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Gene set enrichment analysis of pathophysiological pathways highlights oxidative stress in psychosis

Polygenic risk prediction remains an important aim of genetic association studies. Currently, the predictive power of schizophrenia polygenic risk scores (PRSs) is not large enough to allow highly accurate discrimination between cases and controls and thus is not adequate for clinical integration. S...

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Autores principales: Pistis, Giorgio, Vázquez-Bourgon, Javier, Fournier, Margot, Jenni, Raoul, Cleusix, Martine, Papiol, Sergi, Smart, Sophie E., Pardiñas, Antonio F., Walters, James T. R., MacCabe, James H., Kutalik, Zoltán, Conus, Philippe, Crespo-Facorro, Benedicto, Q Do, Kim
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9763118/
https://www.ncbi.nlm.nih.gov/pubmed/36131045
http://dx.doi.org/10.1038/s41380-022-01779-1
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author Pistis, Giorgio
Vázquez-Bourgon, Javier
Fournier, Margot
Jenni, Raoul
Cleusix, Martine
Papiol, Sergi
Smart, Sophie E.
Pardiñas, Antonio F.
Walters, James T. R.
MacCabe, James H.
Kutalik, Zoltán
Conus, Philippe
Crespo-Facorro, Benedicto
Q Do, Kim
author_facet Pistis, Giorgio
Vázquez-Bourgon, Javier
Fournier, Margot
Jenni, Raoul
Cleusix, Martine
Papiol, Sergi
Smart, Sophie E.
Pardiñas, Antonio F.
Walters, James T. R.
MacCabe, James H.
Kutalik, Zoltán
Conus, Philippe
Crespo-Facorro, Benedicto
Q Do, Kim
author_sort Pistis, Giorgio
collection PubMed
description Polygenic risk prediction remains an important aim of genetic association studies. Currently, the predictive power of schizophrenia polygenic risk scores (PRSs) is not large enough to allow highly accurate discrimination between cases and controls and thus is not adequate for clinical integration. Since PRSs are rarely used to reveal biological functions or to validate candidate pathways, to fill this gap, we investigated whether their predictive ability could be improved by building genome-wide (GW-PRSs) and pathway-specific PRSs, using distance- or expression quantitative trait loci (eQTLs)- based mapping between genetic variants and genes. We focused on five pathways (glutamate, oxidative stress, GABA/interneurons, neuroimmune/neuroinflammation and myelin) which belong to a critical hub of schizophrenia pathophysiology, centred on redox dysregulation/oxidative stress. Analyses were first performed in the Lausanne Treatment and Early Intervention in Psychosis Program (TIPP) study (n = 340, cases/controls: 208/132), a sample of first-episode of psychosis patients and matched controls, and then validated in an independent study, the epidemiological and longitudinal intervention program of First-Episode Psychosis in Cantabria (PAFIP) (n = 352, 224/128). Our results highlighted two main findings. First, GW-PRSs for schizophrenia were significantly associated with early psychosis status. Second, oxidative stress was the only significantly associated pathway that showed an enrichment in both the TIPP (p = 0.03) and PAFIP samples (p = 0.002), and exclusively when gene-variant linking was done using eQTLs. The results suggest that the predictive accuracy of polygenic risk scores could be improved with the inclusion of information from functional annotations, and through a focus on specific pathways, emphasizing the need to build and study functionally informed risk scores.
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spelling pubmed-97631182022-12-21 Gene set enrichment analysis of pathophysiological pathways highlights oxidative stress in psychosis Pistis, Giorgio Vázquez-Bourgon, Javier Fournier, Margot Jenni, Raoul Cleusix, Martine Papiol, Sergi Smart, Sophie E. Pardiñas, Antonio F. Walters, James T. R. MacCabe, James H. Kutalik, Zoltán Conus, Philippe Crespo-Facorro, Benedicto Q Do, Kim Mol Psychiatry Article Polygenic risk prediction remains an important aim of genetic association studies. Currently, the predictive power of schizophrenia polygenic risk scores (PRSs) is not large enough to allow highly accurate discrimination between cases and controls and thus is not adequate for clinical integration. Since PRSs are rarely used to reveal biological functions or to validate candidate pathways, to fill this gap, we investigated whether their predictive ability could be improved by building genome-wide (GW-PRSs) and pathway-specific PRSs, using distance- or expression quantitative trait loci (eQTLs)- based mapping between genetic variants and genes. We focused on five pathways (glutamate, oxidative stress, GABA/interneurons, neuroimmune/neuroinflammation and myelin) which belong to a critical hub of schizophrenia pathophysiology, centred on redox dysregulation/oxidative stress. Analyses were first performed in the Lausanne Treatment and Early Intervention in Psychosis Program (TIPP) study (n = 340, cases/controls: 208/132), a sample of first-episode of psychosis patients and matched controls, and then validated in an independent study, the epidemiological and longitudinal intervention program of First-Episode Psychosis in Cantabria (PAFIP) (n = 352, 224/128). Our results highlighted two main findings. First, GW-PRSs for schizophrenia were significantly associated with early psychosis status. Second, oxidative stress was the only significantly associated pathway that showed an enrichment in both the TIPP (p = 0.03) and PAFIP samples (p = 0.002), and exclusively when gene-variant linking was done using eQTLs. The results suggest that the predictive accuracy of polygenic risk scores could be improved with the inclusion of information from functional annotations, and through a focus on specific pathways, emphasizing the need to build and study functionally informed risk scores. Nature Publishing Group UK 2022-09-21 2022 /pmc/articles/PMC9763118/ /pubmed/36131045 http://dx.doi.org/10.1038/s41380-022-01779-1 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Pistis, Giorgio
Vázquez-Bourgon, Javier
Fournier, Margot
Jenni, Raoul
Cleusix, Martine
Papiol, Sergi
Smart, Sophie E.
Pardiñas, Antonio F.
Walters, James T. R.
MacCabe, James H.
Kutalik, Zoltán
Conus, Philippe
Crespo-Facorro, Benedicto
Q Do, Kim
Gene set enrichment analysis of pathophysiological pathways highlights oxidative stress in psychosis
title Gene set enrichment analysis of pathophysiological pathways highlights oxidative stress in psychosis
title_full Gene set enrichment analysis of pathophysiological pathways highlights oxidative stress in psychosis
title_fullStr Gene set enrichment analysis of pathophysiological pathways highlights oxidative stress in psychosis
title_full_unstemmed Gene set enrichment analysis of pathophysiological pathways highlights oxidative stress in psychosis
title_short Gene set enrichment analysis of pathophysiological pathways highlights oxidative stress in psychosis
title_sort gene set enrichment analysis of pathophysiological pathways highlights oxidative stress in psychosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9763118/
https://www.ncbi.nlm.nih.gov/pubmed/36131045
http://dx.doi.org/10.1038/s41380-022-01779-1
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