Browsing by Author "Toulopoulou, Timothea"

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Open Access
The Association between familial risk and brain abnormalities Is disease specific: an ENIGMA-relatives study of schizophrenia and bipolar disorder
(Elsevier, 2019) Zwarte, S. M. C.; Brouwer, R. M.; Agartz, I.; Alda, M.; Aleman, A.; Alpert, K. I.; Bearden, C. E.; Bertolino, A.; Bois, C.; Bonvino, A.; Bramon, E.; Buimer, E.; Cahn, W.; Cannon, D. M.; Cannon, T. D.; Caseras, X.; Castro-Fornieles, J.; Chen, Q.; Serna, E.; Giorgio, A. D.; Doucet, G.; Eker, M. C.; Erk, S.; Fears, S.; Foley, S.; Frangou, S.; Frankland, A.; Fullerton, J.; Glahn, D.; Goghari, V.; Goldman, A.; Gonul, A.; Gruber, O.; Haan, L.; Hajek, T.; Hawkins, E.; Heinz, A.; Hillegers, M.; Pol, H.; Hultman, C.; Ingvar, M.; Johansson, V.; Jönsson, E.; Kane, K.; Kempton, M.; Koenis, M.; Kopecek, M.; Krabbendam, L.; Krämer, B.; Lawrie, S.; Lenroot, R.; Marcelis, M.; Marsman, J-B; Mattay, V.; McDonald, C.; Meyer-Lindenberg, A.; Michielse, S.; Mitchell, P.; Moreno, D.; Murray, R.; Mwangi, B.; Najt, P.; Neilson, E.; Newport, J.; Os, J.; Overs, B.; Özerdem, A.; Picchioni, M.; Richter, A.; Roberts, G.; Aydoğan, A. S.; Schofield, P.; Şimşek, F.; Soares, J.; Sugranyes, G.; Toulopoulou, Timothea; Tronchin, G.; Walter, H.; Wang, L.; Weinberger, D.; Whalley, H.; Yalın, N.; Andreassen, O.; Ching, C.; Erp, T.; Turner, J.; Jahanshad, N.; Thompson, P.; Kahn, R.; Haren, N.
Abstract Background Schizophrenia and bipolar disorder share genetic liability, and some structural brain abnormalities are common to both conditions. First-degree relatives of patients with schizophrenia (FDRs-SZ) show similar brain abnormalities to patients, albeit with smaller effect sizes. Imaging findings in first-degree relatives of patients with bipolar disorder (FDRs-BD) have been inconsistent in the past, but recent studies report regionally greater volumes compared with control subjects. Methods We performed a meta-analysis of global and subcortical brain measures of 6008 individuals (1228 FDRs-SZ, 852 FDRs-BD, 2246 control subjects, 1016 patients with schizophrenia, 666 patients with bipolar disorder) from 34 schizophrenia and/or bipolar disorder family cohorts with standardized methods. Analyses were repeated with a correction for intracranial volume (ICV) and for the presence of any psychopathology in the relatives and control subjects. Results FDRs-BD had significantly larger ICV (d = +0.16, q < .05 corrected), whereas FDRs-SZ showed smaller thalamic volumes than control subjects (d = −0.12, q < .05 corrected). ICV explained the enlargements in the brain measures in FDRs-BD. In FDRs-SZ, after correction for ICV, total brain, cortical gray matter, cerebral white matter, cerebellar gray and white matter, and thalamus volumes were significantly smaller; the cortex was thinner (d < −0.09, q < .05 corrected); and third ventricle was larger (d = +0.15, q < .05 corrected). The findings were not explained by psychopathology in the relatives or control subjects. Conclusions Despite shared genetic liability, FDRs-SZ and FDRs-BD show a differential pattern of structural brain abnormalities, specifically a divergent effect in ICV. This may imply that the neurodevelopmental trajectories leading to brain anomalies in schizophrenia or bipolar disorder are distinct.
Open Access
Associations between psychosis endophenotypes across brain functional, structural, and cognitive domains
(Cambridge University Press, 2018) Blakey, R.; Ranlund, S.; Zartaloudi, E.; Cahn, W.; Calafato, S.; Colizzi, M.; Crespo-Facorro, B.; Daniel, C.; Díez-Revuelta, A.; Forti, M. D.; Iyegbe, C.; Jablensky, A.; Jones, R.; Hall, M. -H.; Kahn, R.; Kalaydjieva, L.; Kravariti, E.; Lin, K.; McDonald, C.; McIntosh, A. M.; Picchioni, M.; Powell, J.; Presman, A.; Rujescu, D.; Schulze, K.; Shaikh, M.; Thygesen, J. H.; Toulopoulou, Timothea; Haren, N. V.; Os, J. V.; Walshe, M.; Murray, R. M.; Bramon, E.
