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A research team based at the University of Chicago has traced increased susceptibility to bipolar disorder to two overlapping genes found on the long arm of chromosome 13. The study, published in the May 2003 issue of the American Journal of Human Genetics, is the first to implicate this gene complex, and the second to tie any gene, to the development of bipolar disorder, which affects 2 million American adults.
A previous study found that the same gene complex increases risk for schizophrenia. The current finding adds credence to the emerging notion that the same genes may be contribute to both disorders.
"The discovery of susceptibility genes for psychiatric disorders has been one of the most intractable problems in human genetics," said Elliot Gershon, M.D., professor and chairman of psychiatry at the University of Chicago and a co-author of the study. "In the past two years, we seem to have reached a watershed for psychiatric gene discovery, with the identification of genes that increase risk of bipolar disorder and schizophrenia. After years of false starts and unfulfilled promises, we have begun to make real progress."
Bipolar disorder, also known as manic-depressive illness, is a brain disorder that causes profound shifts in a person's mood, with spurts of high energy and elation alternating with longer periods of fatigue and deep sadness. It affects about one percent of adults, usually beginning in late adolescence.
The disorder is caused by multiple genes, each contributing a small part. The bipolar gene on chromosome 13 has a "weak effect," said Gershon, increasing susceptibility to the disease by about 25 percent.
The implicated genes, known as G30 and G72, were discovered through positional cloning, an approach that relies on small differences between family members who have a disease and those who do not to track down the genes that increase risk. With this approach the researchers do not have to know the function of the genes that cause a disease in order to find them. Once found, however, the gene's function can be elucidated.
"Instead of interrogating the usual suspects, positional cloning leads us to novel genes," said Gershon, "and novel genes provide new information, which could help us find better treatments."
The team, headed by research associates Eiji Hattori and Chunyu Liu in Gershon's laboratory, studied two large series of families in which several members have bipolar disorder. The Clinical Neurogenetics pedigrees include 371 individuals from 22 extended families. The National Institute of Mental Health Genetics Initiative pedigrees include 474 individuals from 152 families.
Both series provided strong evidence that one version of a stretch of DNA that includes the two genes was associated with bipolar disorder. This consistency lends power to the finding.
G30 and G72 are "rather strange genes," said co-author Hattori. They are expressed only in primates, with no counterpart in mice. They have no known function. They reside in a sort of "gene desert," near the end of the chromosome, with no other genes nearby, and they overlap on complementary chromosome strands.
The G72/G30 gene complex was discovered at Genset Corporation, which reported association of this complex with schizophrenia in the fall of 2002.
These two reports are the first consistent demonstration of a gene complex associated with both bipolar illness and schizophrenia. For a century, these disorders were thought to be inherited separately. In the past few years, however, the possibility that the same genes contribute to both disorders has gained favor.
One other gene has been implicated in bipolar disorder. In 2002, researchers found that brain-derived neurotrophic factor, a candidate gene, was associated with the disease.
Additional authors are Judith Badner and Susan Christian of the University of Chicago, Tom Bonner and Sevilla Detera-Wadleigh of NIMH, and Richard Gibbs and Manjula Maheshawri of the Human Genome Sequencing Center at Baylor Univeristy. The National Institutes of Health, the National Alliance for Research on Schizophrenia and Depression and the Japan Foundation for Aging and Health supported the research.
Journal
American Journal of Human Genetics