GENETIC ADVANCES: ADDITION BY DIVISION, a report on a presentation 1 given by Francis J. McMahon, M.D. 2 Smooth Sailing, Spring 1997

A requirement for appreciating the complex genetics of affective disorders—the focus of Dr. McMahon's presentation—is an awareness of the effects of gene mutation. Dr. McMahon explained that a gene mutation can have one of three outcomes: A one-to-one relationship: a person who has the gene mutation will have the illness. A partial effect: the illness is present in some people carrying the mutation, but not all. (Here risk factors become important as well as the strength of the gene effect, which is quantified statistically.) A silent relationship: the gene mutation does not produce any illness.

When people think of inherited illnesses, they often think of the one gene/one disease construct. It is becoming quite clear, however, that this basic model does not apply to affective disorders. Dr. McMahon suggested a conceptual model that may be valid for the inheritance of affective disorders, which are clearly a family of disorders. Perhaps their transmission is related to a family of genes instead of a single gene—a seemingly simple concept, but with complex implications. To illustrate, Dr. McMahon contrasted a schematic of the transmission of Huntington's disease (a one-to-one relationship) with a model of the transmission of affective disorders by several minor genes.

(Link to chart 1) He noted that the standard approaches to genetic linkage studies are not sophisticated enough to locate genes for affective disorders. Investigators at Johns Hopkins and their international colleagues are identifying specific places on certain chromosomes where affective disorder genes appear to be located. While chromosome 18 has received the most attention in the popular press, chromosomes 4 and 21, and perhaps the X chromosome, may also be involved. Replications of these studies are lending credence to the implication of at least four genes.

(link to chart 2) The evidence supporting the involvement of several minor genes leads to questions such as whether affective disorders can be divided into genetically simpler sub-types. Since these heterogeneous disorders have such complex genetics, Dr. McMahon and colleagues are now focusing on a number of discrete characteristics that should help to identify specific modes of transmission in bipolar disorders. These characteristics include age of onset of the disorder, parent of origin (which parent passed the disorder on), comorbid conditions (other illnesses that are also present, such as alcoholism or panic disorder), diagnosis (such as bipolar I, with full-blown manias, versus bipolar II, with relatively mild manias), and response to treatment. Other critical characteristics may be found as the research progresses. We know that the age of onset differs in recurrent unipolar depression versus the bipolar disorders, and logic points to genetic differences among the disorders as being responsible. In studies of bipolar disorder, a clear parent-of-origin effect was observed. When the parent of origin was the mother, more offspring and more maternal relatives were affected. Another intriguing study involved comorbidity. In people who have panic disorder as well as bipolar disorder, the two disorders appear to be inherited together from a gene located in a specific region of chromosome 18 that is designated 18q. Dr. McMahon speculated that this gene may transmit one subtype of bipolar disorder.

Dr. McMahon noted that one of the most significant research findings relates to genetic differences between bipolar I and bipolar II disorders. Analysis of certain alleles (different versions of the same gene) on 18q in pairs of siblings having bipolar disorder indicated that pairs with bipolar II were surprisingly homogeneous, whereas pairs with bipolar I were not. Allele sharing was 100 percent for bipolar II, but only 50 percent (i.e., no more than chance) for bipolar I disorder. These findings suggest that the gene on 18q underlies bipolar II and not bipolar I disorder. A current study of differences in treatment response may reveal subtypes of bipolar disorder by finding genetic differences between patients who do and do not respond to lithium. In time, the treatment-response studies will also expand the information base on different genetic forms of affective disorders. Dr. McMahon stated that the future will bring studies on seasonal affective disorder and rapid cycling.

References provided by Dr. McMahon

Blackwood DHR, He L, Morris SW, et al: A locus for bipolar affective disorder on chromosome 4p. Nat Genet 12: 427-430, 1996.MacKinnon DF, McMahon FJ, Simpson SG, et al: Panic disorder with familial bipolar disorder. Biol Psychiatry (In Press).McInnis MG, McMahon FJ, Chase GA, et al: Anticipation in bipolar affective disorder. Am J Hum Genet 53: 385-390, 1993.McMahon FJ, Stine OC, Myers DM, et al: Patterns of material transmission in bipolar affective disorder. Am J Hum Genet 56:1277-1286, 1995.Stine OC, Xu J, Koskella R, McMahon FJ, et al: Evidence for linkage of bipolar disorder to chromosome 18 with a parent-of-origin effect. Am J Hum Genet 57:1384-1394, 1995.

_________________

1 Presented at the DRADA/Johns Hopkins symposium, Baltimore, Maryland, April 1997

2 Assistant Professor of Psychiatry and of Neuroscience, Johns Hopkins University School of Medicine .

by Anne M. Bain, Ed.D.
Smooth Sailing: Spring 1997

For information about the Johns Hopkins genetic study of manic depression: www.med.jhu.edu/bipolar/

No Comments »

No comments yet.

RSS feed for comments on this post. TrackBack URL

Leave a comment

Name (required)

Mail (will not be published) (required)

Website