Abstract
Schizophrenia is a highly heritable disorder with considerable phenotypic heterogeneity. Hallmark psychotic symptoms can be considered as existing on a continuum from non-clinical to clinical populations. Assessing genetic risk and psychotic-like experiences (PLEs) in non-clinical populations and their associated neurobiological underpinnings can offer valuable insights into symptom-associated brain mechanisms without the potential confounds of the effects of schizophrenia and its treatment. We leveraged a large population-based cohort (UKBiobank, N = 3875) including information on PLEs (obtained from the Mental Health Questionnaire (MHQ); UKBiobank Category: 144; N auditory hallucinations = 55, N visual hallucinations = 79, N persecutory delusions = 16, N delusions of reference = 13), polygenic risk scores for schizophrenia (PRSSZ) and multi-modal brain imaging in combination with network neuroscience. Morphometric (cortical thickness, volume) and water diffusion (fractional anisotropy) properties of the regions and pathways belonging to the salience, default-mode, and central-executive networks were computed. We hypothesized that these anatomical concomitants of functional dysconnectivity would be negatively associated with PRSSZ and PLEs. PRSSZ was significantly associated with a latent measure of cortical thickness across the salience network (r = −0.069, p = 0.010) and PLEs showed a number of significant associations, both negative and positive, with properties of the salience and default mode networks (involving the insular cortex, supramarginal gyrus, and pars orbitalis, pFDR < 0.050); with the cortical thickness of the insula largely mediating the relationship between PRSSZ and auditory hallucinations. Generally, these results are consistent with the hypothesis that higher genetic liability for schizophrenia is related to subtle disruptions in brain structure and may predispose to PLEs even among healthy participants. In addition, our study suggests that networks engaged during auditory hallucinations show structural associations with PLEs in the general population.
Highlights
Schizophrenia is associated with a range of alterations in brain structure and function[1,2,3,4], some of which are related to a family history or specific genetic risk factors
In this study we investigated how polygenic risk scores for schizophrenia (PRSSZ) relates to neuroanatomical properties of the salience network, default mode network (DMN), and centralexecutive network (CEN), and thence to Psychotic-like experiences (PLEs); in addition to formally testing whether the association between PRSSZ and PLEs was mediated by brain structure
Central executive network Linear regressions for individual network components No significant associations were found between the grey matter volume (GMV), cortical thickness (CT) or FA and PRSSZ, or the interaction between PRSSZ × age (p > 0.050)
Summary
Schizophrenia is associated with a range of alterations in brain structure and function[1,2,3,4], some of which are related to a family history or specific genetic risk factors. Consistent relationships between delusions, hallucinations, and brain structure and function have, proved elusive—potentially because of power issues in relatively small clinical samples and confounds such as Alloza et al Translational Psychiatry (2020)10:122 antipsychotic drug exposure and substance abuse. A recent study found shared genetic aetiology between PLEs and several psychiatric and neurodevelopmental disorders, indicating that PLEs may be related to a general risk for mental health disorders[9]. Studies of the relationship between PLEs and brain imaging metrics have, been scarce and characterized by small sample sizes (with N ranging from 25 for auditory hallucinations to 76 for any PLEs10–13). PLEs have been associated with altered brain dynamics, in particular with default-mode hypoconnectivity[11,14]
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