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

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

In This Article

Abstract & Introduction

The identification of the genes responsible for major psychiatric illnesses such as bipolar disorder would greatly enhance our understanding of etiology, as well as open new avenues for the development of more specific and effective treatments. Narrowing the focus of the search to determine which parts of the genome to study for susceptibility loci is an important problem in the performance of molecular genetic studies. With the advent of polymorphic DNA markers, linkage and association studies have become more useful methods for the genetic analysis of complex behavioral disorders. However, linkage studies of bipolar disorder have met with mixed success, a potentially more efficient strategy is to examine candidate regions that have been identified through the association of bipolar disorder with rare or uncommon genetic syndromes that are relatively well characterized at the molecular level. Velo-cardio-facial syndrome (VCFS), a congenital multiple anomaly syndrome caused by abnormalities on chromosome 22, has been found in 2 discrepant diagnostic studies to be associated with bipolar disorder and also schizophrenia. In an effort to further delineate the common presentation of bipolar spectrum conditions and the evolution of symptoms from childhood through adolescence, the current report describes in some detail the VCFS behavioral and psychiatric phenotype.

Although there is compelling evidence from twin, family, and adoption studies to support strong genetic determinants for bipolar affective disorder,[1,2,3,4,5] the underlying molecular-genetic basis for this condition remains poorly understood. The identification of the genes responsible for major psychiatric illnesses such as bipolar disorder would greatly enhance our understanding of etiology, as well as open new avenues for the development of more specific and effective treatments.

Many studies using segregation analysis (see Glossary of Genetic Terms) have proved inconclusive in the determination of a mode of genetic transmission for bipolar disorder, although a few have lent support to an autosomal dominant model.[6,7] While bipolar disorder exhibits some familiarity, the illness does not appear to be inherited according to mendelian rules--that is, 1 gene, 1 trait--and it is well known that complex traits or diseases, like intelligence or diabetes, that show no simple mendelian pattern of inheritance are unlikely to yield simple genetic answers.

A number of factors contribute to the complexity of the genetics of bipolar disorder. One factor is reduced penetrance. Penetrance refers to the probability that a person will manifest the disease if they have the gene. The clearest evidence of reduced penetrance is the observation that the concordance rate for monozygotic ("identical") twins with bipolar disorder is less than 100%. For this to be the case, the unaffected identical twin must carry the gene but not manifest the illness. This makes it difficult to determine who may or may not carry the illness-causing allele in families and therefore complicates the linkage and segregation analyses.

In addition to the genetic complexities, there are no specific biologic markers that identify bipolar disorder. Uncertainties about the best definition of disease phenotype, variable expression of the illness, difficulties in the assessment of lifetime diagnosis, and the perplexities of variable age of onset are among the critical issues that play a confounding role in the performance of genetic association and linkage studies. Perhaps the most significant confounding factor is genetic heterogeneity. Taken together, these factors may in large measure account for the lack of replication of studies that have reported positive associations between the illness and a linked marker.[8,9,10,11]

Unlike simple mendelian disorders caused by highly penetrant but rare functional polymorphisms (mutations) in a single gene, the genetic component of complex psychiatric disorders is more likely to be associated with low penetrance but common functional variations in a number of susceptibility genes. In such a model, multiple genes with small effect may contribute to a predisposition for bipolar disorder in an affected individual. These multiple gene effects can contribute additively and interchangeably, like risk factors, to the vulnerability to develop a disorder.[12] There may be combined groups of symptoms from different but related disorders, which are the expression of the genotypic variation that accounts for the genetic influence in bipolar disorder.

Testing such a view would require eschewing criteria specified in DSM-IV for diagnosing bipolar disorder, and instead attempting to determine whether linkage exists between a related group of behavioral traits common to bipolar disorder--for example, prominent cyclic switches in energy and activity levels (rapid switches in mood and arousal states), pronounced tendency to retain and experience extreme separation anxiety throughout life, craving for sweets and carbohydrates, and the predisposition to phase-shift circadian rhythms or the lack of a capacity to modify or stop certain repetitive behaviors and thoughts. This quite different view of the problem would lead to the question, can a gene modify a rather specific group of behaviors that have some developmental program and are associated with bipolar disorder, rather than whether a gene or genes are associated with a common group of symptoms.

