Hopkins Researchers Closing In On Manic-Depressive Gene

Johns Hopkins researchers have confirmed that a gene related to bipolar disorder in families is located in the "long arm" of human chromosome 18. The new results strengthened an earlier Hopkins study, making the linkage among the first genetic connections to a psychiatric illness to be reinforced by a second study.

"If you think of all the human chromosomes as a city, we've clearly found the block where a gene that helps cause some forms of bipolar disorder resides," says Francis McMahon, M.D., associate professor of psychiatry and lead author of a report in the December issue of the American Journal of Human Genetics.

The exact gene and the nature of the protein it makes is not known, but there are some potential suspects in this area. Finding the gene should help scientists make sense of bipolar disorder's physical effects on the brain and develop tests and better treatments, according to McMahon.

"We know that many of the message-sending and mood-regulating chemical systems of the brain are disrupted in bipolar patients," says McMahon. "But it's very difficult to determine the chain of events for all these changes. Finding genes can help us organize symptoms and work the problem from the bottom up: system A disrupts system B, which unsettles system C and so on."

McMahon and his Hopkins colleagues interviewed and took blood samples from 259 individuals from 30 different families in which at least one family member had demonstrated, medically evaluated bipolar disorder, which is marked by extreme emotional swings from explosive elation to suicidal depression. In the general population, one in every 100 persons has the disorder.

Scientists selected sets of markers on chromosome 18 -- patterns of genetic code that allowed them to follow the chromosome's passage from parent to child.

They compared patterns of inheritance of these markers with the psychiatric evaluation of study patients. They found that children who developed bipolar disorder were significantly more likely to receive their copy of chromosome 18 from fathers, even if the fathers didn't have the disorder.

One potential explanation is genetic imprinting, McMahon notes, a phenomenon in which genes are differently "tagged" and differently expressed depending on whether they came from the mother or the father.

Like finding the call numbers for a book in a library, mapping a gene tells scientists where to look for the gene so they can try to "pull it from the shelves," or isolate it, and "read" its contents.

Relatively little is known about the genes on chromosome 18, whose asymmetric shape gives it a "long arm" and a "short arm." The new study indicates the "long arm" probably contains a bipolar disorder gene. One potential suspect in this area is a gene for a melanocortin receptor, a protein that binds to an important hormonal regulator of the brain.

"Theoretically, changes in this receptor could have a whole-brain effect on mood," says McMahon. "It's a shot in the dark, but it's worth following up." Scientists also will try to tighten their search. "It's nice to have the search narrowed down to this city block', but there are still probably several hundred genes in this region," he says. "We'd like to narrow that down to a smaller area where we might have 25 to 50 genes to investigate."

Hopkins researchers have sent their blood samples to the Center for Inherited Disease Research (CIDR), a new facility at Johns Hopkins Bayview Medical Center that helps scientists rapidly search DNA for disease-linked genes.

Created through a contract between the Hopkins School of Medicine and the National Institutes of Health, CIDR will apply the latest technology and new analytical methods to search beyond chromosome 18 for signs of other genes involved in manic depression.

Funding for this study was provided by the Dana Foundation for Brain Research, the National Institutes of Health, and the National Alliance for Research on Schizophrenia and Depression.

Other authors were P.J. Hopkins, J. Xu, M.G. McInnis, S. Shaw, L. Cardon, S.G. Simpson, D.F. MacKinnon, O.C. Stine, R. Sherrington, D.A. Meyers, and J. Raymond DePau