scholarly journals 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

2019 ◽  
Author(s):  
C. Alloza ◽  
M. Blesa-Cábez ◽  
M.E. Bastin ◽  
J.W. Madole ◽  
C.R. Buchanan ◽  
...  
Keyword(s):  
Cortical Thickness ◽  
Large Population ◽  
Central Executive ◽  
Auditory Hallucinations ◽  
Risk Scores ◽  
Psychotic Symptoms ◽  
Polygenic Risk ◽  
Default Mode ◽  
Healthy Participants ◽  
Clinical Populations

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.

scholarly journals Effects of polygenic risk for major mental disorders and cross-disorder on cortical complexity

2021 ◽  
pp. 1-12
Author(s):  
Simon Schmitt ◽  
Tina Meller ◽  
Frederike Stein ◽  
Katharina Brosch ◽  
Kai Ringwald ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Mental Disorders ◽  
Cortical Thickness ◽  
Genetic Risk ◽  
Right Hemisphere ◽  
Autism Spectrum ◽  
Risk Scores ◽  
Grey Matter Volume ◽  
Polygenic Risk ◽  
Risk For Depression

Abstract Background MRI-derived cortical folding measures are an indicator of largely genetically driven early developmental processes. However, the effects of genetic risk for major mental disorders on early brain development are not well understood. Methods We extracted cortical complexity values from structural MRI data of 580 healthy participants using the CAT12 toolbox. Polygenic risk scores (PRS) for schizophrenia, bipolar disorder, major depression, and cross-disorder (incorporating cumulative genetic risk for depression, schizophrenia, bipolar disorder, autism spectrum disorder, and attention-deficit hyperactivity disorder) were computed and used in separate general linear models with cortical complexity as the regressand. In brain regions that showed a significant association between polygenic risk for mental disorders and cortical complexity, volume of interest (VOI)/region of interest (ROI) analyses were conducted to investigate additional changes in their volume and cortical thickness. Results The PRS for depression was associated with cortical complexity in the right orbitofrontal cortex (right hemisphere: p = 0.006). A subsequent VOI/ROI analysis showed no association between polygenic risk for depression and either grey matter volume or cortical thickness. We found no associations between cortical complexity and polygenic risk for either schizophrenia, bipolar disorder or psychiatric cross-disorder when correcting for multiple testing. Conclusions Changes in cortical complexity associated with polygenic risk for depression might facilitate well-established volume changes in orbitofrontal cortices in depression. Despite the absence of psychopathology, changed cortical complexity that parallels polygenic risk for depression might also change reward systems, which are also structurally affected in patients with depressive syndrome.

scholarly journals Neural correlates of polygenic risk score for autism spectrum disorders in general population

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Budhachandra Khundrakpam ◽  
Uku Vainik ◽  
Jinnan Gong ◽  
Noor Al-Sharif ◽  
Neha Bhutani ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
White Matter ◽  
General Population ◽  
Cortical Thickness ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Risk Scores ◽  
Polygenic Risk ◽  
Cortical Regions ◽  
White Matter Connectivity

