Chromosomal Abnormalities and Bipolar Affective Disorder: Velo-Cardio-Facial Syndrome

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Medscape Psychiatry & Mental Health eJournal. 1997;2(4) 

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Allelic Association Studies: The Importance of Accurate Diagnosis

Allelic association studies, which determine correlations in the population between a particular phenotype and an allele, are usually assessed as an allelic or genotypic frequency difference between cases and controls.[12] A number of studies that aim to examine the association between specific behavioral phenotypes identified by diagnostic studies of VCFS patients and potential candidate genes from the 22q11 region have been completed or are under way[38,40,41,42] (Papolos, submitted for publication). Several such association studies have already given an indication that a pathophysiologic relationship exists between individuals who are homozygous, or in the case of VCFS, hemizygous for the gene that produces the low-activity form of the COMT enzyme (Met-158) and several discrete psychiatric or "behavioral" phenotypes. This finding suggests that a complex of behaviors are linked by a single functional polymorphism that alters the catabolic rate of dopamine, norepinephrine, and epinephrine degradation.

In an extension of the initial psychiatric diagnostic study of VCFS, which identified a strong association between bipolar disorder and the syndrome,[40] a positive allelic association has been found between the Met-158 variant of COMT and the rapid-cycling variant of bipolar disorder in 8 of 8 VCFS patients.

Prompted by these findings, investigators examined patients with de novo rapid-cycling bipolar disorder from the general population to determine whether there was an increased frequency of the low-activity COMT allele within that subgoup. In a pilot study of non-VCFS rapid cyclers (N=9), Papolos and associates (submitted for publication) have found a significant association (75%) between the ultra-rapid subtype of bipolar disorder and the frequency of the low-activity COMT allele. This means that of the 18 known alleles of the COMT gene, 75% of a group of 9 ultra-rapid cyclers carried the Met-158 form. In the Caucasian population, the COMT Met-158 allele frequency has been measured at 42% to 45%.[36] If this finding is replicated, and the frequency of the low-activity COMT allele is indeed significantly greater in patients with the rapid-cycling variant of bipolar disorder, then this polymorphism may represent a modifying gene that predisposes to 2 forms of rapid cycling.

Recently, Karayiorgou and coworkers[41] reported a significant association (64%) between the Met-158 low-activity COMT allele and obsessive-compulsive disorder (OCD) in males. In this regard, it is notable that over 85% of the de novo ultra-rapid cyclers (non-VCFS and VCFS) (N=17)[34] (D.F. Papolos, MD, unpublished data, 1997) were observed to have comorbid obsessive-compulsive and anxiety symptoms. Lachman and associates[43] found a significant association between the COMT Met-158 allele and aggression in patients diagnosed with schizophrenia.

Efforts to establish linkage for specific psychiatric disorders to the 22q11 region--that is, the real potential for allelic association studies to find gene polymorphisms that influence behavioral traits or predispose to psychiatric illness in this region, and the treatment implications for VCFS--will all depend on accurate psychiatric characterization of the VCFS phenotype.[44] It is important to resolve the current diagnostic controversy.[42,43,45] In an effort to further delineate the common presentation of bipolar spectrum conditions and the evolution of symptoms from childhood to adolescence and adulthood that we observed,[34] the current report describes in some detail the VCFS behavioral phenotype (see box, Case Reports).

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