ReviewModifiable risk factors for schizophrenia and autism — Shared risk factors impacting on brain development☆
Introduction
In recent decades epidemiology has provided important new clues to the neurodevelopmental origins of disorders such as schizophrenia and autism. Through access to larger and better characterised patient and general population samples, associations between potentially modifiable environmental risk factors and complex neurodevelopmental disorders can be examined. In addition to the publication of primary data, the field now has access to comprehensive systematic reviews (with or without subsequent meta-analysis of the data). As the epidemiological profiles of schizophrenia and autism have been enriched, there has been growing interest in the apparent overlap in risk factors between the two disorders.
Clearly, there are differences between the two disorders; the age of onset and the impairment of language are examples of phenotypic disparity. Autistic disorders are apparent in early childhood, whereas schizophrenia usually manifests after onset of puberty. In autism, there is a severe and profound impairment in language, whereas schizophrenia is characterised by a wide array of neuropsychological deficits including language (Kalkstein et al., 2010). Importantly however, there is also phenotypic overlap between the two syndromes. Both are widely considered to be neurodevelopmental disorders — in other words, both are thought to be the end result of factors that disrupt early brain development (Bale et al., 2010). Both have an excess prevalence in males. For autism, the male:female risk ratio is 4.1:1 (Newschaffer et al., 2007), whilst for schizophrenia, the risk ratio is 1.4:1 (Aleman et al., 2003, McGrath et al., 2004b). Impaired theory of mind (the capacity to interpret one's own and other persons' mental states) is a core deficit in both syndromes (Brune, 2005) and there is some overlap between the disorders in terms of brain volumetrics (Cheung et al., 2010).
The shared and distinct features of the two clinical syndromes have inspired researchers to generate ‘unified’ hypotheses that attempt to synthesise the body of evidence. For example, Crespi and Badcock have proposed that these two disorders exhibit diametric patterns for traits related to social brain development and suggest that differential maternal versus paternal genomic imprinting during brain development underlies the two syndromes (Crespi and Badcock, 2008).
Genetic studies have suggested that certain types of copy number variants are shared between these two disorders. Attention has been drawn to a shared genetic diathesis underlying broadly defined neurodevelopmental disorders (including schizophrenia, autism-related disorders and attention deficit disorder) (Kendler, 2010, Mitchell, 2011). There is a growing recognition that, despite the clinical utility of syndromal labels such as schizophrenia and autism (e.g. with respect to prognosis and treatment options), from the perspective of aetiology and pathogenesis, scientific progress may be facilitated by incorporating a broader category of observation (Owen et al., 2011).
If the same risk factor is associated with more than one disorder, does this make the association less plausible? Influential articles about causality in risk factor epidemiology have often emphasised the importance of specificity between an exposure and outcome. For example Bradford Hill suggested that if one particular risk factor was associated (specifically) with one particular adverse health outcome, this would add weight to the cumulative evidence that exposure was causally related to that outcome (Hill, 1965). The heritage of this proposal can be readily traced to infectious disease epidemiology and Koch's postulates. However, in recent decades it has become clear that some exposures can be confidently linked to many different outcomes (e.g. tobacco smoking with increased risk of several types of cancers and several types of cardiovascular events). Within the field of psychiatry, we are also familiar with the fact that some exposures can be linked to a wide range of mental health outcomes (e.g. childhood exposure to trauma) (Green et al., 2010, Kessler et al., 2010, Scott et al., 2010).
In the spirit of the increased attention to shared genetic mechanisms, we wished to explore environmental risk factors that appear to be shared between autism and schizophrenia. In particular, we are interested in modifiable risk factors, as these lend themselves to public health intervention, and the primary prevention of these disorders.
Section snippets
Literature review
In July 2011 we searched electronic resources (PubMed; Embase and Medline) using the search terms “Autis* and risk factor* and environment” to identify systematic reviews of risk factors for autism. We also searched these same electronic databases and the Schizophrenia Research Forum (www.schizophreniaforum.org); and Schizophrenia Research Institute online Library (www.schizophreniaresearch.org.au/library) using the search terms “schizo* and risk factor* and environment” to identify systematic
Nutrition
Schizophrenia research has examined prenatal nutritional deprivation as a candidate risk factor via the use of ‘natural experiment’ — the rates of schizophrenia have been examined in cohorts exposed in utero to catastrophic famines (the Dutch Hunger Winter and the famine in China associated with the Cultural Revolution). Individuals who were in utero during the Dutch famine showed an increased risk of schizophrenia and schizophrenia spectrum personality disorders (Susser and Lin, 1992). The
Conclusion
In keeping with the evidence of shared genetic factors associated with both schizophrenia and autism, we found evidence from systematic reviews and meta-analyses suggesting that these two disorders also share non-genetic risk factors. Mindful that not all areas of the two disorders had sufficient primary data to justify systematic reviews and meta-analysis, it is striking to find several candidate exposures that are associated with an increased risk of both schizophrenia and autism.
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Author contributions: The study was designed by JM and JS. JH and MD undertook the literature search, and data extraction. All authors contributed to manuscript preparation.