schizophrenia reviewed: toward an integrative genetic model

Schizophrenia Reviewed: Toward an Integrative Genetic ModelSchizophrenia Genesis: The Origins of Madness by I. I. Gottesman; Schizophrenia: EmpiricalResearch and Findings by E. R. Straube; R. D. OadesReview by: William G. Iacono and William M. GrovePsychological Science, Vol. 4, No. 5 (Sep., 1993), pp. 273-276Published by: Sage Publications, Inc. on behalf of the Association for Psychological ScienceStable URL: http://www.jstor.org/stable/40063045 .

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Schizophrenia Genesis: The Origins of Madness, by I.I. Gottesman. New York: W.H. Freeman & Co., 1991. 350 pp. + xiii. $24.95. Schizophrenia: Empirical Research and Findings, by E.R. Straube and R.D. Oades. San Diego: Academic Press, 1992. 637 pp. + xiii. $99.00.

List of Books

PSYCHOLOGICAL SCIENCE

Feature Review

Schizophrenia Reviewed: Toward an Integrative Genetic Model

William G. Iacono and William M. Grove University of Minnesota

At no time in the history of schizophrenia research have the expectations for new discoveries that might elucidate the causes of this baffling disorder been so high. Much of this hopefulness stems from recent advances in neuroscience and molecular biology that provide tools for exploring schizophrenia that were unimagined two decades ago. The ex- citement generated by the opportunities these new procedures offer has begun to dominate current research. This was clearly evident at the 1993 meeting of the International Congress on Schizophrenia Research, at which over 70% of the nearly 400 poster presentations involved biological themes.

The promise of new technology not- withstanding, these two Feature Review books, which together give a comprehensive overview of schizophrenia research, provide a sobering reminder of just how elusive progress has been in this field. The past 100 years of investigation have contributed little to unravel the mysteries of this disorder. In a field in which replication failure is the rule rather than the exception, few correlates of the disorder are generally accepted as reproducible, and fewer still have potential as etiologic clues.

SOME FACTS ABOUT SCHIZOPHRENIA

The most encouraging line of investigation derives from family, twin, and adoption studies. These reports have established beyond reasonable doubt that genes somehow contribute to the etiol- ogy of schizophrenia and related spec- trum disorders. No specific environmental factor has been shown to be sufficient to cause schizophrenia. However, the

high degree of discordance for schizophrenia among monozygotic twins (per- haps 50%) indicates unequivocally that there is a significant environmental con- tribution. How the environment inter- acts with genetic risk to trigger the development of schizophrenia remains unknown.

To determine how the genetic diathe- sis for schizophrenia is transmitted, psy- chopathologists have used quantitative and biological strategies such as segregation and linkage analysis. In segregation analysis, family data are used to evaluate models positing effects of single genes, polygenic aggregates, and combinations thereof. These models are now easily fit by computer programs that allow for sex-modified effects, reduced pene- trance, variable age of onset, and the influence of other variables, such as environmental factors, on risk of illness. Models of schizophrenia that posit a single gene acting alone cannot account for observed family data. Polygenic and mixed models, the latter involving both a major gene and polygenes, are accom- modated equally well. The revolution in molecular biology makes it possible to use linkage analysis to determine if the presence of schizophrenia is correlated with chromosomally localized DNA within families. However, the numerous linkage studies conducted to date have failed to generate meaningful leads con- cerning the genetics of schizophrenia.

The evidence supporting these conclusions is summarized in both of the featured volumes. Gottesman's book, which updates his earlier thought- provoking reviews of the relevant behavioral genetic literature, provides an especially thorough treatment of this subject

matter despite being written for a general audience. Comparing this current vol- ume and his other books, however, re- veals that recent research has provided few new insights into the genetics of schizophrenia. Data consistent with the findings noted above have been available for decades. Recent studies have merely reaffirmed earlier findings with sounder methodology and modern diagnostic criteria.

Straube and Oades 's scholarly book provides a more extensive treatment of the schizophrenia literature, including coverage of theories, neurophysiology, neuroanatomy, psychophysiology, information processing, and longitudinal high-risk investigations. Our interpreta- tion of their review leads to the following broad conclusions about the state of the field.

