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Conclusions

Genetic epidemiological data are beginning to favor the view that schizophrenia, bipolar disorder, and schizoaffective disorders share at least some genetic liability, although more work aimed at exploring these issues in adequately powered and suitably designed family and twin studies is clearly needed. Recent work on specific candidate genes supports this view and suggests that the genetic associations are strongest with clinical syndromes that do not map directly onto either or both of the 2 hypothetical disease entities proposed by Kraepelin. This is not surprising, given the frequency with which clinicians encounter mixed forms and the absence of a clear demarcation or “zone of rarity” between the 2 syndromes.⁵⁷ It also seems congruent with the evidence that schizophrenia and bipolar disorder share a range of other risk factors.⁶ Moreover, general medicine provides multiple examples of genetically complex disorders where distinct diagnostic categories (eg hypertension, hemorrhagic stroke, myocardial infarction, and hypertensive cardiomyopathy) share genetic risk factors.⁵⁸

The comparative work on candidate genes in the major psychiatric disorders is still in its early stages and the findings should be treated with caution until further studies have been reported, given the difficulties in establishing unequivocal evidence for genetic association in complex diseases and the fact that for none of the genes implicated have specific risk variants so far been established. Indeed, it may turn out that many of the candidate genes currently discussed contain multiple risk (and protective) variants with effects on different aspects of psychopathology. A more parsimonious interpretation of the existing data is that variation in DISC1/DISC 2 and NRG1 can confer predisposition to illness in individuals on either side of the Kraepelinian divide and that the effects of both genes will be felt most strongly in disorders with features of both schizophrenia and bipolar disorder. Variation in DTNBP1 seems to predominantly predispose to schizophrenia and negative symptoms, with an effect on bipolar disorder confined to those cases with prominent psychotic features. In contrast, DAOA / G30 appears to be more strongly associated with mood disorder, and the extent to which associations with schizophrenia are seen may depend upon the proportion of cases with prominent mood disorder features.

Such findings will have important implications for future classifications of the major psychiatric disorders because they suggest an overlap in the biological basis of disorders that have, over the last 100 years, been regarded as distinct entities.⁴ We predict that, over the coming years, molecular genetics will catalyze a reappraisal of psychiatric nosology as well as contribute in a major way to our understanding of the pathophysiology and the development of improved treatments. Current genetic findings suggest that rather than classifying psychosis as a dichotomy, a more useful formulation may be to conceptualize alternative categories or a spectrum of clinical phenotypes with susceptibility conferred by overlapping sets of genes⁴ (figure 1).

Fig. 1.

Simplified hypothesized relationship between specific susceptibility genes (above the black line) and clinical phenotype (below the line) using the model outlined in Craddock and Owen⁴. The overlapping ellipses represent overlapping sets of genes: red ...

For the time being, however, such interpretations remain largely speculative as our understanding of the brain mechanisms linking specific gene actions and products to the subjective experience of psychopathological symptoms, such as delusions, hallucinations, or thought disorder is at best rudimentary. There is an “explanatory gap” between the findings of statistical association of a gene variant with the disorder and the demonstration of causality with regard to specific illness phenomena. This gap might be easier to bridge by employing intermediate (or endo-) phenotypes in the domains of cognition, neurophysiology, or neuroanatomy. As objectively measurable quantitative traits, endophenotypes are better anchored in brain biology than clinical symptoms and can help delineate subtypes of disorder with likely distinct genetic basis.^59,60 The dissection of the syndromes of psychosis into “modular” endophenotypes with specific neurocognitive or neurophysiological underpinnings, cutting across the conventional diagnostic boundaries, is beginning to be perceived as a promising approach in the genetics of the major psychiatric disorders.⁶¹

It is important that researchers are willing to embrace and explore such alternative approaches to the phenotype of psychosis in order to interpret the accumulating data and design new research. This will be an iterative process with identified genetic signals allowing refinement of the phenotype and the refined phenotype allowing increased power to detect further genetic signals. To facilitate this approach, it will be important to collect large samples that have a full representation of phenotypes across the mood-psychosis spectrum and detailed, high-quality phenotypic assessments, preferably including dimensional measures (eg, Levinson et al⁶², Craddock et al⁶³).

In conclusion, accumulating evidence supports the existence of an overlap in genetic susceptibility across the traditional Kraepelinian divide with studies of several genes providing to date the most compelling such evidence. This work is at an early stage but has the potential to change our conception of psychiatric nosology as well as our understanding of the pathogenesis of psychopathology.

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