rife with promise has been located on one chromosome by a consortium of researchers working under Douglas Levinson, MD, professor of psychiatry and behavioral sciences at the Stanford University School of Medicine.

"This finding has a very good chance of leading to a discovery of a gene that could yield important information about why some people develop depression," said Levinson. If problematic genetic variations could be identified, it would open the door to a whole new world of investigation, and eventually, treatment possibilities. The team's results are reported in two papers that will be published in the February issue of the American Journal of Psychiatry.

Levinson's group, comprising researchers from six universities, achieved this breakthrough by studying 650 families in which at least two members suffered from repeated bouts of severe depression that began in childhood or early adult life. The first of the studies was a genome-wide scan that looked for evidence of genetic "linkage" within families between depression and DNA markers on the various chromosomes. The linkage study identified regions worthy of more intensive examination.

The second study was a more detailed look at the most suspicious of these regions, located on chromosome 15. Levinson said the team studied six DNA markers in this region in the first study, and an additional 88 in the second. "We found highly significant evidence for linkage to depression in this particular part of chromosome 15," he said. "This is one of the strongest genetic linkage findings for depression so far."

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"It's an important paper," said Peter McGuffin, MD, dean of the Institute of Psychiatry at King's College in London, who was not involved in the study. McGuffin wrote a commentary on the research that appears in the same issue. "This is one of the first big linkage studies on the genetics of depression."

Researchers learned that depression is influenced by genetics by studying patterns of depression in twins and families. No single gene is thought responsible for determining the risk for developing depression. Instead, multiple genes are probably interacting to create what amounts to a genetic baseline level of risk. On top of that baseline, environmental factors are likely mixed in as well, things such as non-genetic physiological problems or psychological traumas.

Some 10 to 15 percent of people suffer from severe depression at some point in their lives, and 3 to 5 percent have it more than once. Women are twice as likely to develop depression as men, although the reason is not yet known.

"We don't think depression is entirely genetic, by any means, but there are important genetic factors," said Levinson. "If we can succeed in finding one or more genes in which there are specific DNA sequence variations that affect one's risk of depression, then we would be able to understand what type of gene is it, what it does in the brain and by what mechanism it could make one more or less predisposed to depression."

Knowing more about which genes are the major factors causing a predisposition for depression would also help researchers sort out the environmental factors that contribute to depression, Levinson said. And knowing more about either genetic or environmental factors could help in developing more effective therapies to treat depression. "The treatments we have now are lifesavers for some people, but there are others who have only a partial response or no response at all," he said. "Understanding the biology would help the search for better treatments."

The next phase of the consortium's research is already under way. This phase is an even more detailed look at more than 2,000 individuals to identify specific genes where there are variations that increase the risk of severe depression, including closer study of the suspicious area of chromosome 15.

Louis Bergeron | EurekAlert!
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