Psychotic-like experiences, polygenic risk scores for schizophrenia and structural properties of the salience, default mode and central-executive networks in healthy participants from UK Biobank

Abstract

<jats:title>Abstract</jats:title><jats:p>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) including information on PLEs, polygenic risk scores for schizophrenia (PRS<jats:sub>SZ</jats:sub>) 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 PRS<jats:sub>SZ</jats:sub> and PLEs. PRS<jats:sub>SZ</jats:sub> was significantly associated with a latent measure of cortical thickness across the salience network (r = −0.069, <jats:italic>p</jats:italic> = 0.010) and PLEs showed a number of significant associations with properties of the salience and default mode networks (involving the insular cortex, supramarginal gyrus and pars orbitalis, <jats:italic>p<jats:sub>FDR</jats:sub></jats:italic> &lt; 0.050); with the cortical thickness of the insula largely mediating the relationship between PRS<jats:sub>SZ</jats:sub> and auditory hallucinations. These results are consistent with the hypothesis that higher genetic liability for schizophrenia is related to subtle disruptions in brain structure and predisposes 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.</jats:p>

Polygenic Risk for Schizophrenia, Brain Structure, and Environmental Risk in UK Biobank

“…For regional measures, we replicated significant associations with reduced CT in insula, lateral orbitofrontal cortex, and inferior frontal gyrus, as reported in previous studies in UK Biobank. 5,12,58 In addition, we observed reduced CT within the frontal lobe, medial orbitofrontal cortex, and posterior cingulate cortex. Reduced CT in these regions has been commonly observed in individuals with schizophrenia 3,17,[59][60][61] and in individuals at high genetic risk of schizophrenia.…”

“…Reduced CT in these regions has been commonly observed in individuals with schizophrenia 3,17,[59][60][61] and in individuals at high genetic risk of schizophrenia. 24,59,62 These regions may also be implicated in the symptoms seen in schizophrenia: the insula is engaged in auditory hallucinations 58 ; the orbitofrontal cortex is thought to play a role in negative symptoms 63 ; and the frontal lobe has shown associations with cognitive impairment in schizophrenia. 64…”

“…[67][68][69] Similarly, the involvement of supramarginal and inferior frontal cortex in auditory hallucinations has been extensively documented 70 and the supramarginal gyrus is associated with delusions of reference and persecutory delusions. 58 Individual differences in these regions may represent general susceptibility to psychotic symptoms and vulnerability to developing schizophrenia.…”

Grey matter morphometric biomarkers for classifying early schizophrenia and PD psychosis: a multicentre study

“…Those regions are highly relevant for the psychopathology in psychosis, and structural alterations are well described in these areas (de Moura et al, 2018; Glahn et al, 2008; Meda et al, 2008; Tanskanen et al, 2010; van Erp et al, 2016; van Haren et al, 2016; Veijola et al, 2014; Vos et al, 2015; Wood et al, 2001). Also functional alterations have been detected in those areas, with regard to functional connectivity in general and in the default and salience networks specifically (Alloza et al, 2020; Avram et al, 2020; Du et al, 2018; Jukuri et al, 2013; Littow et al, 2015; Manoliu et al, 2014; Palaniyappan and Liddle, 2012), as well as cognitive, reward and salience processing (Boehme et al, 2015; Borgan et al, 2021; Ermakova et al, 2018; Haarsma et al, 2020; Katthagen et al, 2020; Kesby et al, 2021; Knolle et al, 2018).…”

Genetic factors influencing a neurobiological substrate for psychiatric disorders

“…An alternative explanation implies that reduced GM exists before disease onset, shaped by genetic or early environmental influences such as childhood adversity (14): Here, premorbid structural abnormalities of the salience network could increase a subject's vulnerability to psychiatric disease. More recently, structural salience network integrity was reported to mediate between polygenic risk for schizophrenia and auditory hallucinations (15). A third explanation involves brain-aging processes that occur in a network-dependent way and often with a strong non-linear component (16)(17)(18): Here, accelerated aging could increase the disease risk over the lifespan by genetic or environmental factors.…”