Genetic Predisposition for Bipolar Affective Disorder
By Brad A. Squire

Descriptions of what are presently known as mood disorders date back to antiquity. The Old Testament and Homer's Iliad both include stories of depressive syndromes. Psychological disturbances were described by Hippocrates as "mania" or "melancholia". The term "melancholia" was used subsequently and with similar meaning by a number of other medical authors through the seventeenth century. In the mid-nineteenth century French psychiatrists described conditions characterized by mood swings and deep depression. Near the end of the nineteenth century a German psychiatrist coined the term "cyclothymia" which meant the same illness could have both periods of mania and depression. Finally in 1899, Emil Kraepelin developed a model of bipolar affective disorder containing most of the criteria necessary to be diagnosed with the disorder today.
Bipolar affective disorder is characterized by extreme mood swings and is also known as manic-depression. An individual suffering a manic episode experiences elevated, expansive, or irritated moods. The symptoms of mania include restlessness, talkativeness, uncontrollable thoughts, inflated sense of self-worth, less need for sleep, and distractibility. An individual suffering a depressive episode experiences a mood of hopelessness. The symptoms of depression include less energy, general disinterest, feelings of worthlessness or guilt, problems concentrating, disturbances of eating and sleeping, and thoughts of suicide or death.

The hypothesis for a biological cause for affective disorders is supported by the observation that both bipolar and unipolar disorders tend to run in families. Twin, adoption, and family studies indicate genetics play an important role in the expression of affective disorders. It appears that the evidence for a genetic cause of bipolar affective disorder is stronger than that for depression. A strong connection exists between the incidence of the disorder in individuals and occurrence in their biological parents. Also, when monozygotic and dizygotic twins are considered, a higher concordance rate for bipolar disorder is found for monozygotic twins.

Genetic linkage studies provide evidence for the inheritability of the disease. The presence of restriction fragment length polymorphisms (RFLP's) associated with bipolar disorder has been observed, as well as linkage to chromosome 11 and to the X chromosome. A specific study was initiated in 1976 of the genetically isolated Old Order Amish (OAA) population in southeastern Pennsylvania. The study focused on families of bipolar patients. Family data indicate the mode of inheritance consistent with the patterns of illness in the offspring is autosomal dominant. Identification of RFLP's by using blood samples of the Amish families led to strong evidence that a linkage exists between a locus for bipolar disorder and two DNA markers on the tip of the short arm of chromosome 11. These two markers are for insulin (INS) and the cellular oncogene Ha-ras-1 (HRAS1). Through linkage analysis, it was concluded the proposed locus for bipolar disorder is most likely to be tightly linked to the HRAS1 locus. Another report indicated a gene on chromosome 11 for bipolar disorder may have been detected in one non-Amish family. A number of studies have suggested linkage of bipolar disorder to markers on the X chromosome: 1) for color blindness and 2) the Xg locus. It appears the most reproduced study involves linkage on chromosome 18. One study has also found a significantly higher frequency in families where the disorder is inherited from mothers.

A particular case inquiry may be considered, assuming that bipolar affective disorder can be inherited as a sex-linked recessive trait or as an autosomal recessive trait. This case inquiry involves two families: the Humboldts and the Morrisons. Both families suffer from bipolar disorder as well as red-green color blindness. In the Humboldt family 5 individuals suffer from both bipolar disorder and color blindness. If bipolar disorder and color blindness are both linked on the X chromosome (as mentioned above), the mode of inheritance for these 5 individuals must be sex-linked recessive. Further evidence for X-linkage is the presence of RFLP's on the X chromosomes of these 5 individuals. Three individuals in the Humboldt family are carriers of the disorder. They are the only ones who do not have the disorder but bear children who have the disorder. In the Morrison family 3 individuals suffer from bipolar affective disorder. Four individuals are colorblind. The mode of inheritance for bipolar disorder in this family must be autosomal recessive. The evidence for this is the fact that 3 of the four colorblind individuals do not have bipolar disorder. Also, all of the individuals with bipolar disorder show the presence of RFLP's on chromosome 11. Furthermore, one of the individuals in the family who does not have bipolar disorder possesses an RFLP on chromosome 11 and has a child with bipolar disorder. If Humboldt III2 marries Morrison III8, a son of theirs has a 27 % chance of expressing bipolar affective disorder (since one parent has the disorder). Tracing the inheritance pattern of bipolar affective disorder can be difficult. One reason is individuals may be carriers and show no sign of the disorder. Another reason is families with forms of the disorder may not have any of the genes thought to cause the disorder. Bipolar loci that have been hypothesized are not specific enough to allow gene isolation and capture studies. Perhaps the most challenging problem is obtaining data from a large number of bipolar families and making this data available to genetic researchers. Training clinicians to be consistent in methods of diagnosis and in collecting family histories may help with this problem of identifying families for pedigree studies. Finally, the environmental factors influencing expression of bipolar affective disorder should not be overlooked.

References
Blehar, Mary C. et al, 1988. Arch Gen Psychiatry 45: 289-292.
DePaulo, Jr., J. Raymond. The Decade of the Brain, a publication
of The National Alliance For The Mentally Ill, Winter 1995 Volume VI Issue 2.
Egeland, Janice A. et al, 1987. Nature 325: 783-787.
Kaplan, Harold I. and Sadock, Benjamin J. Synopsis of Psychiatry, sixth edition.

Return Case Studies in Virtual Genetics 1996-1997