Cohort Profile: Pathways of risk from conception to disease: the Western Australian schizophrenia high-risk e-Cohort

Abstract

Schizophrenia is a severely disabling disorder with a lifetime risk of 1% and a point prevalence of about 5 per 1000. Schizophrenia accounts for 2.3% of the global burden of disease. The aetiology of schizophrenia is complex. While there appears to be a significant genetic contribution, it is possible that many genes of small effect contribute to the disorder and that environmental risk factors interact with the genetic susceptibility. The impact of environmental risks appears to be complex, with no single environmental risk factor of major effect isolated to date. Putative candidate exposures include winter/spring season of birth, pregnancy and birth complications; prenatal starvation; urbanicity; migration and ethnicity, with the incidence apparently higher in second-generation migrants; stress and cannabis use. There have also been reports of possible age-related germ-line mutations such as those associated with older fathers. Much of the research into environmental risk factors has focused on the role of obstetric complications. While the level of reported risk associated with obstetric complications varies, Geddes and Lawrie, in a meta-analysis of published research, reported a pooled odds ratio of 2, a figure corroborated a few years later by Cannon et al., who calculated the individual odds ratio of 2 and under for the majority of the many complications that they reviewed. It appears that changes in the uterine environment such as increased maternal cytokines in response to hypoxia or infection, and stress-induced elevation of circulating corticosteroid levels may predispose some infants to psychopathology. In particular, much attention has been focused on hypoxic/ischemic events associated with and/or resulting in placentation abnormalities leading to fetal growth retardation and neonatal encephalopathy. In order to examine the role of genes, environment and their interaction in the expression of schizophrenia, a number of studies have adopted a prospective, longitudinal approach focusing on so-called ‘strategic’ populations of ‘high-risk’ children. These are children who are at genetically increased risk of developing schizophrenia because they have at least one parent with the disease and are therefore a priori enriched for predisposing genes. High-risk samples offer researchers the opportunity to address efficiently and parsimoniously key questions about risk factors and vulnerability. By parcelling out the separate contribution of genetic liability and environmental exposures, their relative contribution to the onset of schizophrenia and other neuropsychiatric outcomes can be assessed. One of the earliest of the longitudinal investigations of developmental pathways in the children of parents with schizophrenia was initiated by Barbara Fish in the early 1950s. Fish proposed that developmental retardation and neurological soft signs observed amongst the high-risk children in her sample were early markers of an inherited neurointegrative defect in schizophrenia which she named ‘pandysmaturation’. Dr Fish’s seminal work on pandysmaturation laid the groundwork for the formulation of the neurodevelopmental hypothesis of schizophrenia in the late 1980s. In its simplest form, the hypothesis states that critical circuits in the brain are affected by subtle disease processes in early development, with full-blown consequences Published by Oxford University Press on behalf of the International Epidemiological Association