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?

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 by years.

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.