Background A range of endophenotypes characterise psychosis, however there has been limited work understanding if and how they are inter-related.Methods This multi-centre study includes 8754 participants: 2212 people with a psychotic disorder, 1487 unaffected relatives of probands, and 5055 healthy controls. We investigated cognition [digit span (N = 3127), block design (N = 5491), and the Rey Auditory Verbal Learning Test (N = 3543)], electrophysiology [P300 amplitude and latency (N = 1102)], and neuroanatomy [lateral ventricular volume (N = 1721)]. We used linear regression to assess the interrelationships between endophenotypes.Results The P300 amplitude and latency were not associated (regression coef.-0.06, 95% CI-0.12 to 0.01, p = 0.060), and P300 amplitude was positively associated with block design (coef. 0.19, 95% CI 0.10-0.28, p < 0.001). There was no evidence of associations between lateral ventricular volume and the other measures (all p > 0.38). All the cognitive endophenotypes were associated with each other in the expected directions (all p < 0.001). Lastly, the relationships between pairs of endophenotypes were consistent in all three participant groups, differing for some of the cognitive pairings only in the strengths of the relationships.Conclusions The P300 amplitude and latency are independent endophenotypes; the former indexing spatial visualisation and working memory, and the latter is hypothesised to index basic processing speed. Individuals with psychotic illnesses, their unaffected relatives, and healthy controls all show similar patterns of associations between endophenotypes, endorsing the theory of a continuum of psychosis liability across the population.
Open Access
Correlates of psychotic like experiences (PLEs) during Pandemic: An online study investigating a possible link between the SARS-CoV-2 infection and PLEs among adolescents
(Elsevier B.V., 2022-01-05) Yilmaz Kafali, Helin; Turan, Serkan; Akpınar, Serap; Mutlu, Müge; Özkaya Parlakay, Aslınur; Çöp, Esra; Toulopoulou, Timothea
Background This study investigated whether SARS-CoV-2 infection, depression, anxiety, sleep problems, cigarette, alcohol, drug usage contribute to psychotic-like experiences (PLEs) among adolescents during the pandemic. We also aimed to explore whether baseline inflammatory markers or the number of SARS-CoV-2-related symptoms are associated with PLEs, and the latter is mediated by internalizing symptoms. Methods Altogether, 684 adolescents aged 12–18 (SARS-CoV-2 group n = 361, control group (CG) n = 323) were recruited. The Community Assessment of Psychic Experiences-42-Positive Dimension (CAPE-Pos), Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), and Pittsburg Sleep Quality Index (PSQI) questionnaires were completed by all volunteers using an online survey. C-reactive Protein and hemogram values, and SARS-CoV-2-related symptoms during the acute infection period were recorded in the SARS-CoV-2 group. Group comparisons, correlations, logistic regression, and bootstrapped mediation analyses were performed. Results CAPE-Pos-Frequency/Stress scores were significantly higher, whereas GAD-7-Total and PSQI-Total scores were significantly lower in SARS-CoV-2 than CG. Among the SARS-CoV-2 group, monocyte count and the number of SARS-CoV-2-symptoms were positively correlated with CAPE-Pos-Frequency/Stress scores. Besides SARS-CoV-2, cigarette use, GAD-7, and PHQ-9 scores significantly contributed to the presence of at least one CAPE-Pos “often” or “almost always”. PHQ-9 and GAD-7 fully mediated the relationship between the number of SARS-CoV-2 symptoms and CAPE-Pos-Frequency. Conclusions This study is the first to show a possible relationship between SARS-CoV-2 infection and PLEs among adolescents. Depression, anxiety, and cigarette use also contributed to PLEs. The number of SARS-Cov-2-symptoms and PLEs association was fully mediated by internalizing symptoms, but prospective studies will need to confirm this result.
Open Access
DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia
(eLife Sciences Publications Ltd., 2021-02-26) Hannon, E.; Dempster, E. L.; Mansell, G.; Burrage, J.; Bass, N.; Bohlken, M. M.; Corvin, A.; Curtis, C. J.; Dempster, D.; Forti, M. D.; Dinan, T. G.; Donohoe, G.; Gaughran, F.; Gill, M.; Gillespie, A.; Gunasinghe, C.; Hulshoff, H. E.; Hultman, C. M.; Johansson, V.; Kahn, R. S.; Kaprio, J.; Kenis, G.; Kowalec, K.; MacCabe, J.; McDonald, C.; McQuillin, A.; Morris, D. W.; Murphy, K. C.; Mustard, C. J.; Nenadic, I.; O'Donovan, M. C.; Quattrone, D.; Richards, A. L.; Richards, Bart PF; Clair, David St; Therman, T.; Toulopoulou, Timothea; Os, Jim Van; Waddington, J. L.; Sullivan, P.; Vassos, E.; Breen, G.; Collier, D. A.; Murray, R. M.; Schalkwyk, L. S.; Mill, J.
