Impact of Polygenic Risk for Schizophrenia on Cortical Structure in UK Biobank

Neilson, Emma; Shen, Xueyi; Cox, Simon R.; Clarke, Toni‐Kim; Wigmore, Eleanor M.; Gibson, Jude; Howard, David M.; Adams, Mark; Harris, Mat A.; Davies, Gail; Deary, Ian J.; Whalley, Heather C.; McIntosh, Andrew M.; Lawrie, Stephen M.

doi:10.1016/j.biopsych.2019.04.013

Cited by 65 publications

(98 citation statements)

References 109 publications

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“…Summary statistics from large-scale genome-wide association study (GWAS) allow the degree of genetic liability for a heritable trait to be estimated in healthy subjects outside the population in which the original GWAS was conducted 32,33 . Only a small number of studies have analyzed the relationship between polygenic risk score for schizophrenia (PRS SZ ) and neuroimaging biomarkers in healthy samples [32][33][34][35][36][37] but some of these associations map on to regions likely to be involved in the generation of psychotic symptoms and PLEs.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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 < 0.050); with the cortical thickness of the insula largely mediating the relationship between PRS 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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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show abstract

“…Summary statistics from large-scale GWAS allow the degree of genetic liability for a heritable trait to be estimated in healthy subjects outside the population in which the original GWAS was conducted [32,33]. Only a small number of studies have analysed the relationship between polygenic risk score for schizophrenia (PRSSZ) and neuroimaging biomarkers in healthy samples [32][33][34][35][36][37] but some of these associations map on to regions likely to be involved in the generation of psychotic symptoms and PLEs.…”

Section: Introductionmentioning

confidence: 99%

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

Cábez

Bastin

et al. 2019

Preprint

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AbstractSchizophrenia 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 (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 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. 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.

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“…T1 structural measures were processed using FreeSurfer version 5.3 42 to quantify the volumes of 14 subcortical structures as well as the volumes, surface area and thickness of 34 cortical regions per hemisphere according to the Desikan-Killany atlas 43 . Full details of the Freesurfer Quality Control (QC) steps are provided in supplementary materials and have also been reported in full previously 44 . Measures of thickness, surface area and volume were derived for each of the 68 cortical regions.…”

Section: Mri Acquisition and Analysesmentioning

confidence: 99%

DNA methylation signatures of C-reactive protein associations with structural neuroimaging measures and major depressive disorder

Green

Shen

Stevenson

et al. 2020

Preprint

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Background: Inflammatory processes are implicated in the aetiology of Major Depressive Disorder (MDD); however, the relationship between peripheral inflammation, brain structure and depression remains unclear. This study investigates associations between depression, structural neuroimaging measures and two measures of inflammation: serum-based C-reactive protein (CRP) and a methylation-based score for CRP (DNAm CRP) in a large community-based sample. Methods: Serum CRP and DNAm CRP were assessed for participants in Generation Scotland (nMDD cases= 240, nControls= 558) alongside structural brain scans (T1 and diffusion MRI). Linear regression was used to investigate associations between (i) both CRP measures and depressive symptoms, (ii) both CRP measures and structural imaging variables and (iii) inflammation x MDD interaction effects (for both CRP measures) with imaging measures. Results: Increased serum CRP was significantly associated with overall MDD symptom severity and specifically with somatic symptoms- general interest (β= 0.145, pFDR = 6x10-4) and energy levels (β= 0.101, pFDR = 0.027) and also reduced entorhinal cortex thickness (β= -0.095, pFDR = 0.037). DNAm CRP was significantly associated with reduced global grey matter/cortical volume and reduced integrity of 16 white matter tracts and showed larger effect sizes (βaverage= -0.15) compared to serum CRP across all measures (βaverage = 0.01). Conclusions: Acute measures of CRP were related to current depression symptoms, specifically somatic symptoms, whereas methylation signatures of inflammation demonstrated greater differences in global and regional brain structure. This study highlights the utility of combining serological and methylation markers to study chronic inflammation effects on the brain in psychiatric disorders.

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Impact of Polygenic Risk for Schizophrenia on Cortical Structure in UK Biobank

Cited by 65 publications

References 109 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

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

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

DNA methylation signatures of C-reactive protein associations with structural neuroimaging measures and major depressive disorder

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