Theory

There is no plausible, comprehensive theory of schizophrenia that can account for its many manifestations. What theories there are tend to deal only with cer- tain aspects of the disorder (e.g., atten- tion, specific symptoms), have small folio wings, have limited heuristic value, and be difficult to falsify. A prime example of a popular theory with some of these attributes is the vulnerability- stress theory, which states that constitu- tional predisposition and environmental stress combine to cause schizophrenia. As difficult as it is to argue against such a commonsense notion, it is also difficult to generate falsifiable hypotheses from it.

Neurophysiology

The neurochemistry of schizophrenia is too complex to be explained easily by activity in a single neurotransmitter system. The 30 years of intensive effort spent pursuing the dopamine hypothesis make it seem likely that dopamine is involved in schizophrenia in some way. However, there is still no incontestable demonstration that the biochemical basis of schizophrenia rests with disturbed do- paminergic functioning. For example, recently, Su et al. (1993) failed to find any evidence for genetic linkage between the

Address correspondence to William G. Ia-

cono, Department of Psychology, University of Minnesota, 75 East River Rd., Minneapo- lis, MN 55455-0344.

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Schizophrenia Reviewed

dopamine D2 receptor and schizophrenia.

Neuroanatomy

Although there has been no consistent demonstration of a brain lesion or dysfunction associated with schizophrenia, the large number of studies reporting a variety of brain anomalies can be taken to indicate that at least a subgroup of schizophrenics have some type of abnormality in the central nervous system. Static and functional imaging as well as neuropsychological studies point to the frontal lobes as a likely site.

Psychophysiology

Schizophrenic patients, especially those with chronic schizophrenia, have been shown repeatedly to be electro- dermally nonresponsive to innocuous stimuli, have excess low-frequency elec- troencephalographic activity and dimin- ished alpha (especially frontally), have reduced amplitudes of the late components (P300) of the event-related potential, have deficient sensory gating as indicated by a failure to suppress the sec- ond in a series of early brain potentials (P50) in an auditory conditioning para- digm, and have dysfunctional smooth- pursuit eye tracking. Other than there being familial resemblance for some of these measures in the relatives of people with schizophrenia, the significance of these observations remains unclear because they have few well-established correlates.

Information Processing

Although attentional disturbance has long been viewed as a core component of schizophrenia, no specific, clearly delin- eated attentional deficit is known to characterize schizophrenia. This area of research has generated some well- established experimental paradigms in which both schizophrenics and their relatives have been noted to perform aber- rantly. Chief among these paradigms are the continuous performance, span of apprehension, and reaction time crossover tasks.

Longitudinal High-Risk Studies

Investigations of the offspring of schizophrenic parents have yet to shed important insights into the development of this disorder, in part because the stud- ied offspring are still passing through the age of risk and in part because some of the variables commonly examined in schizophrenic adults may not be age- appropriate for children. High-risk children have been found to perform poorly on span of apprehension and continuous performance tasks.

Markers of Genetic Vulnerability

A number of variables, because they have been shown to be deviant in both schizophrenic patients and their well relatives, have been considered as possible indicators of genetic liability for schizophrenia. The single best such measure is smooth-pursuit eye-tracking dysfunction, which has been associated with schizophrenia without exception in more than 40 reports worldwide and found in the relatives of schizophrenics in over 15 studies without failure of replication. Other promising variables with marker potential derive from the span of apprehension and continuous performance tasks, the reaction time crossover effect, and event-related potential paradigms involving P50 and P300 brain potentials.

Where do investigators go from here? Neither of the books under review tack- les this question directly, nor does either make much of an attempt to integrate material across research domains. The implication is that future research should attempt to resolve esoteric issues related to the types of narrowly defined topics highlighted above. Alternatively, as Gottesman concludes in his final chap- ter, researchers can wait to see if new technologies yield breakthroughs that can guide them to important answers about schizophrenia.

AN INTEGRATIVE MODEL FOR GENETIC RESEARCH IN SCHIZOPHRENIA

In our view, another strategy is possible, one that integrates and builds on the handful of encouraging findings doc- umented above. The key to this integra-

tive approach rests with the fact that schizophrenia arises from an inherited predisposition and that biobehavioral markers of genetic vulnerability exist and may identify gene carriers without our having to rely on the appearance of clinical schizophrenia to identify cases. To date, markers have not gained wide- spread acceptance for their potential as tools for understanding the genetics of schizophrenia. This is no doubt in part because the theories linking them to schizophrenia are weak, and because the genetics of the candidate markers are poorly understood. Nevertheless, there is a strong empirical association between some markers and genetic risk for schizophrenia, and the markers them- selves may be interrelated in a way that ties together many of the findings noted above.

Empirical Background

Although our model builds on the ideas and research of other people, our formulation, strongly influenced by our own recent investigations of smooth- pursuit eye tracking, is unique. Our studies, which have been summarized in more detail elsewhere (Iacono & Clem- entz, 1993), indicate the following:

• Smooth-pursuit eye-tracking dysfunction is bimodally distributed in both individuals with schizophrenia and their first-degree biological relatives (Clem- entz, Grove, Iacono, & Sweeney, 1992; Iacono, Moreau, Beiser, Flem- ing, & Lin, 1992). Such a discontinuity in the distribution of eye-tracking performance is consistent with the hypothesis that a single major gene influences pursuit tracking ability.

• Eye-tracking dysfunction is present in only about 50% to 60% of all families with a schizophrenic member (Clem- entz et al., 1992; Iacono et al., 1992). This finding indicates that eye tracking may not be an informative genetic vulnerability indicator for all cases of schizophrenia.

• Among nonorganic psychotic disorders, deviant smooth-pursuit tracking appears to be specific to schizophrenia and related psychoses (Iacono et al., 1992). Among the relatives of schizo-

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William G. Iacono and William M. Grove

phrenics, aberrant pursuit is associated with schizotypal features, especially odd social-interpersonal behavior (Clementz et al., 1992; Grove etal., 1991).

• Schizophrenic patients with deviant smooth pursuit are different from those with normal pursuit in several ways. They show impairment on neuropsychological tasks indicative of frontal lobe disturbance, but not on selected neuropsychological and cogni- tive tests sensitive to dysfunction in other brain areas (Katsanis & Iacono, 1991), a finding that is consistent with the fact that the frontal lobes play a role in the control of eye movements. They also are more likely than normal- tracking schizophrenics to have nega- tive symptoms of schizophrenia, such as flat affect, paucity of expressive gestures, anhedonia, and poverty of speech (Katsanis & Iacono, 1991).

• The pattern of genetic cross- correlations, in which one relative's score on a variable is correlated with the score of other relatives on a different variable, indicates that deficient pursuit tracking, schizotypal features, and abnormal behavior on continuous performance tasks run together in families with a schizophrenic member (Grove et al., 1991). These results suggest that common genetic causes may underlie diverse schizophrenia-related abnormalities.

• Complex segregation analysis carried out on the eye tracking of schizophrenics and their relatives revealed that a model positing a major gene plus poly genes fits the data (Grove, Clem- entz, Iacono, & Katsanis, 1992). The major gene, which accounted for 67% of the variance, tended strongly toward recessivity. Models hypothesiz- ing a single major gene for eye tracking (including a dominant gene) or polygenes acting alone could be re- jected.

The Model

Our model integrates findings on genetics, psychophysiology, information processing, and neuropsychology. It combines a formal genetic mechanism

with several abnormalities seen in the families of schizophrenics.

Our model has the following genetic components:

• a major gene (or a few genes),

• polygenic factors potentiating or ame- liorating effects of the major gene(s), and

• random environmental effects.

Our genetic model is similar to Meehl's (1962), but we conjecture a recessive gene, whereas he supposed dominance. Our conjecture better fits our own data, as well as results summarized by Fara- one and Tsuang (1985), who found that single major locus and mixed genetic models postulating a recessive patho- gene provided the best data fit.

Our model encompasses several abnormalities seen in schizophrenics' families:

• narrowly diagnosed schizophrenia,

• schizotypal personality,

• eye-tracking dysfunction,

• attentional dysfunction, and

• deficits on neuropsychological tests sensitive to frontal convexity lesions.

We assume that all of these traits are strongly influenced by one gene (or at most a very few strong genes) and also be a collection of individually weak, but collectively important, polygenes. The pleiotropic action of the major gene (i.e., the simultaneous influence of this gene on all of these characteristics) accounts for these traits in schizophrenics and in their relatives, and also for the traits' running together in families. We initially conjecture that the major gene is primar- ily responsible for each abnormality, with the polygenes of distinctly lesser significance.

We emphatically exclude the idea that all (or almost all) clinically schizophrenic individuals have deleterious alleles at the postulated major gene locus. Instead, we propose that only about half of all schizophrenics carry this major gene. The other half of patients diagnosed as schizophrenic have a different disorder, involving different genes or other etiol-

ogy. Families in which our single gene is operating can be probabilistically identi- fied by the presence of secondary cases of schizophrenia, by relatives having schizotypal features, or by family members showing clear-cut eye-tracking dysfunction. In this respect, our model dif- fers from Meehl's and that of Matthysse, Holzman, and Lange (1986); they pro- posed a dominant major gene as (nearly) sine qua non for all schizophrenics. By contrast, our model embraces genetic or etiologic heterogeneity. If substantially correct, our model points the way to eventual identification of a discrete cause for a large subgroup of people with schizophrenia.

Our model is testable using modern behavior genetic techniques such as segregation and linkage analysis applied not to schizophrenia families generally, but to the subset of families containing both schizophrenia and eye-tracking dysfunction. An advantage of our genetic model is that this evaluation strategy is more economical and efficient than the traditional method for identifying the genetic mechanism underlying schizophrenia. The latter approach is predicated on the use of large samples involving families with multiply affected members. Sample sizes must be especially large if, as many investigators believe, schizophrenia is etiologically heterogeneous. However, as Gottesman has pointed out, few schizophrenics have any affected relatives, a fact that raises questions about the feasibility of the traditional approach and the generalizability of findings (because the results are based on the study of exceptional families). Our research strategy, by focusing on families with both schizophrenia and eye-tracking dysfunction, homogenizes the study sample by including only the 50% of schizophrenics who carry the major gene. It also greatly increases the repre- sentativeness and yield of data because we are not dependent on the identification of manifest schizophrenia in family members to test the model. Any patients with living relatives who are willing to undergo a clinical interview and an ob- jective assessment of ocular motor ability would be suitable for our purposes.

Note that our list of indicator traits is not exhaustive. Other traits of interest might include, for example, reaction time crossover (DeAmicus & Cromwell,

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Origins of Schizophrenia

1979), sensory gating (Siegel, Waldo, Mizner, Adler, & Freedman, 1984), and span of apprehension (Wagener, Hog- arty, Goldstein, Asarnow, & Browne, 1986). The point is that our model can integrate diverse findings of abnormality in schizophrenics and their relatives, and can in principle explain such findings by a relatively simple genetic mechanism. Such a model is eminently falsifiable, is quite extensible, and (not unimportant) also offers a central role for psycholo- gists in the exploration of the genetics of schizophrenia.

REFERENCES

Clementz, B.A., Grove, W.M., Iacono, W.G., & Sweeney, J.A. (1992). Smooth-pursuit eye movement dysfunction and liability for schizophrenia: Implications for genetic modeling. Journal of Abnormal Psychology, 101, 117- 129.

DeAmicus, L.A., & Cromwell, R.L. (1979). Reac- tion time crossover in process schizophrenic patients, their relatives, and control subjects.

Journal of Nervous and Mental Disease, 167, 593-600.

Faraone, S.V., & Tsuang, M.T. (1985). Quantitative models of the genetic transmission of schizophrenia. Psychological Bulletin, 98, 41-66.

Grove, W.M., Clementz, B.A., Iacono, W.G., & Katsanis, J. (1992). Smooth pursuit ocular motor dysfunction in schizophrenia: Evidence for a major gene. American Journal of Psychiatry, 149, 1362-1368.

Grove, W.M., Lebow, B.S., Clementz, B.A., Cerri, A., Medus, C, & Iacono, W.G. (1991). Famil- ial prevalence and co-aggregation of schizotypy indicators: A multi-trait family study. Journal of Abnormal Psychology, 100, 115- 121.

Iacono, W.G., & Clementz, B.A. (1993). A strategy for elucidating genetic influences on complex psychopathological syndromes (with special reference to ocular motor functioning and schizophrenia). In L.J. Chapman, J.P. Chap- man, & D. Fowles (Eds.), Progress in experimental personality and psychopathology research: Vol. 16 (pp. 11-65). New York: Springer.

Iacono, W.G., Moreau, M., Beiser, M., Fleming, J.A.E., & Lin, T.-Y. (1992). Smooth-pursuit eye tracking in first-episode psychotic patients and their relatives. Journal of Abnormal Psy- chology, 101, 104-116.

Katsanis, J., & Iacono, W.G. (1991). Clinical,

neuropsychological, and brain structural correlates of smooth-pursuit eye tracking performance in chronic schizophrenia. Journal of Abnormal Psychology, 100, 526-534.

Matthysse, S., Holzman, P.S., & Lange, K. (1986). The genetic transmission of schizophrenia: Application of Mendelian latent structure analysis to eye tracking dysfunctions in schizophrenia and affective disorder. Journal of Psy- chiatric Research, 20, 57-76.

Meehl, P.E. (1962). Schizotaxia, schizotypy, schizophrenia. American Psychologist, 17, 827-838.

Siegel, C, Waldo, M., Mizner, G., Adler, L.E., & Freedman, R. (1984). Deficits in sensory gating in schizophrenic patients and their relatives. Archives of General Psychiatry, 41, 607- 612.

Su, Y., Burke, J., O'Neill, F.A., Murphy, B., Nie, L., Kipps, B., Bray, J., Shinkwin, R., Nuallin, M.N., MacLean, C.J., Walsh, D., Diehl, S.R., & Kendler, K.S. (1993). Exclusion of linkage between schizophrenia and the D2 dopamine receptor gene region of chromosome llq in 112 Irish multiplex families. Archives of Gen- eral Psychiatry, 50, 205-211.

Wagener, D.K., Hogarty, G.E., Goldstein, M.J., Asarnow, R.F., & Browne, A. (1986). Infor- mation processing and communication devi- ance in schizophrenic patients and their moth- ers. Psychiatry Research, 18, 365-377.

Commentary to Feature Review

SEARCHING FOR THE ORIGINS OF SCHIZOPHRENIA Rue L. Cromwell University of Kansas

In this Commentary, I deal with selected issues con- cerning the origins of schizophrenia, filling out the pic- ture presented by the books under review. Included are comments on definition, older and enduring notions about origins, some more recent notions, and, finally, some potentially useful but not fully exploited notions. George Bernard Shaw (1907, pp. 140-141) suggested that people are immediately willing to give up an obsolete tool such as a wooden plow or hand-cranked car, but they are most unwilling to give up an obsolete idea or concept. While the concept of schizophrenia does not appear ready to be replaced, some notions about its origins appear worthy of examination.

DEFINITION

Schizophrenia refers to a set of behavioral dimensions that concur in deviant form frequently enough to be re-

ferred to as a syndrome or disorder. Yet M. Bleuler has recently reminded us that his father, who coined the term (E. Bleuler, 1911/1950), viewed it as a group of disorders (see Cromwell, in press-a). Most investigators assume a unity, although some suggest plurality (subtyping). Final evidence has not yet been obtained for either view. From a heuristic standpoint, a plural view would indicate that differential defining criteria would point to differential treatment implications, course, and prognosis.

Another issue in the definition of schizophrenia has been the shift away from the relatively existential definition: Bleuler' s (1911/1950) definition in terms of associa- tive disturbance, affective splitting, ambivalence, and au- tistic meaning assignments and the definition of prior editions of the Diagnostic and Statistical Manual of Men- tal Disorders (American Psychiatric Association, APA, 1952, 1965) in terms of disturbance in reality relation- ships. In place of the existential definitions has come the use of operational criteria (APA, 1980, 1987). With this shift, schizophrenia has become objectively defined pri-

Address correspondence to Rue L. Cromwell, Department of Psy- chology, University of Kansas, Lawrence, KS 66045.

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schizophrenia reviewed: toward an integrative genetic model

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