We performed a systematic analysis of blood DNA methylation profiles from 4483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.
Open Access
Effects of psychosis-associated genetic markers on brain volumetry: A systematic review of replicated findings and an independent validation
(Cambridge University Press, 2022-09-28) Ribeiro, Nuno Vouga; Tavares, Vânia; Bramon, Elvira; Toulopoulou, Timothea; Valli, Isabel; Shergill, Sukhi; Murray, Robin; Prata, Diana
Background. Given psychotic illnesses’ high heritability and associations with brain structure, numerous neuroimaging-genetics findings have been reported in the last two decades. However, few findings have been replicated. In the present independent sample we aimed to replicate any psychosis-implicated SNPs (single nucleotide polymorphisms), which had previously shown at least two main effects on brain volume. Methods. A systematic review for SNPs showing a replicated effect on brain volume yielded 25 studies implicating seven SNPs in five genes. Their effect was then tested in 113 subjects with either schizophrenia, bipolar disorder, ‘at risk mental state’ or healthy state, for whole-brain and region-of-interest (ROI) associations with grey and white matter volume changes, using voxel-based morphometry. Results. We found FWER-corrected (Family-wise error rate) (i.e. statistically significant) associations of: (1) CACNA1C-rs769087-A with larger bilateral hippocampus and thalamus white matter, across the whole brain; and (2) CACNA1C-rs769087-A with larger superior frontal gyrus, as ROI. Higher replication concordance with existing literature was found, in decreasing order, for: (1) CACNA1C-rs769087-A, with larger dorsolateral-prefrontal/superior frontal gyrus and hippocampi (both with anatomical and directional concordance); (2) ZNF804Ars11681373-A, with smaller angular gyrus grey matter and rectus gyri white matter (both with anatomical and directional concordance); and (3) BDNF-rs6265-T with superior frontal and middle cingulate gyri volume change (with anatomical and allelic concordance). Conclusions. Most literature findings were not herein replicated. Nevertheless, high degree/ likelihood of replication was found for two genome-wide association studies- and one candidate-implicated SNPs, supporting their involvement in psychosis and brain structure. © The Author(s), 2022. Published by Cambridge University Press.
Open Access
Genetic copy number variants, cognition and psychosis: a meta-analysis and a family study
(Springer Nature, 2020) Thygesen, J. H.; Presman, A.; Harju-Seppanen, J.; Irizar, H.; Jones, R.; Kuchenbaecker, K.; Lin, K.; Alizadeh, B. Z.; Austin-Zimmerman, I.; Bartels-Velthuis, A.; Bhat, A.; Bruggeman, R.; Cahn, W.; Calafato, S.; Crespo-Facorro, B.; De Haan, L.; De Zwarte, S. M. C.; Di Forti, M.; Diez-Revuelta, A.; Hall, J.; Hall, M.-H.; Iyegbe, C.; Jablensky, A.; Kahn, R.; Kalaydjieva, L.; Kravariti, E.; Lawrie, S.; Luykx, J. J.; Mata, I.; McDonald, C.; McIntosh, A. M.; McQuillin, A.; Muir, R.; Ophoff, R.; Picchioni, M.; Prata, D. P.; Ranlund, S.; Rujescu, D.; Rutten, B. P. F.; Schulze, K.; Shaikh, M.; Schirmbeck, F.; Simons, C. J. P.; Toulopoulou, Timothea; Van Amelsvoort, T.; Van Haren, N.; Van Os, J.; Van Winkel, R.; Vassos, E.; Walshe, M.; Weisbrod, M.; Zartaloudi, E.; Bell, V.; Powell, J.; Lewis, C. M.; Murray, R. M.; Bramon, E.