Abstract Autism spectrum disorder is a highly prevalent and highly heritable neurodevelopmental condition, but studies have mostly taken traditional categorical diagnosis approach (yes/no for autism spectrum disorder). In contrast, an emerging notion suggests a continuum model of autism spectrum disorder with a normal distribution of autistic tendencies in the general population, where a full diagnosis is at the severe tail of the distribution. We set out to investigate such a viewpoint by investigating the interaction of polygenic risk scores for autism spectrum disorder and Age2 on neuroimaging measures (cortical thickness and white matter connectivity) in a general population (n = 391, with age ranging from 3 to 21 years from the Pediatric Imaging, Neurocognition and Genetics study). We observed that children with higher polygenic risk for autism spectrum disorder exhibited greater cortical thickness for a large age span starting from 3 years up to ∼14 years in several cortical regions localized in bilateral precentral gyri and the left hemispheric postcentral gyrus and precuneus. In an independent case–control dataset from the Autism Brain Imaging Data Exchange (n = 560), we observed a similar pattern: children with autism spectrum disorder exhibited greater cortical thickness starting from 6 years onwards till ∼14 years in wide-spread cortical regions including (the ones identified using the general population). We also observed statistically significant regional overlap between the two maps, suggesting that some of the cortical abnormalities associated with autism spectrum disorder overlapped with brain changes associated with genetic vulnerability for autism spectrum disorder in healthy individuals. Lastly, we observed that white matter connectivity between the frontal and parietal regions showed significant association with polygenic risk for autism spectrum disorder, indicating that not only the brain structure, but the white matter connectivity might also show a predisposition for the risk of autism spectrum disorder. Our findings showed that the fronto-parietal thickness and connectivity are dimensionally related to genetic risk for autism spectrum disorder in general population and are also part of the cortical abnormalities associated with autism spectrum disorder. This highlights the necessity of considering continuum models in studying the aetiology of autism spectrum disorder using polygenic risk scores and multimodal neuroimaging.

scholarly journals O4.4. REAL TIME FMRI NEUROFEEDBACK TARGETING STG AND DMN REDUCES AUDITORY HALLUCINATIONS

2020 ◽  
Vol 46 (Supplement_1) ◽  
pp. S10-S10
Author(s):  
Margaret Niznikiewicz ◽  
Kana Okano ◽  
Clemens Bauer ◽  
Paul Nestor ◽  
Elizabetta Del Re ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Real Time ◽  
Default Mode Network ◽  
Superior Temporal Gyrus ◽  
Brain Regions ◽  
Central Executive ◽  
Auditory Hallucinations ◽  
Default Mode ◽  
Central Executive Network ◽  
Voice Recording

Abstract Background Auditory hallucinations (AH) are one of the core symptoms of schizophrenia (SZ) and constitute a significant source of suffering and disability. One third of SZ patients experience pharmacology-resistant AH, so an alternative/complementary treatment strategy is needed to alleviate this debilitating condition. In this study, real-time functional Magnetic Resonance Imaging neurofeedback (rt-fMRI NFB), a non-invasive technique, was used to help 10 SZ patients modulate their brain activity in key brain regions belonging to the network involved in the experience of auditory hallucinations. In two experiments we selected two different brain targets. 1. the superior temporal gyrus (STG) and 2. default mode network (DMN)-central executive network (CEN) connectivity. STG is a key area in the neurophysiology of AH. Hyperactivation of the default mode network (DMN) and of the superior temporal gyrus (STG) in SZ has been shown in imaging studies. Furthermore, several studies point to reduced anticorrelation between the DMN and the central executive network (CEN). Finally, DMN hyperconnectivity has been associated with positive symptoms such as AHs while reduced DMN anticorrelations have been associated with cognitive impairment. Methods In the STG-focused NFB experiment, subjects were trained to upregulate the STG activity while listening to their own voice recording and downregulate it while ignoring a stranger’s voice recording in the course of 21 min NFB session. Visual feedback was provided to subjects at the end of each run from their own STG activity in the form of a thermometer. AH were assessed with auditory hallucination scale pre-NFB and within a week after the NFB session. The DMN-CEN focused NFB experiment was conducted about 1 month later to minimize the carry over effects from the STG-focused NFB and was designed to help SZ patients modulate their DMN and CEN networks. DMN and CEN networks were defined individually for each subject. The goal of the task was to increase CEN-DMN anti-correlations. To achieve that patients were provided with meditation strategies to guide their performance. Feedback was provided in the form of a ball that traveled up if the modulation of DMN-CEN connectivity was successful and traveled down if it was not successful. AH measures were taken before the NFB session and within a week after the session. Results In the STG-focused NFB task, significant STG activation reduction was found in the comparison of pre- relative to post-NFB in the condition of ignoring another person’s voice (p&lt;0.05), FWE-TFCE corrected. AH were also significantly reduced (p&lt;0.01). Importantly, significant correlation was found between reductions in the STG activation and AH reductions (r=.83). In the DMN-CEN focused NFB task, significant increase in the anti-correlations between medial prefrontal cortex (mPFC) and dorsolateral prefrontal cortex (DLPFC) (p&lt;0.05) was observed as well as significant reduction in the mPFC-PCC connectivity (p &lt;0.05), in the pre-post NFB comparisons. AH were significantly reduced in post- relative to pre-NFB comparison (p&lt;0.02). Finally, there was a significant correlation between individual scores in mPFC-STG connectivity and AH reductions. Discussion These the two experiments suggest that targeting both the STG BOLD activation and DMN-CEN connectivity in NFB tasks aimed at AH reduction result both in brain changes and in AH reductions. Together, these results provide strong preliminary support for the NFB use as a means to impact brain function leading to reductions in AH in SZ. Importantly, these results suggest that AH result from brain abnormalities in a network of brain regions and that targeting a brain region belonging to this network will lead to AH symptom reduction.