The first step in proving the existence of a genetic component for a specific psychiatric illness is the demonstration of familial aggregation that cannot be explained by nongenetic factors. The "classic" methods of psychiatric, or more broadly, behavioral genetics include twin studies, adoption studies, and studies of recurrence risks, or morbid risks, in relatives of patients.

A second step is to find evidence that familial patterns of illness are consistent with a specific genetic model. It is at this point that the complexities of psychiatric disorders become serious obstacles, because the simple genetic models--autosomal recessive, autosomal dominant, X-linked dominant, and X-linked recessive--must be modified to account for nongenetic factors. The final and most convincing level of genetic evidence, short of identification of the gene itself, is the demonstration of linkage to a known, and preferably mapped, genetic marker.

Genetic linkage is defined as the violation of Mendel's law of independent assortment. That law states that alleles (ie, different forms of a gene) at 2 chromosomal locations (ie, 2 loci) will assort independently and be transmitted to offspring in random combinations.[10] Two traits segregate together in families because the genes that determine the 2 traits are located near one another on a chromosome. The degree of cosegregation is directly related to the proximity of the 2 genes on the chromosome. This requires observation of cosegregation or linkage of a genetic trait marker, such as color-blindness or a specific polymorphic chromosomal marker, with the disorder in families.[10] With the advent of polymorphic DNA markers, linkage and association studies have become more useful methods for the genetic analysis of complex behavioral disorders such as bipolar disorder.

A commonly used contemporary strategy combines the traditional techniques of genetic linkage analysis with the power of modern recombinant DNA techniques to search for a single common mutation that cosegregates or is inherited with the illness in informative families. However, conventional linkage analysis of multigenerational pedigrees is unlikely to have sufficient power to detect a gene unless the gene accounts for most of the genetic variance for the disease or trait being studied. This does not appear to be the case for bipolar disorder. No single gene appears to account for the majority of the genetic variance.

Linkage studies of bipolar disorder have met with mixed success. An initial report of linkage on the short arm of chromosome 11 was revised, after widening the investigation, to encompass lateral extensions of the original pedigree. After follow-up diagnostic evaluations, it was determined that 2 subjects previously diagnosed as unaffected had late onsets of illness.[6,9,10,13] Reports that have proposed cosegregation of genes found on the X chromosome with bipolar disorder[14] have not been replicated.[15,16] More recently, bipolar disorder has been reported to be linked with markers on chromosomes 18,[17,18] 21,[19,20] 16,[21] and 22.[22,23] The statistical evidence for linkage, however, is unconvincing, and further studies using more closely linked markers in additional multigenerational pedigrees will be required to confirm any of these findings.

Although the entire genome has not been screened for linkage with bipolar disorder, it is conceivable that there are no genes of major effect to be found despite clear evidence for genetic influence demonstrated in twin and adoption studies. Newer linkage methods, such as sib-pair analysis, which do not depend on mode of inheritance assumptions, can detect genes of somewhat smaller effect. However, these methods still depend on the model that a single gene explains most of the genetic effects on the trait, especially if sample sizes are not large.[12]

Narrowing the focus of the search to determine which parts of the genome to study for susceptibility loci is an important problem in the performance of molecular genetic studies. A random or systematic search of the entire genome depends on the single gene diathesis model and requires a multitude of well-diagnosed and informative, multigenerational families. Initiating and then replicating such studies will prove to be costly.

Another potentially more efficient strategy is to examine candidate regions that have been identified through association of bipolar disorder with rare or uncommon genetic syndromes, which are relatively well characterized at the molecular level. Medical genetics has often benefited from observations in circumstances where well-defined mendelian traits or chromosomal aberrations have served as clues for uncovering general disease mechanisms.

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