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      The Role of Schizotypy in the Study of the Etiology of Schizophrenia Spectrum Disorders

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          Abstract

          Schizotypy provides a useful construct for understanding the development of schizophrenia spectrum disorders. As research on the epidemiology of psychotic symptoms and clinical risk for psychosis has expanded, conceptual challenges have emerged to comprehend the nature and borders of the space comprised between personality variation and psychosis. Schizotypy is considered in light of these more recent constructs. It is suggested that rather than being superseded by them due to their higher specificity and predictive power for transition to psychosis, schizotypy integrates them as it constitutes a dynamic continuum ranging from personality to psychosis. The advantages of schizotypy for studying schizophrenia etiology are discussed (eg, it facilitates a developmental approach and the identification of causal, resilience, and compensating factors and offers a multidimensional structure that captures etiological heterogeneity). An overview of putative genetic, biological, and psychosocial risk factors is presented, focusing on communalities and differences between schizotypy and schizophrenia spectrum disorders. The found notable overlap supports etiological continuity, and, simultaneously, differential findings appear that are critical to understanding resilience to schizophrenia. For example, discrepant findings in genetic studies might be interpreted as suggestive of sets of independent genetic factors playing a differential role in schizotypy and schizophrenia: some would influence variation specifically on schizotypy dimensions (ie, high vs low schizotypy, thereby increasing proneness to psychosis), some would confer unspecific liability to disease by impacting neural properties and susceptibility to environmental factors (ie, high vs low resilience to disorder) and some might contribute to disease–specific characteristics. Finally, schizotypy’s promise for studying gene-environment interactions is considered.

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          The environment and schizophrenia.

          Psychotic syndromes can be understood as disorders of adaptation to social context. Although heritability is often emphasized, onset is associated with environmental factors such as early life adversity, growing up in an urban environment, minority group position and cannabis use, suggesting that exposure may have an impact on the developing 'social' brain during sensitive periods. Therefore heritability, as an index of genetic influence, may be of limited explanatory power unless viewed in the context of interaction with social effects. Longitudinal research is needed to uncover gene-environment interplay that determines how expression of vulnerability in the general population may give rise to more severe psychopathology.
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            Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence.

            This review critically summarizes the neuropathology and genetics of schizophrenia, the relationship between them, and speculates on their functional convergence. The morphological correlates of schizophrenia are subtle, and range from a slight reduction in brain size to localized alterations in the morphology and molecular composition of specific neuronal, synaptic, and glial populations in the hippocampus, dorsolateral prefrontal cortex, and dorsal thalamus. These findings have fostered the view of schizophrenia as a disorder of connectivity and of the synapse. Although attractive, such concepts are vague, and differentiating primary events from epiphenomena has been difficult. A way forward is provided by the recent identification of several putative susceptibility genes (including neuregulin, dysbindin, COMT, DISC1, RGS4, GRM3, and G72). We discuss the evidence for these and other genes, along with what is known of their expression profiles and biological roles in brain and how these may be altered in schizophrenia. The evidence for several of the genes is now strong. However, for none, with the likely exception of COMT, has a causative allele or the mechanism by which it predisposes to schizophrenia been identified. Nevertheless, we speculate that the genes may all converge functionally upon schizophrenia risk via an influence upon synaptic plasticity and the development and stabilization of cortical microcircuitry. NMDA receptor-mediated glutamate transmission may be especially implicated, though there are also direct and indirect links to dopamine and GABA signalling. Hence, there is a correspondence between the putative roles of the genes at the molecular and synaptic levels and the existing understanding of the disorder at the neural systems level. Characterization of a core molecular pathway and a 'genetic cytoarchitecture' would be a profound advance in understanding schizophrenia, and may have equally significant therapeutic implications.
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              Common disorders are quantitative traits.

              After drifting apart for 100 years, the two worlds of genetics - quantitative genetics and molecular genetics - are finally coming together in genome-wide association (GWA) research, which shows that the heritability of complex traits and common disorders is due to multiple genes of small effect size. We highlight a polygenic framework, supported by recent GWA research, in which qualitative disorders can be interpreted simply as being the extremes of quantitative dimensions. Research that focuses on quantitative traits - including the low and high ends of normal distributions - could have far-reaching implications for the diagnosis, treatment and prevention of the problematic extremes of these traits.
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                Author and article information

                Journal
                Schizophr Bull
                Schizophr Bull
                schbul
                schbul
                Schizophrenia Bulletin
                Oxford University Press (US )
                0586-7614
                1745-1701
                March 2015
                25 March 2015
                25 March 2015
                : 41
                : Suppl 2 , Proceedings, International Workshop on Schizotypy: Integration, Development, and Future Research (Geneva, Switzerland, 12-2013)
                : S408-S416
                Affiliations
                1Departament de Psicologia Clínica i de la Salut , Universitat Autònoma de Barcelona , Spain;
                2University of North Carolina at Greensboro , Greensboro, NC;
                3Centre for Biomedical Research Network on Mental Health (CIBERSAM) , Instituto de Salud Carlos III , Madrid, Spain;
                4Sant Pere Claver – Fundació Sanitària , Barcelona, Spain;
                5Justus-Liebig-University Giessen , Giessen, Germany
                Author notes
                *To whom correspondence should be addressed; Departament de Psicologia Clínica i de la Salut, Facultat de Psicologia (Edifici B), Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain; telephone: +34 93 5813864, fax: +34 93 5812125, e-mail: neus.barrantes@ 123456uab.cat
                Article
                10.1093/schbul/sbu191
                4373635
                25810055
                50122a21-de60-4dd2-88e7-060cbe8c5cbd
                © The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence ( http://creativecommons.org/licenses/by-nc-nd/3.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 4 December 2014
                : 8 December 2014
                Page count
                Pages: 9
                Categories
                Supplement Articles

                Neurology
                psychotic-like experiences,psychosis,psychosis proneness,risk factors,genetics,environment
                Neurology
                psychotic-like experiences, psychosis, psychosis proneness, risk factors, genetics, environment

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