Stressful Life Events and Self-Control: Testing Gene x Environment Interaction with a Polygenic Approach

2019 ◽  
Author(s):  
Yayouk Willems ◽  
Jouke-Jan Hottenga ◽  
Lannie Ligthart ◽  
Gonneke WIllemsen ◽  
Dorret Boomsma ◽  
...  
Keyword(s):  
Complex Traits ◽  
Large Population ◽  
Self Control ◽  
Risk Scores ◽  
Life Stressors ◽  
Control Problems ◽  
Environment Interaction ◽  
Polygenic Risk ◽  
Polygenic Scores ◽  
Low Self Control

Background: Ill decisions and reckless behaviors due to low self-control are concurrently and longitudinally costly, and revealing possible factors contributing to individual differences in self-control is necessary. It is hypothesized that genetically sensitivity interacts with life stressors in the prediction of the development of low self-control (gene environment interaction), yet attempts to test this hypothesis mostly concern candidate gene studies yielding inconclusive results. The goal of this research was to bring findings from large scale gene identification studies into the developmental psychology framework, taking the polygenic nature of complex traits into account. Methods: Using data of a large population-based twin sample, we tested whether polygenic risk scores for self-control problems – based on the most recent ADHD GWAS – predict self-control problems in adults, and whether this polygenic risk scores interact with the presence of environmental stressors. Results: While polygenic scores and life stressors significantly predicted low self-control, we did not find a significant interaction effect. Conclusions: Empirically, finding statistical evidence for this hypothesis remains a challenge, and more research is needed to investigate how to better detect G x E.

The use of Polygenic Risk Scores to Inform Aetiology of Mood and Psychotic Disorders

2017 ◽  
Vol 41 (S1) ◽  
pp. S166-S166
Author(s):  
J. Harrison ◽  
S. Mistry
Keyword(s):  
Bipolar Disorder ◽  
Genetic Basis ◽  
Psychotic Disorders ◽  
Mental Illnesses ◽  
Risk Scores ◽  
Psychotic Symptoms ◽  
Polygenic Risk ◽  
Genetic Overlap ◽  
Competing Interest

IntroductionPolygenic risk scores (PRS) incorporate many small genetic markers that are associated with conditions. This technique was first used to investigate mental illnesses in 2009. Since then, it has been widely used.ObjectivesWe wanted to explore how PRS have been used to the study the aetiology of psychosis, schizophrenia, bipolar disorder and depression.AimsWe aimed to conduct a systematic review, identifying studies that have examined associations between PRS for bipolar disorder, schizophrenia/psychosis and depression and psychopathology-related outcome measures.MethodsWe searched EMBASE, Medline and PsychInfo from 06/08/2009 to 14/03/2016. We hand-searched the reference lists of related papers.ResultsAfter removing duplicates, the search yielded 1043 publications. When irrelevant articles were excluded, 33 articles remained. We found 24 studies using schizophrenia PRS, three using bipolar PRS and nine using depression PRS. Many studies successfully used PRS to predict case/control status. Some studies showed associations between PRS and diagnostic sub-categories. A range of clinical phenotypes and symptoms has been explored. For example, specific PRS are associated with cognitive performance in schizophrenia, psychotic symptoms in bipolar disorder, and frequency of episodes of depression. PRS have also demonstrated genetic overlap between mental illnesses. It was difficult to assess the quality of some studies as not all reported sufficient methodological detail.ConclusionsPRS have enabled us to explore the polygenic architecture of mental illness and demonstrate a genetic basis for some observed features. However, they have yet to give insights into the biology, which underpin mental illnesses.Disclosure of interestThe authors have not supplied their declaration of competing interest.

