Neurobiology of schizotypal phenotypes - Schizotypy as a framework for dimensional psychiatry
Complex, dimensional phenotypes represent a valuable framework for the analysis of fundamental neurobiological mechanisms of psychiatric disorders. They facilitate the deconstruction of diagnostic entities and the study of protective processes that prevent progression into clinical domains. Within t...
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|Summary:||Complex, dimensional phenotypes represent a valuable framework for the analysis of fundamental neurobiological mechanisms of psychiatric disorders. They facilitate the deconstruction of diagnostic entities and the study of protective processes that prevent progression into clinical domains. Within the psychosis spectrum, schizotypy describes a multidimensional personality construct with behavioural, cognitive, and emotional characteristics similar to key symptoms of schizophrenia, that can equally be grouped into the dimensions positive (magical thinking, unusual perceptions and beliefs), negative (introversion, anhedonia), and disorganised (cognitive disorganisation, eccentricity). Within a continuum model of psychosis, schizotypy is discussed as variation of healthy function, and as risk phenotype of schizophrenia and psychosis proneness, assuming a (partially) overlapping genetic architecture along the spectrum. Current aetiological models propose an impact of genetic liability, in interaction with environmental risk and modulated by protective factors like cognitive function, through disruptions in neuronal development. In fact, recent studies show that schizotypy is associated with brain structural variation, partially overlapping with regions that are also impaired in patients with schizophrenia spectrum disorders.
This dissertation characterised neurobiological determinants of schizotypy regarding its genetic basis and neural networks, aiming to develop a multimodal model to integrate those into a joint framework.
STUDIES I and IV investigated the genetic structure of schizotypy, demonstrating its association with common variants (single nucleotide polymorphisms, SNPs) in genes (CACNA1C and ZNF804A) involved in processes of neuronal development and identified as risk genes for schizophrenia and other psychiatric disorders (STUDY I). In this association, biological sex has a moderating role. However, a direct association of a polygenic schizophrenia risk score, based on cumulative SNP-risk, was not established (STUDY IV).
STUDIES II and III analysed brain structural correlates of schizotypy dimensions, finding an association of the positive dimension (and symptom-associated distress) with grey matter volume in associative brain areas precuneus, striatum and inferior temporal gyrus. STUDY II further indicates that this relationship can be buffered by above average general cognitive function.
Study V ultimately integrates the previous results into a joint multivariate model that proves to explain a substantial amount of phenotypic variance. The model shows that the interaction effect of polygenic and poly-environmental risk on positive schizotypy is mediated through brain structural variation in the precuneus, and modulated by the level of executive function.
In conclusion, this dissertation shows that schizotypy is associated with genetic polymorphisms involved in neuronal development and function. While those are identified as schizophrenia risk variants, the lack of an association with polygenic schizophrenia risk suggests a limited overlap of the genetic architectures of the phenotypes. The confirmation of the multivariate model, however, indicates an indirect effect through variations in brain structure and modulated by intra- and extrapersonal factors. Accordingly, particularly positive schizotypy is associated with structural alterations in brain regions central for the integration, evaluation, and attribution of perceptual information within associative neuronal networks.
Thus, schizotypy is a valuable endophenotype of the schizophrenia spectrum, showing that pathophysiological aberrations lie on a continuum with variation of healthy functioning. Schizotypy, however, also describes the manifestation of interindividual variation in behaviour, cognition, and emotion, with its underlying mechanisms representing an exemplary framework for the study of dimensional, phenotypic spectra.|
|Physical Description:||134 Pages|