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Psychosis Endophenotypes: A Gene-Set-Specific Polygenic Risk Score Analysis

Wang, Baihan; Irizar, Haritz; Thygesen, Johan H; Zartaloudi, Eirini; Austin-Zimmerman, Isabelle; Bhat, Anjali; Harju-Seppänen, Jasmine; ... Bramon, Elvira; + view all (2023) Psychosis Endophenotypes: A Gene-Set-Specific Polygenic Risk Score Analysis. Schizophrenia Bulletin , Article sbad088. 10.1093/schbul/sbad088. (In press). Green open access

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Abstract

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.

Type: Article
Title: Psychosis Endophenotypes: A Gene-Set-Specific Polygenic Risk Score Analysis
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/schbul/sbad088
Publisher version: https://doi.org/10.1093/schbul/sbad088
Language: English
Additional information: © The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: EEG, P300, bipolar disorder, neurodevelopment, schizophrenia
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Division of Psychiatry
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Health Informatics
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Division of Psychiatry > Mental Health Neuroscience
URI: https://discovery.ucl.ac.uk/id/eprint/10175640
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