April 1996

Scientists Close in on Multiple Gene Sites for Manic Depressive Illness

Evidence is mounting that manic depressive illness, a major public health problem affecting one percent of the population, stems from multiple genes. Scientists have pinpointed new sites on 5 chromosomes that may contain the thus far elusive genes that predispose for the illness, also known as bipolar affective disorder. Patients experience recurrent mood and energy swings and face a 20% risk of death by suicide if untreated. Three independent research teams, two supported by the National Institute of Mental Health (NIMH), report on the genetic linkages in the April 1st issue of Nature Genetics.

"While still provisional, these studies taken together signal real progress," said Steven Hyman, M.D., newly appointed Director of NIMH. "Science is now beginning to deliver on the promise that modern molecular genetics holds for the mentally ill."

One of the NIMH-funded studies found evidence for bipolar disorder susceptibility genes on chromosomes 6, 13 and 15 in a large Old Order Amish pedigree, consisting of 17 interrelated families affected by the illness. The findings suggest a complex mode of inheritance, similar to that seen in diseases like diabetes and hypertension, rather than a single dominant gene, say the principal investigators, Edward Ginns, M.D., Ph.D., NIMH; Steven M. Paul, M.D., NIMH and Lilly Research Laboratories; and Janice Egeland, Ph.D., University of Miami.

"An individual's risk for developing bipolar disorder probably increases with each susceptibility gene carried," said Dr. Ginns, chief of the NIMH Clinical Neuroscience Branch. "Inheriting just one of the genes is probably not sufficient." Moreover, different genes account for the illness in different families, complicating the task of finding and replicating linkages across populations. "To boost the odds of detection, we have traced the transmission of the illness over several generations in a few genetically isolated large families, thus limiting the number of possible genes involved and increasing each gene's effect," explained Dr. Paul, who was NIMH Scientific Director before becoming head of central nervous system research at Lilly.

Bipolar disorder and other related mood disorders occur at an unusually high rate among the Amish families studied. Yet, the Old Order Amish community as a whole has the same prevalence of psychiatric illness as other populations, noted Janice Egeland, Ph.D., a professor at the University of Miami Department of Psychiatry and Project Director of the Amish Study, funded by NIMH over the past two decades. All of the bipolar affected members analyzed can trace their ancestry back to a mid-18th Century pioneer family suffering with the illness. The families studied also have a relatively narrow spectrum of affective disorders, with bipolar being the predominant diagnosis. Family members were rigorously diagnosed by clinicians unaware of family relationships and genetic marker status.

In the latest phase of the study, the researchers employed sophisticated gene mapping and other advanced methodologies in the screening of human chromosomes, which included 551 DNA markers in 207 individuals. Exhaustive analyses carried out by Jurg Ott, Ph.D., and colleagues at Columbia University, employing multiple models of genetic transmission, yielded evidence for linkage of bipolar disorder to DNA markers on chromosomes 6, 13, and 15. The research group also includes investigators at Yale University, The Human Genome Research Center (Evry, France) and Genome Therapeutics Corporation.

Drs. Ginns and Paul propose that bipolar affective disorder is caused by the variable effects of multiple genes, probably including more than were suggested in their study. They hypothesize that an individual's particular mix of such genes determines the various features of the illness: age-of-onset, type of symptoms, severity and course. Dr. Egeland and her colleagues are continuing to identify additional members of the Amish kinships and are closely monitoring children at risk for developing the illness. Testing of additional DNA markers in the identified chromosomal regions is in progress as investigators attempt to close in more precisely on the illness-causing genes. Although the same genes responsible for bipolar affective disorder among the Amish may also transmit the illness in other populations, it is likely that additional sets of susceptibility genes are also involved.

Two families from Costa Rica's Central Valley were the focus of a second NIMH-supported study in the same journal. Like the Amish pedigree, they come from a community that has remained genetically isolated, and which can trace its lineage back to a small number of founders in the 16th to 18th Centuries. Also as in the Amish study, the investigators, led by Nelson Freimer, M.D., of the University of California, San Francisco, employed a large number of chromosomal markers, 475, to screen for possible gene locations. Among bipolar affected individuals, a new region on the long arm of chromosome 18 was implicated.

In a third study, Dr. Douglas Blackwood of Edinburgh University and colleagues, using l93 DNA markers, traced vulnerability to the illness to a region of chromosome 4 in a large Scottish family with a 10-fold higher than normal rate of bipolar disorder. They then found the same association for the chromosome 4 marker in bipolar affected individuals in 11 other Scottish families.

"Scientists agree that individuals with a genetic predisposition do not invariably develop bipolar disorder," noted NIMH Acting Scientific Director Sue Swedo, M.D. "Environmental factors can also play a role in determining how genes are expressed and cause illness." Moreover, other major affective disorders typically occur in the same families who have bipolar disorder. One's risk for developing major depression, bipolar, or schizoaffective disorder rises to 50-74% if both parents have an affective disorder and one has bipolar disorder. There is also evidence that desirable traits, such as creativity, may occur along with bipolar illness. Scientists are hopeful that identification of genes -- and the brain proteins they code for -- will make it possible to develop better treatments and preventive interventions targeted at the underlying illness process.

As part of its genetics initiative on bipolar disorder, the NIMH is promoting the identification of, and sharing data from, well-diagnosed families among research groups. Members of families interested in participating in genetics research should contact NIMH Public Inquiries (5600 Fishers Ln., Rm 7C-02, Rockville, MD 20857) for information.

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