Evidence for an Interaction Between Familial Liability and Prenatal Exposure to Infection in the Causation of Schizophrenia

Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin 9, Ireland.
American Journal of Psychiatry (Impact Factor: 12.3). 07/2009; 166(9):1025-30. DOI: 10.1176/appi.ajp.2009.08010031
Source: PubMed


The authors sought to determine whether prenatal exposure to infection and a positive family history of psychotic disorders interact synergistically to increase the risk of later developing schizophrenia.
The authors linked two national registers, the Medical Birth Register and the Finnish Population Register, to identify all women in Helsinki who received hospital treatment during pregnancy for an upper urinary tract infection (N=9,596) between 1947 and 1990. The Finnish Hospital Discharge Register was used to ascertain psychiatric outcomes in adulthood of offspring exposed to infection prenatally. Family history of psychotic disorders was determined by linking the Hospital Discharge Register and the Population Register. The authors used an additive statistical interaction model to calculate the amount of biological synergism between positive family history and prenatal exposure to infection.
Prenatal exposure to infection did not significantly increase the risk of schizophrenia. However, the effect of prenatal exposure to pyelonephritis was five times greater in those who had a family history of psychosis compared to those who did not. The synergy analysis suggested that an estimated 38%-46% of the offspring who developed schizophrenia and had both prenatal exposure to infection and a positive family history of psychotic disorders did so as a result of the synergistic action of both risk factors.
These findings support a mechanism of gene-environment interaction in the causation of schizophrenia.

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Available from: Matti Huttunen, Oct 23, 2015
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    • "Schizophrenia is one of the most severe psychiatric disorders with worldwide lifetime prevalence approaching 1%, and characterized by psychotic features (delusions and hallucinations), disorganization, dysfunction in normal affective responses, and altered cognitive functions (Andreasen, 1995). Previous studies have implicated schizophrenia as an illness involved by interactions of one or more environmental insults with predisposing genetic susceptibility (Cannon et al., 2003; Caspi and Moffitt, 2006; Clarke et al., 2009). Among these environmental hazards, viral infection is one of the most widely accepted factors that could increase risk of future development of schizophrenia. "
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    ABSTRACT: Schizophrenia is a brain disorder with high heritability. Recent studies have implicated genes involved in the immune response pathway in the pathogenesis of schizophrenia. Interferon regulatory factor 3 (IRF3), a virus-immune-related gene, activates the transcription of several interferon-induced genes, and functionally interacts with several schizophrenia susceptibility genes. To test whether IRF3 is a schizophrenia susceptibility gene, we analyzed the associations of its SNPs with schizophrenia in independent population samples as well as reported data from expression quantitative trait loci (eQTL) in healthy individuals. We observed multiple independent SNPs in IRF3 showing nominally significant associations with schizophrenia (P < 0.05); more intriguingly, a SNP (rs11880923), which is significantly correlated with IRF3 expression in independent samples (P < 0.05), is also consistently associated with schizophrenia across different cohorts and in combined samples (odds ratio = 1.075, Pmeta = 2.08 × 10(-5)), especially in Caucasians (odds ratio = 1.078, Pmeta = 2.46 × 10(-5)). These results suggested that IRF3 is likely a risk gene for schizophrenia, at least in Caucasians. Although the clinical associations of IRF3 with diagnosis did not achieve genome-wide level of statistical significance, the observed odds ratio is comparable with other susceptibility loci identified through large-scale genetic association studies on schizophrenia, which could be regarded simply as small but detectable effects. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Journal of Psychiatric Research 03/2015; 64. DOI:10.1016/j.jpsychires.2015.03.008 · 3.96 Impact Factor
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    • "Influenza has been the most widely studied pathogen in the MIA literature, because of its prevalence in the general population. Other studies have, however, revealed that less prevalent infections and viruses including bacterial infections (Clarke et al., 2009; Sorensen et al., 2009), bronchopneumonia (Brown et al., 2000), polio (Suvisaari et al., 1999; Cahill et al., 2002), herpes simplex virus (Buka et al., 2001, 2008; Babulas et al., 2006), rubella (Brown et al., 2000, 2001), and toxoplasma gondii (Brown et al., 2005; Mortensen et al., 2007) are also associated with increased risk for schizophrenia in the offspring of those infected. This common effect across various infections suggests that a specific infection or virus does not, in and of itself, increase the risk of schizophrenia. "
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    ABSTRACT: Maternal exposure to infection occurring mid-gestation produces a three-fold increase in the risk of schizophrenia in the offspring. The critical initiating factor appears to be the maternal immune activation (MIA) that follows infection. This process can be induced in rodents by exposure of pregnant dams to the viral mimic Poly I:C, which triggers an immune response that results in structural, functional, behavioral, and electrophysiological phenotypes in the adult offspring that model those seen in schizophrenia. We used this model to explore the role of synchronization in brain neural networks, a process thought to be dysfunctional in schizophrenia and previously associated with positive, negative, and cognitive symptoms of schizophrenia. Exposure of pregnant dams to Poly I:C on GD15 produced an impairment in long-range neural synchrony in adult offspring between two regions implicated in schizophrenia pathology; the hippocampus and the medial prefrontal cortex (mPFC). This reduction in synchrony was ameliorated by acute doses of the antipsychotic clozapine. MIA animals have previously been shown to have impaired pre-pulse inhibition (PPI), a gold-standard measure of schizophrenia-like deficits in animal models. Our data showed that deficits in synchrony were positively correlated with the impairments in PPI. Subsequent analysis of LFP activity during the PPI response also showed that reduced coupling between the mPFC and the hippocampus following processing of the pre-pulse was associated with reduced PPI. The ability of the MIA intervention to model neurodevelopmental aspects of schizophrenia pathology provides a useful platform from which to investigate the ontogeny of aberrant synchronous processes. Further, the way in which the model expresses translatable deficits such as aberrant synchrony and reduced PPI will allow researchers to explore novel intervention strategies targeted to these changes.
    Frontiers in Behavioral Neuroscience 12/2013; 7:217. DOI:10.3389/fnbeh.2013.00217 · 3.27 Impact Factor
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    • "These patients also performed significantly worse in neuropsychological measures of psychomotor speed, executive functioning and verbal memory.115,116) Prenatal infection and subsequent inflammatory attack on a background of genetic liability serves to further increase the risk of developing SCZ, consistent with the idea that genetic factors are necessary for inflammation to affect in utero brain development.119) "
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    ABSTRACT: Schizophrenia (SCZ) is a polygenic, multi-factorial disorder and a definitive understanding of its pathophysiology has been lacking since it was first described more than a century ago. The predominant pharmacological approach used to treat SCZ is the use of dopamine receptor antagonists. The fact that many patients remain symptomatic, despite complying with medication regimens, emphasises the need for a more encompassing explanation for both the causes and treatment of SCZ. Recent neuroanatomical, neurobiological, environmental and genetic studies have revived the idea that inflammatory pathways are involved in the pathogenesis of SCZ. These new insights have emerged from multiple lines of evidence, including the levels of inflammatory proteins in the central nervous system of patients with SCZ and animal models. This review focuses on aberrant inflammatory mechanisms present both before and during the onset of the psychotic symptoms that characterise SCZ and discusses recent research into adjunctive immune system modulating therapies for its more effective treatment.
    Clinical Psychopharmacology and Neuroscience 12/2013; 11(3):107-117. DOI:10.9758/cpn.2013.11.3.107
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