The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included ten primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200 kb, <1% MAF) as well as known schizophrenia-associated CNVs in patients with psychotic disorders, their unaffected relatives and controls (N = 3428) from the Psychosis Endophenotypes International Consortium (PEIC). The carriers of specific schizophrenia-associated CNVs showed poorer performance than non-carriers in immediate (P = 0.0036) and delayed (P = 0.0115) verbal recall. We found suggestive evidence that carriers of schizophrenia-associated CNVs had poorer block design performance (P = 0.0307). We do not find any association between CNV burden and cognition. Our findings show that the known high-risk CNVs are not only associated with schizophrenia and other neurodevelopmental disorders, but are also a contributing factor to impairment in cognitive domains such as memory and perceptual reasoning, and act as intermediate biomarkers of disease risk.
Open Access
The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) consortium: a collaborative cognitive and neuroimaging genetics project
(Elsevier, 2018) Blokland, G. A. M.; Del Re, E. C.; Mesholam-Gately, R. I.; Jovicich, J.; Trampush, J. W.; Keshavan, M. S.; DeLisi, L. E.; Walters, J. T. R.; Turner, J. A.; Malhotra, A. K.; Lencz, T.; Shenton, M. E.; Voineskos, A. N.; Rujescu, D.; Giegling, I.; Kahn, R. S.; Roffman, J. L.; Holt, D. J.; Ehrlich, S.; Kikinis, Z.; Dazzan, P.; Murray, R. M.; Di Forti, M.; Lee, J.; Sim, K.; Lam, M.; Wolthusen, R. P. F.; De Zwarte, S. M. C.; Walton, E.; Cosgrove, D.; Kelly, S.; Maleki, N.; Osiecki, L.; Picchioni, M. M.; Bramon, E.; Russo, M.; David, A. S.; Mondelli, V.; Reinders, A. A. T. S.; Falcone, M. A.; Hartmann, A. M.; Konte, B.; Morris, D. W.; Gill, M.; Corvin, A. P.; Cahn, W.; Ho, N. F.; Liu, J. J.; Keefe, R. S. E.; Gollub, R. L.; Manoach, D. S.; Calhoun, V. D.; Schulz, S. C.; Sponheim, S. R.; Goff, D. C.; Buka, S. L.; Cherkerzian, S.; Thermenos, H. W.; Kubicki, M.; Nestor, P. G.; Dickie, E. W.; Vassos, E.; Ciufolini, S.; Marques, T. R.; Crossley, N. A.; Purcell, S. M.; Smoller, J. W.; Van Haren, N. E. M.; Toulopoulou, Timothea; Donohoe, G.; Goldstein, J. M.; Seidman, L. J.; McCarley, R. W.; Petryshen, T. L.
Background: Schizophrenia has a large genetic component, and the pathways from genes to illness manifestation are beginning to be identified. The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) Consortium aims to clarify the role of genetic variation in brain abnormalities underlying schizophrenia. This article describes the GENUS Consortium sample collection. Methods: We identified existing samples collected for schizophrenia studies consisting of patients, controls, and/or individuals at familial high-risk (FHR) for schizophrenia. Samples had single nucleotide polymorphism (SNP) array data or genomic DNA, clinical and demographic data, and neuropsychological and/or brain magnetic resonance imaging (MRI) data. Data were subjected to quality control procedures at a central site. Results: Sixteen research groups contributed data from 5199 psychosis patients, 4877 controls, and 725 FHR individuals. All participants have relevant demographic data and all patients have relevant clinical data. The sex ratio is 56.5% male and 43.5% female. Significant differences exist between diagnostic groups for premorbid and current IQ (both p < 1 × 10− 10). Data from a diversity of neuropsychological tests are available for 92% of participants, and 30% have structural MRI scans (half also have diffusion-weighted MRI scans). SNP data are available for 76% of participants. The ancestry composition is 70% European, 20% East Asian, 7% African, and 3% other. Conclusions: The Consortium is investigating the genetic contribution to brain phenotypes in a schizophrenia sample collection of > 10,000 participants. The breadth of data across clinical, genetic, neuropsychological, and MRI modalities provides an important opportunity for elucidating the genetic basis of neural processes underlying schizophrenia.
Open Access
The impact of psychosis genome-wide associated ZNF804A variation on verbal fluency connectivity
(Elsevier, 2018) Tecelão, D.; Mendes, A.; Martins, D.; Bramon, E.; Toulopoulou, Timothea; Kravariti, E.; Murray, R.; Prata, D.
