Genetic factors Of the currently known risk factors for schizophrenia, family history is by far the most robust. However, Mortensen and colleagues (1999) reported that the PAR of having one or both parents affected was only 3.8%. While the interaction between genetic and nongenetic risk factors is almost certainly more complicated than these figures suggest,  the finding reinforces the fact that,  while risk factors with large odds ratios are attractive targets, their real effect on the population may be small. Current evidence suggests that many different genes, each of small effect, contribute to the risk of schizophrenia. If we could identify individuals with these genes, then it may be feasible to deliver some type of selective intervention to those identified as susceptible. The timing of this intervention could be prenatal, early life, or around the time of maximal risk. However, it is entirely plausible that the genes that contribute to susceptibility are relatively common, and that most individuals with these genes are unaffected. Genetic risk factors may not readily translate into universal interventions. Despite the ever-increasing pace of discovery in molecular biology, gene therapy seems a distant hope at the moment. Season and place of birth People born in winter and spring tend to have a slightly increased relative risk of developing schizophrenia compared with those born in autumn and summer. Mortensen and colleagues (1999) reported a very small effect size (1.11) for season of birth in their Danish sample. However, as a substantial fraction of the population are exposed (i.e. born during winter/spring), the attributable risk was substantial (10.5%). Season of birth is a risk indicator and thus can only serve to generate candidate risk-modifying variables.  Currently,  candidate exposures that may be related to the season of birth effect include perinatal viral exposures (Torrey et al., 1997) and low prenatal vitamin D (McGrath, 1999). While the season of birth effect in the northern hemisphere population is robust (Torrey et al.,  1997),  a meta-analysis of data from southern hemisphere studies did not support an effect (McGrath and Welham, 1999). This north - south difference may help clarify the nature of the underlying risk-modifying factors.

People born in the city tend to have a greater risk of developing schizophrenia than those born in rural regions (Marcelis et al., 1998; Mortensen et al., 1999). The relative risk of developing schizophrenia when born in the city versus being born in the country is about 2.4. However, because exposure to urban birth was relatively frequent in both the Danish and Dutch studies, the PAR for this variable was substantial (in the order of 30 to 35%). Place of birth, once again, appears to be a proxy marker for a risk-modifying variable such as viral infection, nutrition, low vitamin D and unspecified toxic exposures (Mortensen, 2000). Place and season of birth should provide fertile domains for the generation of candidate exposures.  However,  until we can identify risk-modifying variables responsible for these effects, prevention research is not feasible. Pregnancy and birth complications Links between pregnancy and birth complications and an increased risk of schizophrenia have been examined over many decades. While the data are not entirely consistent, the weight of the evidence supports a modest increased risk of schizophrenia in those exposed to a variety of obstetric complications. The PAR related to these exposures is not clear but is probably modest (5 - 10%). There is an extensive literature on how to improve perinatal outcomes, much of it based on randomized controlled trials. Intervention at a population level (all pregnant women) could include general options related to improving antenatal care and more specific options such as smoking cessation. One attractive feature of this type of intervention is that disorders other than schizophrenia could be averted, and pregnant women tend to be more receptive to health promotion than the general community. This is another example of an intervention with low prevention paradox. One group may derive additional benefit from optimal antenatal care -  women with schizophrenia. Women with schizophrenia tend to experience more obstetric complications at delivery (Sacker et al., 1996; Bennedsen, 1998). It has also been suggested that the effect of family history together with obstetric complications amplifies the subsequent risk of schizophrenia in the offspring (Mednick et al., 1987). If this is true, it follows that optimizing antenatal care to women who have a ‘high-risk’ fetus may be a suitable avenue for selective prevention.