Gene for manic depression?

Gene for Manic Depression?

A decade-long study of the geneticallyand culturally isolated Amish population in southern Pennsylvania has yielded the first evidence that there is a gene somewhere along the tip of a specific chromosome that predisposes its bearers to manic depression, and possibly to severe depression without mania. Genetic studies of other populations indicate, however, that there is no single "manic-depression gene.'

The critical gene among the Amish is inthe area near the short end of chromosome 11, report psychiatrist Janice A. Egeland of the University of Miami (Fla.) School of Medicine and her colleagues based at the Massachusetts Institute of Technology and Yale University. Although the DNA sequence of the gene, which determines its physiological and biochemical functions, has not been established, the gene is dominant, say the researchers in the Feb. 25 NATURE. Its inheritance from either parent renders a person susceptible to manic depression.

"The real challenge now will be to findan assay that will identify the specific gene [involved in manic depression],' notes molecular biologist Daniela S. Gerhard, a participant in the project who is now at Washington University in St. Louis.

Egeland and her associates have hadlittle success in pinning down a chromosome position for such a gene in the past, but recent advances in recombinant DNA techniques permitted the identification of two genes at the tip of chromosome 11 that appear together only among Amish family members with a psychiatric "mood disorder.'

The study focused on three Amishfamilies with mood disorders spread through three generations. Of the 81 family members, 14 had some form of manic depression, 5 had severe depression and 62 had no psychiatric symptoms.

DNA samples were isolated from bloodsamples and the investigators located areas at the tip of chromosome 11 containing one gene responsible for the production of insulin and another, called Ha-ras-1 (HRAS1), that produces a protein believed to be involved in benign forms of cancer. DNA-cutting enzymes were used to slice into these two sites so that genetic forms or mutations of each gene could be identified.

In the two oldest Amish generationsunder study, specific forms of insulin and HRAS1 appeared in combination only among those with a mood disorder. In the third generation, the same pattern occurred among those with psychiatric symptoms, as well as among some symptom-free individuals. Since manic depression often is not noticable until sometime between 15 and 35 years of age, the researchers say the latter group may be at risk for developing the illness later.

A computer programs was then used todetermine the probability of the two markers appearing at the same chromosome position as the proposed gene predisposing individuals to manic depression. Based on the estimate that 85 percent of those in the sample who inherited the gene would develop the disorder, this assumption was statistically confirmed. The exact location of the proposed gene appears to be closer to the HRAS1 position.

It is not known whether chromosome 11markers will appear in Amish families with mood disorders that do not include manic depression, acknowledge the researchers. Theoretically, the ability to tag at-risk individuals through DNA analysis could lead to studies of life events that might trigger the genetic

predisposition. For now, the scientists are considering possible molecular mechanisms of manic depression, such as a defect in a chromosome 11 gene involved in formation of the neurotransmitter dopamine.

Suspicions that one gene does notunderlie all cases of manic depression are supported by two other studies in the same issue of NATURE. DNA analysis by European researchers of families in Iceland with several generations of mood disorders and a similar analysis of non-Amish families in the United States, reported by scientists at the National Institute of Mental Health, found no evidence of a gene predisposing to manic depression at the end of chromosome 11.

"This isn't surprising,' says Gerhard."Manic depression occurs among 1 percent of the population and I wouldn't expect it to be a one-gene disease.'