Schizophrenia (SCZ) and bipolar disorder (BD) have high heritability. Genome-wide association studies (GWAS) have identified ZNF804A as a significant risk gene for both illnesses. A validation of this finding at the brain systems-level is imperative as there is still little understanding of how it heightens risk. Based in part on our recent findings of an effect on widespread decreased white matter microstructural fractional anisotropy (putatively a proxy of its integrity), particularly strong in SCZ, we asked whether the risk allele has a detrimental effect on regional brain activation and functional connectivity during a type of cognitive processing which is, together with its neural correlates, impaired in BD and SCZ: verbal fluency. Functional MRI and genotype data was collected from 80 healthy volunteers, and 54 SCZ and 40 BD patients. A standard multifactorial analysis of variance using statistical parametric mapping and significance correction of FWE p < 0.05 was used. We found the GWAS risk allele A was associated with decreased positive functional coupling between the left precentral gyrus/inferior frontal gyrus (i.e. the most highly recruited area for the task) and: 1) the left inferior frontal gyrus, and 2) the left posterior cingulate gyrus, encompassing the precuneus; both as a main effect across controls and psychosis patients. Such association of the risk allele with reduced functional connectivity (with no area where the opposite main effect was detected), converges with findings in other tasks, our previous finding of its widespread impact on brain white matter microstructure, and with the dysconnectivity hypothesis of SCZ.
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Intelligence, educational attainment, and brain structure in those at familial high‐risk for schizophrenia or bipolar disorder
(Wiley, 2020) de Zwarte, S. M. C.; Brouwer, R.; Agartz, I.; Alda, M.; Alonso-Lana, S.; Bearden, C.; Bertolino, A.; Bonvino, A.; Bramon, E.; Buimer, E.; Cahn, W.; Canales-Rodríguez, E.; Cannon, D. M.; Cannon, T. D.; Caseras, X.; Castro-Fornieles, J.; Chen, Q.; Chung, Y.; De la Serna, E.; del Mar Bonnin, C.; Demro, C.; Di Giorgio, A.; Doucet, G.; Eker, M.; Erk, S.; Fatjó-Vilas, M.; Fears, S.; Foley, S.; Frangou, S.; Fullerton, J.; Glahn, D.; Goghari, V.; Goikolea, J.; Goldman, A.; Gonul, A.; Gruber, O.; Hajek, T.; Hawkins, E.; Heinz, A.; Ongun, C.; Hillegers, M.; Houenou, J.; Pol, H.; Hultman, C.; Ingvar, M.; Johansson, V.; Jönsson, E.; Kane, F.; Kempton, M.; Koenis, M.; Kopecek, M.; Krämer, B.; Lawrie, S.; Lenroot, R.; Marcelis, M.; Mattay, V.; McDonald, C.; Meyer-Lindenberg, A.; Michielse, S.; Mitchell, P.; Moreno, D.; Murray, R.; Mwangi, B.; Nabulsi, L.; Newport, J.; Olman, C.; van Os, J.; Overs, B.; Ozerdem, A.; Pergola, G.; Picchioni, M.; Piguet, C.; Pomarol-Clotet, E.; Radua, J.; Ramsay, I.; Richter, A.; Roberts, G.; Salvador, R.; Saricicek-Aydogan, A.; Sarró, S.; Schofield, P.; Simsek, E.; Simsek, F.; Soares, J.; Sponheim, S.; Sugranyes, G.; Toulopoulou, Timothea; Tronchin, G.; Vieta, E.; Walter, H.; Weinberger, D.; Whalley, H.; Wu, M. -J.; Yalin, N.; Andreassen, O.; Ching, C.; Thomopoulos, S.; van Erp, T.; Jahanshad, N.; Thompson, P.; Kahn, R.; van Haren, N.
First‐degree relatives of patients diagnosed with schizophrenia (SZ‐FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First‐degree relatives of patients diagnosed with bipolar disorder (BD‐FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD‐FDRs are inconsistent. Here, we performed a meta‐analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ‐FDRs, 867 BD‐FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ‐FDRs showed a pattern of widespread thinner cortex, while BD‐FDRs had widespread larger cortical surface area. IQ was lower in SZ‐FDRs (d = −0.42, p = 3 × 10−5), with weak evidence of IQ reductions among BD‐FDRs (d = −0.23, p = .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group‐effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ‐FDRs and more pronounced effects in BD‐FDRs. To conclude, SZ‐FDRs and BD‐FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ‐FDRs and BD‐FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment.
