Browsing by Author "Bhat, A."

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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
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.