Schizophrenia appears to be a disorder of development that results from a series of neurological insults from fetal life onward (Rapoport et al., 2005). Whether or not schizophrenia manifests appears to be the result of a conglomeration of these factors, both genetic and environmental in origin (Sullivan et al., 2003), as shown in the Figure.
No one factor appears to be most significant in the genesis of schizophrenia. This is evident despite the very significant resources that have been expended in the search to understand the patho-etiology of schizophrenia. This may be because there are multiple factors involved; multiple different disorders with varied pathologies present with the schizophrenia phenotype; or a combination of both. The search to uncover the pathological basis to schizophrenia has, however, provided broad generalizations that have yielded more specific etiological candidates as a result of newer, more powerful methodologies, particularly those resulting from the Human Genome Project. Interestingly, some of the genetic candidates identified providing explanatory models that may incorporate identified environmental risk factors.
Risk for schizophrenia appears to begin as early as the first trimester in pregnancy, with exposure to influenza associated with increased risk of later developing schizophrenia (Brown et al., 2004). Other prenatal factors are also implicated in the second and third trimesters. These include maternal rubella and respiratory infections, low socioeconomic class, maternal deprivation resulting from war or famine, urban birth, obstetric complications, and birth in late winter/early spring (Dohrenwend et al., 1992; Lewis and Murray, 1987; Marcelis et al., 1999; Susser et al., 1996; Torrey et al., 1997).
A direct observation of genetic and environmental factors interacting in the perinatal period was demonstrated when it was shown that fetal hypoxia, an environmental insult, was associated with decreased grey matter and increased cerebrospinal fluid (CSF) in patients with schizophrenia and their relatives but not in genetically low-risk individuals (Cannon et al., 1993).
Many of the prenatal factors listed are also associated with low folate, and it has also been suggested that some of these antenatal factors may exert at least a part of their effect through reducing maternal folate levels (Marzullo and Fraser, 2005). Low folate in turn may exert influence through elevation of plasma homocysteine (Doolin et al., 2002). The response of homocysteine to folate is, however, dependent upon the presence of specific genetic polymorphisms involved in homocysteine metabolism. The most notable of these polymorphisms is the folate-sensitive product of the 677C —>T methylenetetrahydrofolate gene variant, which participates in the remethylation of homocysteine to methionine. Presence of this gene variant results in elevated homocysteine in the presence of low folate (Murakami et al., 2001). This elevated homocysteine itself has modulatory effects at the N-methyl-D-aspartate (NMDA) receptor, the central element in the glutamatergic theory of schizophrenia (Kornhuber and Weller, 1997).
In addition, the 677C—>T polymorphism has been found to be present at higher levels in patients with schizophrenia than the general population (Arinami et al., 1997; Regland et al., 1997). However, not all studies have been able to confirm this association (Virgos et al., 1999). The variability in findings is perhaps most notable for linkage studies that utilize population-wide gene frequencies, though evidence is becoming stronger for possible linkage for schizophrenia at chromosomal sites.