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Pathways linking school bullying and psychotic experiences: Multiple mediation analysis in Chinese adolescents and young adults
(Frontiers Media S.A., 2022-10-28) Chen, Lu Hua; Toulopoulou, Timothea
It is found that people with psychotic experiences have a 4-fold increased risk of developing a psychotic disorder later in life. Indeed, accumulating evidence has suggested that the association between school bullying and psychotic experiences works linearly. Previous studies are mainly carried out in a Western context, and only seldomly do studies address whether the association exists in the Chinese population and the related psychological and cognitive mechanisms. Therefore, we carried out the current study to address this gap in the literature focusing on the lifelong school bullying experiences of Chinese adolescents and young adults. We examined them in relation to psychotic experiences while assessing the mediating role of self-esteem, the personality trait of neuroticism, and a cognitive bias in thinking called interpretation bias. We found that multiple victimizations were quite common in Hong Kong secondary schools. In addition to a significant association between school bullying and psychotic experiences, we found partial mediating effects of proposed psychological and cognitive mediators in constructed multiple mediation models utilizing bootstrapping approach. Specifically, bullying quantity reflecting the number of victimizations, had its association with psychotic experiences partially mediated by the personality trait of neuroticism. In contrast, bullying duration reflecting the lasting of victimization was associated with psychotic experiences partially mediated by the personality trait of neuroticism and interpretation bias. Our findings enhance our knowledge of mechanisms underpinning the psychosis spectrum development and have implications for school-based intervention programs targeting bullying victims. Copyright © 2022 Chen and Toulopoulou.
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A polygenic risk score analysis of psychosis endophenotypes across brain functional, structural, and cognitive domains
(John Wiley & Sons, Inc., 2018) Ranlund, S.; Calafato, S.; Thygesen, J. H.; Lin, K.; Cahn, W.; Crespo-Facorro, B.; Díez, A.; Forti, M. D.; Iyegbe, C.; Jablensky, A.; Jones, R.; Hall, M.; Kahn, R.; Kalaydjieva, L.; Kravariti, E.; McDonald, C.; McIntosh, A. M.; McQuillin, A.; Picchioni, M.; Prata, D. P.; Rujescu, D.; Schulze, K.; Shaikh, M.; Toulopoulou, Timothea; Haren, N.; Zwarte, S. M. C.; Os, J.; Vassos, E.; Walshe, M.; Lewis, C.; Murray, R. M.; Powell, J.; Bramon, E.
This large multi‐center study investigates the relationships between genetic risk for schizophrenia and bipolar disorder, and multi‐modal endophenotypes for psychosis. The sample included 4,242 individuals; 1,087 patients with psychosis, 822 unaffected first‐degree relatives of patients, and 2,333 controls. Endophenotypes included the P300 event‐related potential (N = 515), lateral ventricular volume (N = 798), and the cognitive measures block design (N = 3,089), digit span (N = 1,437), and the Ray Auditory Verbal Learning Task (N = 2,406). Data were collected across 11 sites in Europe and Australia; all genotyping and genetic analyses were done at the same laboratory in the United Kingdom. We calculated polygenic risk scores for schizophrenia and bipolar disorder separately, and used linear regression to test whether polygenic scores influenced the endophenotypes. Results showed that higher polygenic scores for schizophrenia were associated with poorer performance on the block design task and explained 0.2% (p = 0.009) of the variance. Associations in the same direction were found for bipolar disorder scores, but this was not statistically significant at the 1% level (p = 0.02). The schizophrenia score explained 0.4% of variance in lateral ventricular volumes, the largest across all phenotypes examined, although this was not significant (p = 0.063). None of the remaining associations reached significance after correction for multiple testing (with alpha at 1%). These results indicate that common genetic variants associated with schizophrenia predict performance in spatial visualization, providing additional evidence that this measure is an endophenotype for the disorder with shared genetic risk variants. The use of endophenotypes such as this will help to characterize the effects of common genetic variation in psychosis.
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Polygenic risk score increases schizophrenia liability through cognition-relevant pathways
(Oxford University Press, 2019) Toulopoulou, Timothea; Zhang, X.; Cherny, S.; Dickinson, D.; Berman, K. F.; Straub, R. E.; Sham, P.; Weinberger, D. R.
