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Biology 103
2001 Second Web Report
On Serendip

GENE LINKAGE AND BIPOLAR DISORDER/ MANIC DEPRESSION

Debbie Wang

Anyone who has, or knows, or is a family member to someone with manic depression or bipolar affective disorder, as it is called now, knows how difficult it can be to go through the stages of medication changes. This period of constant change in medications takes an emotional and physical toll of side effects in the search for the proper combination of different mood stabilizing and anti-psychotic drugs for each patient through a method of trial and error. The possibility of finding a genetic linkage could have a huge impact on, and provide better treatment of the mental illness. Bipolar disorder is characterized by dramatic emotional series of highs and lows, experienced by "mood swings between mania and depression" respectively. (5) Hippocrates called the psychological disorders "mania" or "melancholia" while a German psychiatrist in the late 1800's gave the label "cyclothymia". (7) Today, Bipolar disorder is said to affect 7 out of every 1,000 (2), that's 0.7 % of the world's population. (5) Within those figures, it is estimated that 3% of Americans have bipolar disorder. (1) Of those patients who have bipolar disorder, approximately 75% have "at least one close relative with manic-depression or severe depression" (1), and of those patients there is a "20% risk of death by suicide if untreated". (6)

Early findings from the study of genome linkage in bipolar disorder such as the one presented in November 1994 by Dr. Miron Baron found evidence of linkage in "DNA markers from region q22.3 of chromosome 21" within a particular U.S. family of 67 members with 18 who had a range from bipolar disorder to recurrent major depression. The entire study involved over 900 people from either the U.S. or Israel of 47 different families that had high numbers of individuals with bipolar disorder. These studies showed that bipolar genetic linkage systems were comparable to that of diabetes and Alzheimer's disease in that they "are more complex; they likely involve multigene systems and environmental factors" as opposed to having single genetic factor such as the case with cystic fibrosis and Huntington's chorea. (3) Previously thought to be found only on chromosome 18 and 21, new studies such as that of Dr. John Nurnberger Jr.'s have shown that chromosomes 1, 6, 7, 10, and possible some other areas are susceptibility genes in bipolar disorder (1), while other studies such as one funded by the National Institute of Mental Health (NIMH) have found importance in chromosomes 6, 13, and 15 in Amish population studies. (6) Michele T. Pato, genetic psychiatrist in describing the complex multiple gene interaction of bipolar disorder states: "It's not sweet peas, like [early geneticist Gregor] Mendel". (2)

The studies that have been done have each used their own choice of population subjects, focusing on their gene pools. A NIMH funded project in 1976 in the southeastern part of Pennsylvania (7) involved the study of an Old Order Amish pedigree in which had 17 interrelated families affected by bipolar disorder. Choosing Amish communities as study subjects is not uncommon because of the high rate of bipolar disorder among the Amish. In this particular study, their methods of genetic mapping has found that "all of the bipolar affected members analyzed can trace their ancestry back to a mid-18th Century pioneer family suffering with the illness" and Dr. Ginn and Dr.Paul, who worked on this study think that the cause of bipolar lies in the effects of multiple genes and that a certain combination of particular genes is a determinant of the disorder's individual characteristics in each person. (6) The study involved the identification of restriction length polymorphisms (RFLP's) from samples of blood in which the results "led to strong evidence" that bipolar linkage can be found on two DNA markers (which are the markers for insulin and cellular oncogene Ha-ras-1) on the tip of the short arm of chromosome 11. (7)

Another population group studied have been the Azores by Dr Carlos N. and Michele T. Pato. The reason for their choice in the $2.6 million project was due to the remoteness of the population on the subtropical island, which causes little intermarriage with "outsiders", keeping the genetic codes from mixing with other gene pools and becoming varied. Michele Pato says that the "benefit to studying an ethnically similar population" is that they can "eliminate a whole bunch of the genome, because we know that the whole culture shares that part of the genome". In a population of 250,000, they have gathered 2,000 subjects and family members in hopes of reaching a goal of 5,000. The methods that are taken with these studies include the collection of psychiatric history in the family as well as a blood sample where the white blood cells are cultured and multiplied. DNA is the extracted from the nuclei and the search for chromosome markers has begun. Errors in the study can be caused by the fact that mental disorders are not solely genetic conditions. Instead, possessing the gene does not necessarily mean the individual will develop bipolar disorder, but that " it merely predisposes him or her to developing it. Stressful life events and childhood traumas have been identified as triggers that can increase" the chance of the person developing the disorder as an adult. (2)

Studies done on twins, adoption, and families have shown an importance of genes in the presence of disorders. In twins, a higher rate of bipolar is found in monozygotic/identical twins than in dizygotic/fraternal twins. In parents, a higher frequency of the disorder is seen when inherited from the mother (7), while statistics state that the risk of developing major depression, bipolar, or schizoaffective disorder is increased 50-74% if both parents have "an affective disorder", with one having bipolar. (6) Within families that possess a predisposition, evidence suggests that those who are not bipolar are predisposed "for milder, but qualitatively similar behavioral characteristics". (4) The study of predisposition of bipolar disorder in gene linkage in addition to further studies of brain and body chemistry within those who are bipolar will allow us to understand more about bipolar and possibly other mental illnesses as well, which in turn will aid in better treatment for patients.

WWW Sources

1) Researchers Find Genetic "Hot Spots" of Manic-Depression

2) Manic Depression: the Ecstasy and the Agony

3) New Evidence for Genetic Cause of Manic Depression

4) Gene Hunting

5) Comparing Genetic Material of Multiple Generations of Family Members

6) Scientists Close in on Multiple Gene Sites for Manic Depressive Illness

7) Genetic Predisposition for Bipolar Affective Disorder




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