Browsing by Author "Kravariti, E."

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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
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 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.
Open Access
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.
Open Access
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.
Open Access
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.