Browsing by Author "Murray, R. M."

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    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.
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    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.
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    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.
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    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.
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    MIR137 polygenic risk for schizophrenia and ephrin-regulated pathway: Role in lateral ventricles and corpus callosum volume
    (Asociacion Espanola de Psicologia Conductual, 2024-04-09) Blokland, G. A. M.; Maleki, N.; Jovicich, J.; Mesholam-Gately, R. I.; Delisi, L. E.; Turner, J. A.; Shenton, M. E.; Voineskos, A. N.; Kahn, R. S.; Roffman, J. L.; Holt, D. J.; Ehrlich, S.; Kikinis, Z.; Dazzan, P.; Murray, R. M.; Lee, J.; Sim, K.; Lam, M.; de Zwarte, S. M. C.; Walton, E.; Kelly, S.; Picchioni, M. M.; Bramon, E.; Makris, N.; David, A. S.; Mondelli, V.; Reinders, A. A. T. S.; Oykhman, E.; Morris, D. W.; Gill, M.; Corvin, A. P.; Cahn, W.; Ho, N.; Liu, J.; Gollub, R. L.; Manoach, D. S.; Calhoun, V. D.; Sponheim, S. R.; Buka, S. L.; Cherkerzian, S.; Thermenos, H. W.; Dickie, E. W.; Ciufolini, S.; Marques, T. Reis; Crossley, N. A.; Purcell, S. M.; Smoller, J. W.; Van Haren, N. E. M.; Toulopoulou, Timothea; Donohoe, G.; Goldstein, J. M.; Keshavan, M. S.; Petryshen, T. L.; del Re, E. C.
    Background/Objective. Enlarged lateral ventricle (LV) volume and decreased volume in the corpus callosum (CC) are hallmarks of schizophrenia (SZ). We previously showed an inverse correlation between LV and CC volumes in SZ, with global functioning decreasing with increased LV volume. This study investigates the relationship between LV volume, CC abnormalities, and the microRNA MIR137 and its regulated genes in SZ, because of MIR137 's essential role in neurodevelopment. Methods . Participants were 1224 SZ probands and 1466 unaffected controls from the GENUS Consortium. Brain MRI scans, genotype, and clinical data were harmonized across cohorts and employed in the analyses. Results. Increased LV volumes and decreased CC central, mid -anterior, and mid -posterior volumes were observed in SZ probands. The MIR137-regulated ephrin pathway was significantly associated with CC:LV ratio, explaining a significant proportion (3.42 %) of CC:LV variance, and more than for LV and CC separately. Other pathways explained variance in either CC or LV, but not both. CC:LV ratio was also positively correlated with Global Assessment of Functioning, supporting previous subsample findings. SNP -based heritability estimates were higher for CC central:LV ratio (0.79) compared to CC or LV separately. Discussion. Our results indicate that the CC:LV ratio is highly heritable, influenced in part by variation in the MIR137-regulated ephrin pathway. Findings suggest that the CC:LV ratio may be a risk indicator in SZ that correlates with global functioning.
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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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    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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    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.