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Introduction
A family history of schizophrenia is the strongest single indicator of individual schizophrenia risk. In any study of risk factors for schizophrenia it is therefore essential to include family history of schizophrenia as a potential confounder. Also there is mounting evidence that gene-environment interactions may be important in schizophrenia aetiology, and, since molecular genetic studies have not identified single major genes that determine a major fraction of the genetic liability for schizophrenia, it has been suggested that indirect measures of liability such as, for example, a family history of psychosis may be preferable compared with the inclusion of single nucleotide polymorphisms or haplotypes in studies of gene-environment interactions (Van Os et al. 2008).
There is, however, no general consensus as to which measure of familial risk that would be the most relevant to include as a confounder or interacting risk factor. A large majority of schizophrenia patients have no first-degree relatives with the disease (Gottesman, 1991; Mortensen et al. 1999), and it seems unlikely that this large majority of patients should not have a genetic liability. Therefore, a family history of schizophrenia alone is most probably a very imprecise measure of genetic risk. High-risk studies of offspring of mothers with schizophrenia have documented an increased occurrence of other disorders considered to be part of the schizophrenia spectrum, but it is not clear if there is an increased occurrence of other disorders among relatives (Parnas et al. 1993). For example, the classical adoption study by Kety et al. (1968) did not find a higher occurrence of other disorders among the biological parents of schizophrenic adoptees than among the biological parents of controls. Similarly Onstad (1991) did not find an excess of disorders outside of the schizophrenia spectrum amongst the first-degree relatives of twin probands with schizophrenia. The statistical power in these studies to detect any association with disorders other than schizophrenia was limited, however.
On the other hand, several studies have found an increased occurrence of other disorders among first-degree relatives of patients with schizophrenia. Some have suggested a possible genetic overlap with affective disorders in general or bipolar affective disorder and schizo-affective disorder (Cardno et al. 2002; Laursen et al. 2005; Maier et al. 2005; Craddock et al.