scholarly journals Cannabis, schizophrenia genetic risk, and psychotic experiences: a cross-sectional study of 109,308 participants from the UK Biobank

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Michael Wainberg ◽  
Grace R. Jacobs ◽  
Marta di Forti ◽  
Shreejoy J. Tripathy
Keyword(s):  
Cross Sectional Study ◽  
Cannabis Use ◽  
Auditory Hallucinations ◽  
Risk Scores ◽  
Visual Hallucinations ◽  
Psychotic Experiences ◽  
Sectional Study ◽  
Cross Sectional ◽  
Persecutory Delusions ◽  
Polygenic Risk

AbstractCannabis is known to produce acute, transient psychotic-like experiences. However, it is unclear whether cannabis disproportionately increases the risk of specific types of psychotic experiences and whether genetic predisposition influences the relationship between cannabis use and psychotic experiences. In this cross-sectional study of 109,308 UK Biobank participants, we examined how schizophrenia polygenic risk modulates the association between self-reported cannabis use and four types of self-reported psychotic experiences (auditory hallucinations, visual hallucinations, persecutory delusions, and delusions of reference). Cohort-wide, we found a strong, dose-dependent relationship between cannabis use and all four types of psychotic experiences, especially persecutory delusions. Cannabis users’ psychotic experiences tended to be earlier-onset and cause greater distress than non-users’, but were not more likely to lead to help-seeking. Participants with high schizophrenia polygenic risk scores showed stronger associations between cannabis use and auditory hallucinations, visual hallucinations, and delusions of reference, as well as psychotic experiences overall. For instance, cannabis ever-use was associated with 67% greater adjusted odds of delusions of reference among individuals in the top fifth of polygenic risk, but only 7% greater adjusted odds among the bottom fifth. Our results suggest that cannabis use is a predictive risk factor for psychotic experiences, including early-onset and distressing experiences. Individuals genetically predisposed to schizophrenia may be especially vulnerable to psychotic experiences as a result of using cannabis, supporting a long-postulated hypothesis. This study exemplifies the utility of population-scale biobanks for elucidating gene-by-environment interactions relating substance use to neuropsychiatric outcomes and points to the translational potential of using polygenic risk scores to inform personalized harm reduction interventions.

scholarly journals Associations between polygenic liability for schizophrenia and level of psychosis and mood-incongruence in bipolar disorder

2017 ◽  
Author(s):  
Judith Allardyce ◽  
Ganna Leonenko ◽  
Marian Hamshere ◽  
Antonio F. Pardiñas ◽  
Liz Forty ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Logistic Regression ◽  
Multinomial Logistic Regression ◽  
Bipolar Affective Disorder ◽  
Research Network ◽  
Risk Scores ◽  
Psychotic Symptoms ◽  
P Value ◽  
Polygenic Risk ◽  
Psychotic Features

