by
|
by |
|
| This article will appear in a forthcoming issue of Trends in Molecular Medicine. | |
Abstract
Schizophrenia, a complex brain disorder, is characterised by a wide range of signs and symptoms that reflect disturbances in cognitive, emotional, perceptual, and motor processes [1]. From the earliest formal descriptions of schizophrenia over a century ago, affected individuals were recognized to differ substantially in the particular profile of clinical features that they exhibited and in the severity and course of their illness. This clinical heterogeneity, in concert with the more recent identification of differences across individuals in the presence and magnitude of various brain abnormalities, has lead to the opinion that what we diagnose clinically as schizophrenia encompasses a set of disorders that differ with respect to their underlying causes and mechanisms of disease.
Etiology of Schizophrenia
Given the complexity of the disorder, it is not surprising that the identification of specific etiological factors in schizophrenia continues to present a great challenge. Available data indicate that genetic, environmental, and developmental factors all contribute to the risk of developing schizophrenia. In contrast to the 1 percent lifetime incidence of schizophrenia in the general population, the incidence of schizophrenia in the relatives of affected individuals increases with the percentage of shared genes [2]. For example, when one member of a twin pair has the illness, the risk of schizophrenia in the other twin is approximately 17 percent for fraternal twins and approaches 50 percent for identical twins. In addition, among adoptees, the risk of schizophrenia is related to the presence of the illness in the biological, but not in the adoptive, parents [3]. However, these data suggest that genetic factors are not sufficient for the appearance of the illness. Several environmental factors, usually occurring early in life, also appear to increase the risk for schizophrenia. These include severe maternal malnutrition during the first trimester, maternal influenza during the second trimester of pregnancy, and perinatal brain damage or maternal preeclampsia [4], although it should be noted that most individuals with a history of these problems do not develop schizophrenia. Finally, the delay in appearance of the clinical features of schizophrenia until the late teens or early 20s probably reflects the role of developmental processes in the pathogenesis of this illness [5,6].
Thus, the current data suggest that schizophrenia encompasses a heterogeneous group of disorders whose etiopathogenesis involves the interplay of complex genetic influences and environmental risk factors operating on brain maturational processes. Investigations of genetic factors have implicated a number of chromosomal loci as sites of potential susceptibility genes [7]. However, positional cloning approaches have yet to translate these linkage data into reliable single-gene findings, and the list of potential schizophrenia risk genes is currently composed of only a few candidates, including REELIN [8], DISC1-2 [9], KCNN3 [10], and NOTCH-4 [11]. Unfortunately, even these candidates fail to show a consistent signal across different groups of subjects [12,13]. Clearly, the pursuit of genes that influence (but are unlikely to determine) the appearance of schizophrenia is confounded both by the clinical heterogeneity of the illness and by the fact that, despite the evidence for a genetic basis of schizophrenia, over 60 percent of affected individuals have neither a first nor second degree relative afflicted with schizophrenia [14].
Periodic catatonia
One strategy for identifying susceptibility genes is to study families with multiple affected individuals who share a clinical subtype of schizophrenia that appears to be more homogeneous than the broader disorder. Meyer and colleagues [15] recently used this approach to identify a novel gene in a family with a subtype of schizophrenia termed periodic catatonia. Catatonia, a nonspecific clinical syndrome that occurs in other psychiatric disorders (such as bipolar disorder), refer to psychomotor disturbances that can be either akinetic and stuporous, or hyperkinetic and excited. Periodic catatonia was identified as a subtype of schizophrenia by Karl Leonhard. In this classification scheme, Leonhard recognized both "systematic schizophrenias," which encompass the majority of individuals with schizophrenia, and "unsystematic schizophrenias," which refers to three relatively rare forms of illness, including periodic catatonia [16]. Leonhard described periodic catatonia as an independent disorder with considerable hereditary loading that was characterized clinically by alternating hyperkinetic and akinetic states, with hallucinations and delusions present early in the course of illness.
