After years of frustrating searches for genes that contribute to mental illness, researchers at Johns Hopkins studying families with a severe form of manic depressive illness, called psychotic bipolar disorder, may be one step closer to finding the genetic underpinnings of both bipolar disorder and schizophrenia.

"Finding a gene for bipolar disorder is like finding a needle in a haystack, but by focusing our search on families with a distinctive form of the illness we were able to pinpoint a region of the genome where disease genes are likely to be found," said James Potash, assistant professor of psychiatry and lead author of a report on the study in the April issue of the American Journal of Psychiatry.

Although genes are unlikely to tell the whole story of major psychiatric diseases, the persistent frequency of mental illness in about 1 percent of the global human population, regardless of cultural or ethnic differences, and its tendency to run in families have always pointed to a strong genetic role. "But pinning down that role is complicated by the many variations in symptoms, even within the same family," Potash said. "There are probably many different genes and environmental factors that can cause any given mental illness."

Motivated by previous suggestions that certain broad regions of the DNA sequence, especially on human chromosomes 13 and 22, may contain genes that contribute to both bipolar disorder and schizophrenia, Potash and colleagues focused on those families with the psychotic form of bipolar disorder. Like bipolar disorder, psychotic bipolar disorder is characterized by seesawing episodes of depression and mania, but it is distinctive because these mood changes often are accompanied by such psychotic symptoms as hallucinations and delusions.

The concept for the new study is that of two slightly overlapping circles, Potash explained. In one circle are all the genes that contribute to schizophrenia. The other circle has all the genes that contribute to bipolar disorder, while the intersection of the two circles contains genes that are common to both diseases as well as for psychotic bipolar disorder.

The researchers evaluated and took blood samples from 65 patients with bipolar disorder and from their extended families. They extracted blood cell DNA and scanned it with DNA probes, looking for matching sequences that are more likely to appear in people with mental illness than in those without it. By noting where these markers lay on chromosomes, the researchers were able to narrow in on where the genes were located.

Out of 65 bipolar disorder families studied, the 10 families in which three or more members had psychotic bipolar disorder showed strong genetic "linkage" to specific regions on chromosomes 13 and 22. These results differed significantly from those for all 65 families, which showed little or no linkage evidence in these two regions.

"These results confirmed our expectation that genes for the psychotic form of bipolar disorder are likely to be found in the same regions that show linkage to both bipolar disorder as a whole and to schizophrenia," Potash said.

One important implication of the study is that these "overlap genes" may contribute to brain abnormalities that are shared by bipolar disorder and schizophrenia and could help explain why the same antipsychotic medications are effective treatments for both diseases, Potash said.

Other authors on the report are Dean MacKinnon, Sylvia Simpson, Francis McMahon, J. Raymond DePaulo, Melvin McInnis, Peter Zandi, Virginia Willour, Tsuo-H. Lan, Yuqing Huo, Dimitrios Avramopoulos and Yin Shugart.

The study was funded by the National Institute of Mental Health, the National Alliance for Research on Schizophrenia and Depression, the Stanley Medical Research Institute, the Dana Foundation, the Alexander Wilson Schweizer Fund, the Affective Disorders Fund and the George Browne Laboratory Fund.

Related Web sites:
Johns Hopkins Department of Psychiatry and Behavioral Sciences
'The American Journal of Psychiatry'