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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
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.
The National Institute of Mental Health is a component of the National Institutes of Health,
an agency of the U.S. Public Health Service, part of the U.S. Department of Health and
Information provided by the NIMH.