In a previous study of periodic catatonia, a genome scan of 12 multiplex pedigrees revealed evidence for significant linkage on chromosome 15q15 and suggestive evidence of linkage on chromosome 22q13, the latter finding supported principally by a single large family [17]. Within this family, Meyer and colleagues [15] identified a novel gene at the 22q13 locus comprising 12 exons spanning over 28 Mb. This gene, called WKL1, appears to encode a cation channel that is distantly related to the shaker potassium channel subfamily [18]. Meyer et al. [15] found that a 1121 C→A transversion encodes a missense mutation of Leu→Met in the coding region that probably corresponds to the transmembrane portion of the ion channel. In the single pedigree examined, seven of 17 family members heterozygous for the mutation had periodic catatonia, whereas none of six family members homozygous for the wild-type gene was affected, suggesting a major role for the mutation in the development of the disease phenotype. This finding is of particular interest because there are no other known schizophrenia susceptibility genes where the mutation and a specific clinical syndrome co-segregate with this strength. However, as noted above, other genetic, environmental, and/or developmental factors, in addition to the mutation in WKL1, must also be required for the appearance of periodic catatonia; some individuals carrying the mutated allele did not manifest the illness (figure 1).
In a broader context, the study of Meyer et al. [15] raises questions regarding current strategies for characterizing the molecular basis of complex brain disorders, such as schizophrenia. Given the evidence for a polygenic basis for the illness, informative linkage analyses might often have to be performed at the level of families, reducing the statistical power of these investigations. Indeed, even within subtypes of schizophrenia, the genetic vulnerability is likely to be different. As noted above, in a larger cohort of subject with the periodic catatonia, a different locus (15q15) showed a much stronger association with the illness, with a logarithm of odds (LOD) score of 3.57 (indicating a very high probability of linkage). The 22q13 linkage caused by the WKL1 abnormality was weaker (with a LOD score of 1.85). However, the study of Meyer et al. [15] clearly associated the mutation in WKL1 with familial catatonic schizophrenia in the family studied. Indeed, the result of previous studies suggests that in addition to WKL1, there might be several other schizophrenia susceptibility genes present on chromosome 22q11-13 (reference 19).
Disease Subtypes Provide Useful Genetic Markers
The findings of Meyer et al. [15] might also serve as an informative example of a subtype of a complex illness where the frequency of a gene defect is rare, but it makes a major contribution to the development of the distinguishing phenotype of the illness subtype. In searching for genes that play a major role in complex disorders, one might argue that defects in different genes whose protein products perform similar functions (e.g., ionic homeostasis) will result in some shared clinical manifestations. Interestingly, mutations in other K+-channel-encoding genes (KCNA1 and KCNQ2-3) lead to episodic ataxia/myokimia and neonatal epilepsy [20,21] - clinical syndromes that bear some pathophysiological relationships to the akinetic and hyperkinetic features of periodic catatonia. These phenotypic similarities might also support the suggestion that the mutation in WKL1 is more likely to be responsible for the distinctive psychomotor component of periodic catatonia than for the psychotic symptoms and cognitive deficits that are common to the wider population of subjects with schizophrenia.
The number of schizophrenia susceptibility genes is unknown [19,22], but it might be quite large. Thus, it is possible that the association of schizophrenia with a given chromosomal locus might be the consequence of several different genes in that region, each of which is weakly associated with the illness. However, when these non-significant linkages to individual genes are combined at the locus level, they could reach statistical significance. If this were the case, linkage studies involving heterogeneous groups of subjects with schizophrenia with many different molecular signatures would yield only occasional, cohort-dependent results, perhaps like those seen across the existing literature [7]. Defects in different combinations of genes, which converge on the same functional pathway, could lead to a common, diagnostically-reliable, clinical phenotype, yet with differences across individuals in specific clinical features [23]. Because of the currently unknown number of susceptibility factors and potential protective genes, studies of large pedigrees, more homogenous cohorts with narrower subtypes of schizophrenia, as well as subjects with disease-associated traits (e.g. endophenotypes [14]) will be a major focus of ongoing and future studies. The combined outcome of such studies could have a greater likelihood of reducing the effect of genetic heterogeneity and, thus of uncovering the genetic bases for schizophrenia.
Searching for Schizophrenia Genes - a review of molecular-genetic approaches. From Trends in Molecular Medicine, 2001, 7:4:169-174. Full text available from BioMedNet.
Nuts and Bolts of Psychiatric Genetics: Building on the Human Genome Project - a review of genetic strategies in the identification of candidate genes for the major psychoses. From Trends in Genetics, 2001, 17:1:35-40. Full text available from BioMedNet.
Pharmacogenomics of Psychiatric Disorders - a review of recent research and future directions. From Trends in Pharmacological Sciences, 2001, 22:2:75-83. Full text available from BioMedNet.
Schizophrenia Research Topics - a comprehensive site for searching the scientific research on schizophrenia, from Internet Mental Health.
Schizophrenia - general information from the National Institute of Mental Health. Includes press releases, editorials, congressional testimony, and various publications.
Related HMS Beagle article: