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Deconstructing a complex disease?

The overview of the evidence suggests that phenotypic variability has been confounding the search for the causes of schizophrenia since the inception of the diagnostic category. Attempts at redefining its boundaries by either 'lumping' or 'splitting' strategies²⁴ have been undertaken over decades, with limited success. Most such attempts, based on various rearrangements of clinical symptoms and syndromes have ended in a failure to find natural boundaries between proposed clinical subtypes, either by locating a 'zone of rarity' between them, or by demonstrating a nonlinear relationship between the symptom profiles and a validating variable, such as outcome or heritability.⁵¹ The inconsistent and poorly replicated results of genetic linkage and association studies using the diagnostic category as the sole schizophrenia phenotype are kindling discontent with the current nosology of schizophrenia, based on the recognition that 'current nosology, now embedded in DSM-IV, although useful for other purposes, does not define phenotypes for genetic study'.¹⁹⁴ It is now almost certain that the current broad diagnostic concept of schizophrenia does not demarcate a specific genetic entity.

Schizophrenia geneticists are facing a particularly difficult situation, seeking to discover specific genes contributing to an overinclusive diagnostic category for which no specific biological substrate has yet been identified – most likely due to extensive genetic heterogeneity and an admixture of different underlying disease subtypes. Many 'top-down' attempts have been made to define an overarching disturbance in schizophrenia, sought in 'a weakening of the mainsprings of volition' and 'loss of inner unity of mental activities';¹ 'structural loosening of associations';⁴⁵^,³⁰⁵ 'intrapsychic ataxia';³⁰⁶ 'neurointegrative defect';³⁰⁷ 'cognitive dysmetria';³⁰⁸ and 'dysconnection disorder'.³⁰⁹^,³¹⁰ Although intuitively appealing, such formulations achieve little more than highlighting one or another of the many facets of a complex syndrome. It is doubtful that a specific genetic basis for a causa prima explaining the phenomenology of schizophrenia will ever be found. In contrast, it appears almost certain that the genetic polymorphisms and neurobiological deficits underlying schizophrenia are multiple, varied, and partly shared with predisposition to other disorders, although they primarily express a 'common final pathway' within the schizophrenia spectrum. Such polymorphisms and deficits need not be intrinsically pathological and may represent extreme variants of normal structure and function. Above a certain density threshold, their additive or nonlinear interaction could give rise to the diagnostic symptoms in probands, but subclinical manifestations as endophenotype traits will be detectable in otherwise healthy people, with a higher relative risk in biological relatives of probands.

While reasoning along such lines is increasingly common among researchers, the approaches proposed to deal with the phenotype bottleneck in schizophrenia research differ substantially. On one hand, there are proposals to abandon the 'Kraepelinian dichotomy' of schizophrenic and affective disorders in favour of a 'psychosis-spectrum illness'⁹^,³¹¹ or a 'shift from narrow phenotypes to broad endophenotypes', associated with an even broader spectrum of abnormal behaviours and emotions.³¹² On the other hand, there is an emerging 'splitting' agenda seeking and testing narrowly constrained phenotypes that may tag distinct variants or subtypes of schizophrenia,³¹³ resolving at least part of its aetiological heterogeneity. 'Candidate' endophenotypes or markers of pathogenetic processes affecting cognition, brain morphology and neurophysiology constitute the mainstay of this approach. Several genetic linkage and association studies employing such endophenotypes have produced promising results¹⁷⁵^,¹⁷⁶^,¹⁷⁹^,¹⁸⁰^,¹⁹¹^,¹⁹²^,²⁴³^,³⁰²^,³¹⁴ that set a high priority for replication.

In the absence of direct evidence that schizophrenia is either a homogeneous multifactorial disease or an amalgamation of aetiologically distinct component disorders, both 'lumping' and 'splitting' strategies are legitimate and should be put to the test. The question is, which approach holds at present greater promise for advancing schizophrenia genetics? Two arguments reinforce doubts that greater power for genetic studies would be achieved by redefining the clinical boundaries of the phenotype. First, lumping different disorders into an expanding phenotype of 'psychosis' runs against the grain of a large body of clinical research indicating that psychotic symptoms in the context of schizophrenia, other nonaffective psychotic illnesses, and affective disorders are phenomenologically different³¹⁵ and may be influenced by different genetic mechanisms, notwithstanding partial overlap in their effects. This would increase, rather than decrease, heterogeneity. Secondly, despite the availability of diagnostic criteria for research and structured diagnostic instruments, misclassification error in the fine-grain assessment of symptoms is likely to remain a factor compounding further the heterogeneity of family or case–control samples collected at different sites and at different times. Such heterogeneity is likely to be a serious problem in whole-genome association studies, which require very large case-control samples, feasible only by pooling data collections from multiple sites. In contrast, subtyping strategies are supported by mounting evidence that sample stratification, particularly using quantitative traits as covariates, can reduce heterogeneity and substantially increase power.³¹⁶^,³¹⁷^,³¹⁸^,³¹⁹^,³²⁰^,³²¹ This approach has scored successes in the genetics of other complex diseases and its application to schizophrenia genetics will bring the disorder into the mainstream of current research into the common genetic diseases.

What kind of data would constitute supportive evidence for distinct component disorders or subtypes within schizophrenia? Converging evidence from endophenotype-based studies suggests that measures of neurocognitive dysfunction arguably provide the largest effect sizes and increases in relative risk to relatives among a host of 'candidate' endophenotypes,²³⁶^,²³⁷^,²⁴¹^,²⁸¹^,²⁹⁴^,²⁹⁵ being also cost efficient for phenotyping large samples. In particular, several characteristic patterns of short-term and working memory impairment against a background of generalized cognitive deficit have been replicated across studies and are present in a substantial proportion ( 50%) of schizophrenia patients. As many of neurocognitive tests tap into several component processes, composite endophenotypes, integrating multiple neurocognitive measures, are more likely to capture variation that is genetically influenced than single-feature endophenotypes. The subtypes generated by such approaches should be capable of classifying individuals, rather than variables, and the resulting classification is likely to be polythetic (based on subsets of correlated features, rather than on the presence of all defining attributes). Whether subtypes are discrete taxa, that is, identifiable by marked areas of discontinuity with other subtypes; dimensional, representing continua with fuzzy boundaries; or hybrid (class-quantitative, with dimensions superimposed on discrete categories), is testable with taxometric methods common in biological classifications.³²³^,³²⁴ In the context of genetic research, the most significant criterion of their validity will be the gain in predictive power and 'process understanding'³²⁵ in the sense of mechanistic explanation of disease phenomena.

To sum up, we do not know whether schizophrenia is a single process with pleiotropic manifestations at the level of cerebral organization, or a collection of aetiologically unrelated but dynamically interacting processes. Although there are good grounds for the suspicion that schizophrenia is not a homogeneous entity, this has never been directly demonstrated, mainly because few studies of the appropriate kind have ever been undertaken. Its manifestations in toto do not fit neatly into the proposed disease models, although reasoning by analogy suggests an affinity to other complex multifactorial diseases, such as cancer, ischemic heart disease, or diabetes. For the time being, the clinical concept of schizophrenia is supported by empirical evidence that its multiple facets form a broad syndrome with some internal cohesion and a characteristic evolution over time. The dissection of the syndrome into modular endophenotypes with specific neurocognitive or neurophysiological underpinnings is beginning to be perceived as a promising approach in schizophrenia genetics. The current evidence is neither final nor static, and needs to be re-examined as new concepts and technologies coming from molecular genetics, cognitive science, or brain imaging bring forth new perspectives on disease causation and brain function. This must be complemented by a refined, reliable, and valid phenotyping not only at the level of symptoms, but involving correlated neurobiological features. The study of endophenotypes cutting across the conventional diagnostic boundaries may reveal unexpected patterns of associations with symptoms, personality traits, or behaviour. The mapping of clinical phenomenology on specific brain dysfunction (and vice versa) is becoming feasible and the resulting functional psychopathology³²²^,³²⁶ may in the future substantially recast the present nosology.

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