Cognitive deficit is thought to represent, at least in part, genetic mechanisms of risk for schizophrenia, with recent evidence from statistical modelling of twin data suggesting direct causality from the former to the latter. However, earlier evidence was based on inferences from twin not molecular genetic data and it is unclear how much genetic influence ‘passes through’ cognition on the way to diagnosis. Thus, we included direct measurements of genetic risk (e.g. schizophrenia polygenic risk scores) in causation models to assess the extent to which cognitive deficit mediates some of the effect of polygenic risk scores on the disorder. Causal models of family data tested relationships among key variables and allowed parsing of genetic variance components. Polygenic risk scores were calculated from summary statistics from the current largest genome-wide association study of schizophrenia and were represented as a latent trait. Cognition was also modelled as a latent trait. Participants were 1313 members of 1078 families: 416 patients with schizophrenia, 290 unaffected siblings, and 607 controls. Modelling supported earlier findings that cognitive deficit has a putatively causal role in schizophrenia. In total, polygenic risk score explained 8.07% [confidence interval (CI) 5.45–10.74%] of schizophrenia risk in our sample. Of this, more than a third (2.71%, CI 2.41–3.85%) of the polygenic risk score influence was mediated through cognition paths, exceeding the direct influence of polygenic risk score on schizophrenia risk (1.43%, CI 0.46–3.08%). The remainder of the polygenic risk score influence (3.93%, CI 2.37–4.48%) reflected reciprocal causation between schizophrenia liability and cognition (e.g. mutual influences in a cyclical manner). Analysis of genetic variance components of schizophrenia liability indicated that 26.87% (CI 21.45–32.57%) was associated with cognition-related pathways not captured by polygenic risk score. The remaining variance in schizophrenia was through pathways other than cognition-related and polygenic risk score. Although our results are based on inference through statistical modelling and do not provide an absolute proof of causality, we find that cognition pathways mediate a significant part of the influence of cumulative genetic risk on schizophrenia. We estimate from our model that 33.51% (CI 27.34–43.82%) of overall genetic risk is mediated through influences on cognition, but this requires further studies and analyses as the genetics of schizophrenia becomes better characterized.
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Psychosis endophenotypes: a gene-set-specific polygenic risk score analysis
(Oxford University Press, 2023-08-14) Wang, B.; Irizar, H.; Thygesen, J. H.; Zartaloudi, E.; Austin-Zimmerman, I.; Bhat, A.; Harju-Seppänen, J.; Pain, O.; Bass, N.; Gkofa, V.; Alizadeh, B. Z.; Van Amelsvoort, T.; Arranz, M. J.; Bender, S.; Cahn, W.; Stella Calafato, M.; Crespo-Facorro, B.; Di Forti, M.; Giegling, I.; De Haan, L.; Hall, J.; Hall, M.; Van Haren, N.; Iyegbe, C.; Kahn, R. S.; Kravariti, E.; Lawrie, S. M.; Lin, K.; Luykx, J. J.; Mata, I.; McDonald, C.; McIntosh, A. M.; Murray, R. M.; Picchioni, M.; Powell, J.; Prata, D. P.; Rujescu, D.; Rutten, B. P. F.; Shaikh, M.; Simons, C. J. P.; Toulopoulou, Timothea; Weisbrod, M.; Van Winkel, R.; Kuchenbaecker, K.; McQuillin, A.; Bramon, E.
Background and Hypothesis: Endophenotypes can help to bridge the gap between psychosis and its genetic predispositions, but their underlying mechanisms remain largely unknown. This study aims to identify biological mechanisms that are relevant to the endophenotypes for psychosis, by partitioning polygenic risk scores into specific gene sets and testing their associations with endophenotypes. Study Design: We computed polygenic risk scores for schizophrenia and bipolar disorder restricted to brain-related gene sets retrieved from public databases and previous publications. Three hundred and seventy-eight gene-set-specific polygenic risk scores were generated for 4506 participants. Seven endophenotypes were also measured in the sample. Linear mixed-effects models were fitted to test associations between each endophenotype and each gene-set-specific polygenic risk score. Study Results: After correction for multiple testing, we found that a reduced P300 amplitude was associated with a higher schizophrenia polygenic risk score of the forebrain regionalization gene set (mean difference per SD increase in the polygenic risk score: -1.15 μV; 95% CI: -1.70 to -0.59 μV; P = 6 × 10-5). The schizophrenia polygenic risk score of forebrain regionalization also explained more variance of the P300 amplitude (R2 = 0.032) than other polygenic risk scores, including the genome-wide polygenic risk scores. Conclusions: Our finding on reduced P300 amplitudes suggests that certain genetic variants alter early brain development thereby increasing schizophrenia risk years later. Gene-set-specific polygenic risk scores are a useful tool to elucidate biological mechanisms of psychosis and endophenotypes, offering leads for experimental validation in cellular and animal models.
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Schizophrenia polygenic risk score influence on white matter microstructure
(Elsevier, 2020) Simões, B.; Vassos, E.; Shergill, S.; McDonald, C.; Toulopoulou, Timothea; Kalidindi, S.; Kane, F.; Murray, R.; Bramon, E.; Ferreira, H.; Prata, D.
