by Margit Burmeister, Ph.D.
The decade of the brain is nearly halfway through, the Human Genome Project
has made tremendous progress, and gene defects in more than 40 inherited
disorders have been identified; Neurofibromatosis, Huntington's disease,
Cystic Fibrosis, to name just a few. We have even heard of specific gene
defects causing more common diseases, such as breast and colon cancer
or Alzheimer's, but still no word about genes for bipolar disorder (manic
depression) or any other mental illness. Why is it so much harder to find
genetic defects responsible for mental illness?
Is Bipolar Disorder an inherited disease?
Some time ago, mental illness was thought to be due to "bad mothering",
imposing painful blame on the family members of mentally ill patients.
Fortunately, these times are gone. Now, we hear over and over again that
inherited (genetic) factors are largely responsible for bipolar disorder.
By making incorrect assumptions, one might miss the
true genetic linkage,
or "discover" a linkage that, in fact, does not exist.
What is the basis for such claims of a genetic predisposition to bipolar
disorder? Observation of families has shown that children of one parent
with bipolar disorder are seven to twenty times more likely to have manic
depression than children of parents who do not have bipolar disorder.
That by itself is no -- proof for example, going to Medical School, or
going to Law School also runs in families, but nobody argues that genes
are responsible for directing children to Medical or Law School. So additional
evidence is needed.
To tease out genetic from environmental factors, scientists turn to twin
and adoption studies. Adoption studies have shown that it is bipolar disorder
in the biological rather than the adoptive parents that is relevant for
the increased risk of bipolar disorder in children. Thus, there is strong
evidence against the direct influence of parenting. In twin studies, identical
twins, who share all their genes, are compared with fraternal twins, who
share only about half of their genes, just like other siblings. When one
identical twin has bipolar disorder, the other has a 60 to 80% chance
of also being affected, whereas the odds are only about 20% for fraternal
twins. Taken together, the evidence is thus overwhelming that genes are
a major player in bipolar disorder. Nevertheless, these studies also indicate
that there is some environmental effect not everybody who has a gene for
bipolar disorder becomes manic depressive.
Are there Genes Specifically for Bipolar Disorder?
What these studies indicate is that a predisposition to bipolar disorder
is clearly inherited whether a person becomes ill depends on other factors.
Is this predisposition specific for bipolar disorder, or is it a predisposition
for mental illness in general? It is unusual to find schizophrenia in
the biological parents of bipolar patients, suggesting that these are
two separate diseases. However, the diagnosis of schizoaffective disorder
has features of both diseases, and this diagnosis is made occasionally
in the relatives of those who have either bipolar disorder or schizophrenia,
indicating that there is some overlap between the two conditions.
Family, twin and adoption studies also show that major depression without
manic episodes is commonly found in relatives of bipolar patients. However,
depression is quite common and can be caused by environmental as well
as genetic factors. There is also some indication that relatives of bipolar
patients are more likely to abuse alcohol and other drugs. Thus, many
studies indicate that people who carry a genetic risk for bipolar disorder
may develop other psychiatric illnesses or may remain well. These studies,
however, do allow geneticists to calculate the probability, within a range,
that a person will develop bipolar disorder, given the family constellation.
For persons who are interested in finding out more about the genetics
of bipolar disorder in their own families, genetic counselors are available
to provide this service.
Linkage Analysis: How Geneticists Find Disease Genes
The most common first step in identifying genes that cause a genetic disease
is by linkage analysis. This entails collecting blood samples from families
in which some members have the disease in question. With such blood samples,
scientists can trace the inheritance of parts of chromosomes through the
generations. Chromosomes are made of DNA, the genetic information that
is inherited from generation to generation. How does linkage work? Just
imagine a large family of people that descended from a great grandfather
who had bipolar disorder. If all his descendants who have bipolar disorder
have the exact same part of Chromosome 2 as their great grandfather, whereas
all unaffected descendants inherited that specific part of Chromosome
2 from someone unrelated to that great grandfather, then one can conclude
that a part of Chromosome 2 carries the gene causing bipolar disorder
in this family.
Now, we hear over and over again that inherited (genetic)
factors are largely responsible for bipolar disorder. What is the basis
for such claims of a genetic predisposition to bipolar disorder?
While this concept is simple in principle, many questions are difficult
to answer: what about a person who had an episode or two of depression?
Was he depressed because he carries the bipolar disease gene, or for another
reason? Since the identical twin studies indicated that one can be a carrier
of the bipolar gene but not have the disease, some family members may carry
the predisposing genetic material, but are not ill. In addition, a family
has to be very large, with many members suffering from bipolar disorder
in order to prove linkage to a particular region of a chromosome.
Is this predisposition specific for bipolar disorder,
or is it a predisposition for mental illness in general?
As long as the same chromosome carries the disease gene in different families,
scientists can accumulate data from several different families, and a combined
analysis is done to determine the chromosomal location of the disease gene.
However, there is good evidence that bipolar disorder can be caused by many
different genes, and maybe even several genes acting in concert. If each
family carries a different "bipolar gene", then combining data
from different families is of little help. Thus, the diagnostic problems
and the multitude of genes make this task much more difficult. In addition,
a lot of factors have to be assumed in linkage studies for example, whether
one or two copies of the predisposing gene are necessary to get the disorder,
how likely it is that a healthy person of a certain age nevertheless carries
a predisposing gene, and many more. These variables are not known with certainty.