AbstractImportanceBipolar disorder (BD) overlaps schizophrenia in its clinical presentation and genetic liability. Alternative approaches to patient stratification beyond current diagnostic categories are needed to understand the underlying disease processes/mechanisms.ObjectivesTo investigate the relationship between common-variant liability for schizophrenia, indexed by polygenic risk scores (PRS) and psychotic presentations of BD, using clinical descriptions which consider both occurrence and level of mood-incongruent psychotic features.DesignCase-control design: using multinomial logistic regression, to estimate differential associations of PRS across categories of cases and controls.Settings & Participants4399 BDcases, mean [sd] age-at-interview 46[12] years, of which 2966 were woman (67%) from the BD Research Network (BDRN) were included in the final analyses, with data for 4976 schizophrenia cases and 9012 controls from the Type-1 diabetes genetics consortium and Generation Scotland included for comparison.ExposureStandardised PRS, calculated using alleles with an association p-value threshold < 0.05 in the second Psychiatric Genomics Consortium genome-wide association study of schizophrenia, adjusted for the first 10 population principal components and genotyping-platform.Main outcome measureMultinomial logit models estimated PRS associations with BD stratified by (1) Research Diagnostic Criteria (RDC) BD subtypes (2) Lifetime occurrence of psychosis.(3) Lifetime mood-incongruent psychotic features and (4) ordinal logistic regression examined PRS associations across levels of mood-incongruence. Ratings were derived from the Schedule for Clinical Assessment in Neuropsychiatry interview (SCAN) and the Bipolar Affective Disorder Dimension Scale (BADDS).ResultsAcross clinical phenotypes, there was an exposure-response gradient with the strongest PRS association for schizophrenia (RR=1.94, (95% C.1.1.86, 2.01)), then schizoaffective BD (RR=1.37, (95% C.I. 1.22, 1.54)), BD I (RR= 1.30, (95% C.I. 1.24, 1.36)) and BD II (RR=1.04, (95% C.1. 0.97, 1.11)). Within BD cases, there was an effect gradient, indexed by the nature of psychosis, with prominent mood-incongruent psychotic features having the strongest association (RR=1.46, (95% C.1.1.36, 1.57)), followed by mood-congruent psychosis (RR= 1.24, (95% C.1. 1.17, 1.33)) and lastly, BD cases with no history of psychosis (RR= 1.09, (95% C.1. 1.04, 1.15)).ConclusionWe show for the first time a polygenic-risk gradient, across schizophrenia and bipolar disorder, indexed by the occurrence and level of mood-incongruent psychotic symptoms.

scholarly journals Dissection of Major Depressive Disorder using polygenic risk scores for Schizophrenia in two independent cohort

2016 ◽  
Author(s):  
HC Whalley ◽  
MJ Adams ◽  
LS Hall ◽  
T-K Clarke ◽  
AM Fernandez-Pujals ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Psychological Distress ◽  
Depressive Disorder ◽  
Genetic Risk ◽  
Large Population ◽  
Case Control ◽  
Risk Scores ◽  
Uk Biobank ◽  
Major Depressive ◽  
Polygenic Risk

AbstractMajor depressive disorder (MDD) is known for its substantial clinical and suspected causal heterogeneity. It is characterised by low mood, psychomotor slowing, and increased levels of the personality trait neuroticism; factors which are also associated with schizophrenia (SCZ). It is possible that some cases of MDD may have a substantial genetic loading for SCZ. A sign of the presence of SCZ-like MDD sub-groups would be indicated by an interaction between MDD status and polygenic risk of SCZ on cognitive, personality and mood measures. In the current study, we hypothesised that higher SCZ-polygenic risk would define larger MDD case-control differences in cognitive ability, and smaller differences in distress and neuroticism. Polygenic risk scores (PGRS) for SCZ and their association with cognitive variables, neuroticism, mood, and psychological distress were estimated in a large population-based cohort (Generation Scotland: Scottish Family Health Study, GS:SFHS). Individuals were divided into those with, and without, depression (n=2587 & n=16,764 respectively) to test whether there was an interaction between MDD status and schizophrenia risk. Replication was sought in UK Biobank (n=33,525). In both GS:SFHS and UK Biobank we found significant interactions between SCZ-PGRS and MDD status for measures of psychological distress and neuroticism. In both cohorts there was a reduction of case-control differences on a background of higher genetic risk of SCZ. These findings suggest that depression on a background of high genetic risk for SCZ may show attenuated associations with distress and neuroticism. This may represent a causally distinct form of MDD more closely related to SCZ.

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