Dataset Information

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: 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 (PRS_SZ) 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_SZ and PLEs. PRS_SZ 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, p_FDR?SZ 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.

SUBMITTER: Alloza C

PROVIDER: S-EPMC7186224 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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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.

Alloza C C Blesa-Cábez M M Bastin M E ME Madole J W JW Buchanan C R CR Janssen J J Gibson J J Deary I J IJ Tucker-Drob E M EM Whalley H C HC Arango C C McIntosh A M AM Cox S R SR Lawrie S M SM

Translational psychiatry 20200427 1

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 ...[more]

PMID: 32341335

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Project description:BackgroundSchizophrenia is a heritable psychiatric disorder with a polygenic architecture. Genome-wide association studies have reported that an increasing number of risk-associated variants and polygenic risk scores (PRSs) explain 17% of the variance in the disorder. Substantial heterogeneity exists in the effect of these variants, and aggregating them based on biologically relevant functions may provide mechanistic insight into the disorder.MethodsUsing the largest schizophrenia genome-wide association study conducted to date, we associated PRSs based on 5 gene sets previously found to contribute to schizophrenia pathophysiology-postsynaptic density of excitatory synapses, postsynaptic membrane, dendritic spine, axon, and histone H3-K4 methylation-along with respective whole-genome PRSs, with neuroimaging (n > 29,000) and reported psychotic-like experiences (n > 119,000) variables in healthy UK Biobank subjects.ResultsSeveral variables were significantly associated with the axon gene-set (psychotic-like communications, parahippocampal gyrus volume, fractional anisotropy thalamic radiations, and fractional anisotropy posterior thalamic radiations (β range -0.016 to 0.0916, false discovery rate-corrected p [pFDR] ≤ .05), postsynaptic density gene-set (psychotic-like experiences distress, global surface area, and cingulate lobe surface area [β range -0.014 to 0.0588, pFDR ≤ .05]), and histone gene set (entorhinal surface area: β = -0.016, pFDR = .035). From these, whole-genome PRSs were significantly associated with psychotic-like communications (β = 0.2218, pFDR = 1.34 × 10-7), distress (β = 0.1943, pFDR = 7.28 × 10-16), and fractional anisotropy thalamic radiations (β = -0.0143, pFDR = .036). Permutation analysis revealed that these associations were not due to chance.ConclusionsOur results indicate that genetic variation in 3 gene sets relevant to schizophrenia may confer risk for the disorder through effects on previously implicated neuroimaging variables. Because associations were stronger overall for whole-genome PRSs, findings here highlight that selection of biologically relevant variants is not yet sufficient to address the heterogeneity of the disorder.

Dataset Information

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.

Publications

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.

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