By making incorrect assumptions, one might miss the true genetic linkage,
or "discover" a linkage that, in fact, does not exist. To date,
whenever scientists seemed to find evidence for linkage of bipolar disorder
to a particular chromosome, the results could not be confirmed.
New Methods to Detect Linkage
Acknowledging these problems, geneticists have more recently turned to
a different way of trying to identify the chromosomes that carry genes
predisposing to bipolar disorder. In this new method, called "affected
pedigree member method", only clearly affected family members are
counted. Those relatives who do not have bipolar disorder are not included
in the statistical analysis. In addition, many fewer assumptions have
to be made. However, this method requires DNA samples from many more families.
Using these methods, scientists have recently found tentative evidence
that one gene for bipolar disorder might be near the center of Chromosome
18. In contrast to earlier linkage studies, these results could in fact
be confirmed by other investigators. However, at most this postulated
predisposing gene may account for only a quarter of all families. Thus
scientists are searching for many more genes. And to get from the knowledge
that a specific chromosome carries a gene to identifying the gene itself
will take many years.
Chromosome Rearrangements: An important clue
While the chromosomal location for most genetic diseases was identified
by linkage, the identification of the actual genes often took advantage
of findings in a few, very rare patients. These persons have the specific
genetic disease, and a chromosome rearrangement called "balanced
translocation". What does this mean? In most people, the 22 chromosome
pairs look exactly the same in structure the order of genes on each chromosome
pair is the same. However, in about one in a thousand people, two individual
chromosomes have broken and reconnected, but with the wrong piece. Thus,
a person with a balanced translocation has, for example, one each of normal
Chromosomes #3 and #9, and two additional chromosomes in which the top
part of Chromosome 3 may be hooked up with the bottom part of Chromosome
9 and vice versa. The genetic material is all there, thus balanced, but
in a different order.
Most people with balanced translocations therefore have no problems during
their lives, and they never find out about it. Women with balanced translocations
are more likely to have spontaneous miscarriages, and the diagnosis is
often made after several miscarriages. However, if the chromosomes break
in the middle of a gene that causes a disease, the carrier of the balanced
translocation can get this disease. For scientists, that is an extremely
important clue: it is relatively simple to identify the gene that lies
at such a breakpoint. As an example, a women with neurofibromatosis that
had several miscarriages had been diagnosed as carrying a balanced translocation
involving Chromosome 17.
When she read many years later in newspapers that a gene for neurofibromatosis
had been localized by linkage to human Chromosome 17, she remembered that
this was the chromosome that was broken in her cells. She contacted the
investigators, told them her story, and it turned out that indeed one
of her chromosomes had broken right at the neurofibromatosis gene! Her
initiative helped the search for this gene tremendously. Similarly, many
of the over 40 genes that are already known were identified with the help
of such exceedingly rare cases.
Only very few studies have found balanced translocations in bipolar disorder.
Given that bipolar disorder is relatively frequent, and translocations
are as well, there will be people who by chance have both. Thus, it will
be particularly important to find families in which more than one member
has both, bipolar disorder and a balanced translocation, or patients in
which the balanced translocation is in a chromosome such as # 18 that
has already been implicated in bipolar disorder. While such cases will
be rare, their identification may speed up the search for a bipolar gene
Since the identical twin studies indicated that one
can be a carrier of the bipolar gene but not have the disease, some family
members may carry the predisposing genetic material, but are not ill.
Family Participation: the Crucial Step
The above discussion leads us to an important point: Genetic studies depend
on the cooperation, of patients and their family members. In a genetic
study for bipolar disorder or other mental illness, many family member
are interviewed in detail and blood samples are taken. The more complicated
the disease, the larger these studies have to be. Thousands of DNA samples
from carefully diagnosed individuals from families will offset some of
the problems in linkage analysis. Rare patients with bipolar disorder
who carry a translocation need to be identified. The willingness of families
to volunteer their time for research studies is very much needed and appreciated
by the scientific community. Often, a family member acts as the "family
facilitator," organizes the contact with the extended family, convinces
cousins and aunts that it is worthwhile, and in this manner promotes scientific
progress. The most important acknowledgment in scientific papers on genetics
of psychiatric illness therefore always goes to the hundreds and thousands
of family members who participated.
What are the Benefits of Genetic Studies?
We anticipate that identifying genes that predispose to bipolar disorder
will benefit individuals with bipolar disorder, their families as well
as mental health professionals in several ways. If the gene for bipolar
disorder has an already known function, it might be possible to devise
improved therapies with this knowledge. Knowledge from genetics might
also guide therapeutic decisions: Maybe those helped by a particular drug
such as Lithium carry a different gene than those who are not. Knowledge
of these genes will also provide a better understanding of how bipolar
disorder runs in families, and thus provide more specific information
for genetic counseling. So , even though the process may be slow, it will
eventually help those suffering from a severe mental illness and their
relatives who also have cause to worry about themselves.
(This article was first published in 1995)
MARGIT BURMEISTER, Ph.D. is an Assistant Research Scientist at the Medical
Health Research Institute and an Assistant Professor in the Departments
of Psychiatry at the University of Michigan where she serves as Director
of the Bipolar Genetics Research Study.