Schizophrenia has probably been more extensively investigated using family, twin and adoption studies than almost any other disorder. The family data are entirely consistent in showing a higher risk in relatives than in the general population. This averages around 10% in siblings and offspring but is usually somewhat lower in parents reflecting the fact that schizophrenia is associated with markedly reduced fecundity. Thus schizophrenia sufferers who have children tend to be those who had their offspring comparatively early and whose onset of disorder is comparatively late (Gottesman, 1991). As with the affective disorders, the pattern seen in families is not Mendelian and single gene explanations, even allowing for incomplete penetrance, are implausible mathematically (O'Rourke et al., 1982) and statistically (McGue et al., 1985).

There have now been many twin studies of schizophrenia all of which point to a definite genetic component. However, a criticism of studies carried out before the 1980s was that they used clinical diagnoses that were arguably more subjective and less reliable than modern, so called operational definitions of disorder such as those now contained in the American Psychiatric Association's Diagnostic and Statistical Manual (DSM) from the third edition (DSM III) onwards (American Psychiatric Association, 1980). To rectify this, Farmer et al. (1987) reassessed one of the best characterised schizophrenia twin series, that from the Maudsley Hospital twin register, London reported by Gottesman and Shields (1972). In fact applying the more rigorous DSM III definition led to a heritability estimate for liability to schizophrenia of around 80%, rather higher than had been found using a somewhat broader clinical diagnosis (McGue et al., 1985). There have been five more recent twin studies where the cases have been defined using operational criteria (Table 30.2). One of these was a further updating and extension of the Maudsley series. Cardno et al. (1999) found proband-wise concordances of 20/47 (43%) in MZ twins compared with 0/50 (0%) in DZ twins using DSM IIIR (American Psychiatric Association, 1987) criteria. For the International Classification of Diseases, 10th edition (ICD 10) defined schizophrenia (World Health Organization, 1992), the rates were 21/50 (42%) in MZ twins and 1/58 (2%) in DZ twins.

Applying genetic model fitting, Cardno et al. (1999) estimated that the broad heritability, or proportion of variation in liability to schizophrenia resulting from genetic effects, was about 84% for the DSM IIIR and 83% for the ICD 10 definition of schizophrenia.

The adoption data on schizophrenia are particularly extensive and date from pioneering studies commenced in the 1960s by Heston (1966), Kety and others (1968). The time and energy devoted to adoption studies perhaps reflects the fact that schizophrenia was at the time seen as a battle ground both in the "nature—nurture'' debate and in the debate about whether psychiatric disorders were "real" disorders at all. Essentially three designs have been employed in utilizing the 'natural experiment' of adoption. These are often referred to as the adoptees design, the adoptees' family design and the cross-fostering study. Results from all three designs are summarized in Table 30.3. For many, the adoption study results settled the debates about schizophrenia once and for all, leading Kety to famously remark that if ''schizophrenia is a myth, it is a myth with a strong genetic basis.''

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