Schizophrenia (SZ) and bipolar disorder (BD) are highly heritable, share symptomatology, and have a polygenic architecture. The impact of recent polygenic risk scores (PRS) for psychosis, which combine multiple genome-wide associated risk variations, should be assessed on heritable brain phenotypes also previously associated with the illnesses, for a better understanding of the pathways to disease. We have recently reported on the current SZ PRS's ability to predict 1st episode of psychosis case-control status and general cognition. Herein, we test its penetrance on white matter microstructure, which is known to be impaired in SZ, in BD and their relatives, using 141 participants (including SZ, BP, relatives of SZ or BP patients, and healthy volunteers), and two white matter integrity indexes: fractional anisotropy (FA) and mean diffusivity (MD). No significant correlation between the SZ PRS and FA or MD was found, thus it remains unclear whether white matter changes are primarily associated with SZ genetic risk profiles.
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The effect of SARS-CoV-2 virus on resting-state functional connectivity during adolescence: Investigating brain correlates of psychotic-like experiences and SARS-CoV-2 related inflammation response
(Elsevier B.V., 2023-12) Yilmaz Kafali, H.; Dasgin, Hacer; Sahin Cevik, Didenur; Sozan, S. S.; Oguz, Kader K.; Mutlu, M.; Ozkaya Parlakay, A.; Toulopoulou, Timothea
We first aimed to investigate resting-state functional connectivity (rs-FC) differences between adolescents exposed to SARS-CoV-2 and healthy controls. Secondly, the moderator effect of PLEs on group differences in rs-FC was examined. Thirdly, brain correlates of inflammation response during acute SARS-CoV-2 infection were investigated. Eighty-two participants aged between 14 and 24 years (SARS-CoV-2 (n = 35), controls (n = 47)) were examined using rs-fMRI. Seed-based rs-FC analysis was performed. The positive subscale of Community Assessment of Psychotic Experiences-42 (CAPE-Pos) was used to measure PLEs. The SARS-CoV-2 group had a lesser rs-FC within sensorimotor network (SMN), central executive network (CEN) and language network (LN), but an increased rs-FC within visual network (VN) compared to controls. No significant differences were detected between the groups regarding CAPE-Pos-score. However, including CAPE-Pos as a covariate, we found increased rs-FC within CEN and SN in SARS-CoV-2 compared to controls. Among the SARS-CoV-2 group, neutrophil/lymphocyte and thrombocyte*neutrophil/lymphocyte ratio was correlated with decreased/increased FC within DMN and SN, and increased FC within CEN. Our results showed rs-FC alterations within the SMN, CEN, LN, and VN among adolescents exposed to SARS-CoV-2. Moreover, changes in rs-FC associated with PLEs existed in these adolescents despite the absence of clinical changes. Furthermore, inflammation response was correlated with alterations in FC within the triple network system.
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Thought and language disorder as a possible endophenotype in schizophrenia: Evidence from patients and their unaffected siblings
(Elsevier B.V., 2023-04) Çabuk, Tuğçe; Mutlu, E.; Toulopoulou, Timothea
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Use of schizophrenia and bipolar disorder polygenic risk scores to identify psychotic disorders
(2018) Calafato, M. S.; Thygesen, J. H.; Ranlund, S.; Zartaloudi, E.; Cahn, W.; Crespo-Facorro, B.; Díez-Revuelta, A.; Forti, M. D.; Hall, M. -H.; Iyegbe, C.; Jablensky, A.; Kahn, R.; Kalaydjieva, L.; Kravariti, E.; Lin, K.; McDonald, C.; McIntosh, A. M.; McQuillin, A.; Picchioni, M.; Rujescu, D.; Shaikh, M.; Toulopoulou, Timothea; Os, J. V.; Vassos, E.; Walshe, M.; Powell, J.; Lewis, C. M.; Murray, R. M.; Bramon, E.
Background There is increasing evidence for shared genetic susceptibility between schizophrenia and bipolar disorder. Although genetic variants only convey subtle increases in risk individually, their combination into a polygenic risk score constitutes a strong disease predictor. Aims To investigate whether schizophrenia and bipolar disorder polygenic risk scores can distinguish people with broadly defined psychosis and their unaffected relatives from controls. Method Using the latest Psychiatric Genomics Consortium data, we calculated schizophrenia and bipolar disorder polygenic risk scores for 1168 people with psychosis, 552 unaffected relatives and 1472 controls. Results Patients with broadly defined psychosis had dramatic increases in schizophrenia and bipolar polygenic risk scores, as did their relatives, albeit to a lesser degree. However, the accuracy of predictive models was modest. Conclusions Although polygenic risk scores are not ready for clinical use, it is hoped that as they are refined they could help towards risk reduction advice and early interventions for psychosis. Declaration of interest R.M.M. has received honoraria for lectures from Janssen, Lundbeck, Lilly, Otsuka and Sunovian.