Table 2.1 Lifetime expectancy of broadly defined schizophrenia in the relatives of schizophrenics. Table reproduced with permission from Kendell RE, Zealley AK.

Companion to Psychiatric Studies. Edinburgh: Churchill

GENETICS

The most important risk factor for schizophrenia is having an affected relative (Figure 2.5 and Table 2.1)3–5. Twin and adoption studies have been used to show that this is consequent upon genetic transmission.

The consistently greater concordance in monozygotic (MZ) than dizygotic (DZ) twins4–10 (Figure 2.6) has been taken to indicate a genetic effect but does not prove this beyond doubt, since MZ twins may be treated more similarly by their parents (Figure 2.7). However, adoption studies have demonstrated conclusively that liability to schizophrenia is transmitted through genes and not through some intrafamilial environmental effect (Figure 2.8)11,12.

Various models of genetic transmission of schizophrenia have been considered but found not to fit the data. There is no evidence to support the single major locus model, which implies that a gene of major effect causes schizophrenia but has incomplete penetrance or variable expression. The polygenic model implies that there are many contributing genes, while the multifactorial model

Figure 2.7 A pair of monozygotic twins discordant for schizophrenia. The twin on the right has schizophrenia

postulates that there are both genetic and environmental factors. The so-called multifactorial polygenic model involves an interaction between multiple loci and environmental factors, with schizophrenia being expressed only in individuals who exceed a certain threshold of liability.

Although the mode of transmission has not been absolutely clarified, molecular and genetic epidemiological studies concur that it is most likely to involve a number of genes of small effect interacting with environmental factors, i.e. the multifactorial polygenic model. An alternative not yet excluded is the heterogeneity model, which proposes that schizophrenia consists of several distinct conditions, each with a distinct etiology.

Molecular genetic studies have attempted to identify the particular genes that may be involved in the predisposition to schizophrenia. To date, no loci have been consistently replicated. This indicates that the susceptibility genes must each

ADOPTION STUDIES

Figure 2.8 Studies of people with schizophrenia adopted away from home show conclusively that there is genetic liability to schizophrenia: there is an increase in the risk of schizophrenia associated with being a biological, but not an adoptive parent of an individual with schizophrenia. Data from references 11 and 12

Frequency (%)

EXPOSURE TO OBSTETRIC COMPLICATIONS

Number of obstetric complications

Figure 2.9 Obstetric complications are more common in people with schizophrenia compared with controls. Patients with schizophrenia are especially likely to have suffered multiple complications