On the origin of schizophrenia: Testing evolutionary theories in the post-genomic era.

Considering the relatively high heritability of schizophrenia and the fact that it significantly reduces the reproductive fitness of affected individuals, it is not clear how the disorder is still maintained in human populations at a disproportionally high prevalence. Many theories propose that the disorder is a result of a trade-off between costs and benefits of the evolution of exclusively human adaptations. There have also been suggestions that schizophrenia risk alleles are accompanied with increase in fitness of affected persons or their relatives in both past and current social contexts. The discoveries of novel schizophrenia-related genes and the advancements in comparative genomics (especially comparisons of the human genome and the genomes of related species, such as chimpanzees and extinct hominids) have finally made certain evolutionary theories testable. In this paper, we review the current understanding of the genetics of schizophrenia, the basic principles of evolution that complement our understanding of the subject, and the latest genetic studies that examine long-standing evolutionary theories of schizophrenia using novel methodologies and data. We find that the origin of schizophrenia is complex and likely governed by different evolutionary mechanisms that are not mutually exclusive. Furthermore, the most recent evidence implies that schizophrenia cannot be comprehended as a trait that has elevated fitness in human evolutionary lineage, but has been a mildly deleterious by-product of specific patterns of the evolution of the human brain. In other words, novel findings do not support previous hypotheses stating that schizophrenia risk genes have an evolutionary advantage.

Glucocorticoid receptor alpha translational isoforms as mediators of early adversities and negative emotional states.

Childhood trauma (CT) increases the risk for psychopathology through disturbed acquisition and extinction of fear. The effects of CT are mediated by abnormalities of the hypothalamic-pituitary-adrenal axis and glucocorticoid receptor (GR). Since, the alterations in GRα translational isoforms have been documented in psychiatric disorders we sought to: 1) explore whether multiple GRα isoforms in the human peripheral blood mononuclear cells of two independent cohorts (whole cell n = 40; and nuclear extracts n = 43, adult subjects) mediate the effect of CT on negative affectivity (NA) measured by Depression, Anxiety and Stress Scales (DASS), and 2) examine their role/function during fear extinction in the animal model. In multiple regression analysis, CT, nuclear 40-kDa GRα, their interactions and FKBP5 explained 22%-35% of variance in DASS scores. Structural equation modeling showed that CT had a significant direct effect on 40-kDa and DASS in both cohorts, and on the nuclear 25-kDa GRα. The association between 40-kDa and total DASS was significantly mediated by nuclear FKBP5, whereas on DASS anxiety, over FKBP5 in both cohorts and nuclear full length GRα. Nuclear 40-kDa GRα and its interaction with CT had a significant direct effect on DASS anxiety. In mice, the successful extinction learning was followed by nuclear translocation of 40-kDa GRα and induction of BDNF exon IV expression. Our data revealed that the association between CT and adult NA in non-clinical subjects is mediated by the GRα translational isoforms, in particular 40-kDa GRα, and emphasized its role in fear extinction and neural plasticity.

Population-based differences in immune system response contribute to an increased risk of schizophrenia in African migrants?

Among the highest incidences of schizophrenia is the one documented in second-generation migrants of African descent in the Western countries. Interestingly, people of African and European ancestry demonstrate significant genetic-based differences in immune system regulation and response. As a result, the pro-inflammatory phenotype is more pronounced in people of African descent than it is in Europeans. At the same time, the role of the immune system in the etiology of schizophrenia is gaining increased recognition. Here, we propose that the population-specific genetic variation within the immune system interacts with unfavourable environments to contribute to a higher risk of schizophrenia in people of African ancestry. Our hypothesis is supported by recent findings from two separate fields of research-population genetics and psychoneuroimmunology. Moreover, we highlight the need to include African populations in genetic studies of schizophrenia.