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Macare, Christine-Johanna (2015): An imaging (behaviour-)genetics perspective on schizotypy and antisaccades. Dissertation, LMU München: Graduate School of Systemic Neurosciences (GSN)



Study One: Substantial genetic overlap between Schizotypy and Neuroticism: A Twin Study Schizotypy can be seen as a cluster of personality traits, phenomologically similar to, yet expressed in an attenuated form compared to the full-blown features of schizophrenia spectrum disorders. By placing schizotypy on the spectrum of schizophrenia spectrum disorders, the former might be used to reveal the aetiology of schizophrenia spectrum disorders. Similar to schizophrenia spectrum disorders, schizotypy correlates phenotypically with personality traits, most notably neuroticism. The aim of the first study was to decompose this phenotypic correlation between schizotypy and neuroticism and quantify its genetic and environmental components. Using a sample of 3,349 (1,449 monozygotic (MZ), 1,105 dizygotic (DZ) same-sex (DZss) and 795 DZ opposite-sex (DZos)) twins, we showed that positive schizotypy, specifically, the perceptual and ideational components of schizotypy, correlated on a phenotypical level with neuroticism (Pearson’s r=.37). Despite the differentiation of positive schizotypy and neuroticism on phenotypical levels, both traits showed a substantial amount of overlap on genetic levels (51% of genetic influences were shared, 95% confidence interval (CI) from 38 to 64%). Even more interesting was that in genetic terms neuroticism was able to explain positive features of schizotypy completely. A Cholesky decomposition including anhedonia, hypomania and impulsivity features of schizotypy fully accounted for the heritable variance in perceptual and ideational components of schizotypy, meaning that the genetic underpinnings of positive features of schizotypy could be explained away by genetic influences on neuroticism and other features of schizotypy (e.g. anhedonia, hypomania and impulsivity). Therefore, positive schizotypy could be considered as an artefact in genetic terms. The findings of the first study help in facilitating and guiding the search for molecular genetic variants of schizotypy and could be extrapolated to the schizophrenia spectrum. Study Two: The Schizotypal Brain - An fMRI Antisaccade Task Study Study two aimed at enriching the detailed investigation of psychometric schizotypy (see Study one) by revealing the neural correlates of psychometric schizotypy. Here, we tried to probe the neural correlates of schizotypy by using a measure that shows associations with schizotypy levels, i.e. performance on the antisaccade task. As shown in Study one, positive features of schizotypy are only present at psychometric levels and can be reduced to genetic variation that impacts on neuroticism and other schizotypy features. In Study two, we therefore focussed specifically on negative and disorganisation-related features of schizotypy and investigated their underlying neural correlates. One hundred forty-two healthy participants underwent functional magnetic resonance imaging (fMRI) during the antisaccade task and assessment of psychometric schizotypy. We did not replicate the association between positive schizotypy and antisaccade error rate at the phenotypic level. We did however replicate the brain network underlying antisaccade task performance. Deactivations in occipital areas were linked to schizotypy features, specifically negative schizotypy. Brain activation patterns in schizotypy were broadly consistent with those demonstrated previously across the schizophrenia spectrum. Findings might be interpreted as supporting the neural overlap between schizotypy and the schizophrenia spectrum and help in gaining a better understanding of the neuropathology underlying schizophrenia spectrum disorders. Study Three: Preliminary Findings of Heritability of the Neural Correlates of Antisaccade Performance Performance on the antisaccade task is impaired across the schizophrenia spectrum and in schizotypy, has been explicitly stated as one of the most useful endophenotypes across the schizophrenia spectrum (Greenwood, Light, Swerdlow, Radant, & Braff, 2012) and is therefore supposed to be a useful tool for revealing the neural correlates underlying these phenotypes. In a third study, we put this assumption to the test by investigating the amount of genetic influences on the neural correlates of antisaccade task performance. Using a twin fMRI design, we successfully replicated the commonly observed brain activations for the antisaccade task including activations in a fronto-parieto-occipital subcortical network. In a sample of one hundred thirty-two healthy same-sex reared-together twins (90 MZ; 32 male and 42 DZ; 24 male), who first performed the antisaccade task in the laboratory, we found evidence for significant genetic influences as estimated by heritability estimates of 47% (95% CI 22 to 65%) to antisaccade task performance. Of these participants, 96 twins (60 MZ, 28 male; 36 DZ, 22 male) underwent fMRI whilst performing the antisaccade task. We found tentative evidence for significant heritability of the blood oxygen level-dependent (BOLD) response in the left thalamus (50%, 95% CI: 18 to 72%) as shown in the contrast comparing the BOLD response during antisaccades with the BOLD response during prosaccades, an oculomotor control task. Due to the small sample of twins further replication in larger samples is warranted to firmly establish the amount of genetic influences on the neural correlates underlying antisaccade task performance.