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Polygenic disruption of retinoid signalling in schizophrenia and a severe cognitive deficit subtype

Retinoid metabolites of vitamin A are intrinsically linked to neural development, connectivity and plasticity, and have been implicated in the pathophysiology of schizophrenia. We hypothesised that a greater burden of common and rare genomic variation in genes involved with retinoid biogenesis and s...

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Autores principales: Reay, William R., Atkins, Joshua R., Quidé, Yann, Carr, Vaughan J., Green, Melissa J., Cairns, Murray J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156344/
https://www.ncbi.nlm.nih.gov/pubmed/30532020
http://dx.doi.org/10.1038/s41380-018-0305-0
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author Reay, William R.
Atkins, Joshua R.
Quidé, Yann
Carr, Vaughan J.
Green, Melissa J.
Cairns, Murray J.
author_facet Reay, William R.
Atkins, Joshua R.
Quidé, Yann
Carr, Vaughan J.
Green, Melissa J.
Cairns, Murray J.
author_sort Reay, William R.
collection PubMed
description Retinoid metabolites of vitamin A are intrinsically linked to neural development, connectivity and plasticity, and have been implicated in the pathophysiology of schizophrenia. We hypothesised that a greater burden of common and rare genomic variation in genes involved with retinoid biogenesis and signalling could be associated with schizophrenia and its cognitive symptoms. Common variants associated with schizophrenia in the largest genome-wide association study were aggregated in retinoid genes and used to formulate a polygenic risk score (PRS(Ret)) for each participant in the Australian Schizophrenia Research Bank. In support of our hypothesis, we found PRS(Ret) to be significantly associated with the disorder. Cases with severe cognitive deficits, while not further differentiated by PRS(Ret), were enriched with rare variation in the retinoic acid receptor beta gene RARB, detected through whole-genome sequencing. RARB rare variant burden was also associated with reduced cerebellar volume in the cases with marked cognitive deficit, and with covariation in grey matter throughout the brain. An excess of rare variation was further observed in schizophrenia in retinoic acid response elements proximal to target genes, which we show are differentially expressed in the disorder in two RNA sequencing datasets. Our results suggest that genomic variation may disrupt retinoid signalling in schizophrenia, with particular significance for cases with severe cognitive impairment.
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spelling pubmed-71563442020-04-27 Polygenic disruption of retinoid signalling in schizophrenia and a severe cognitive deficit subtype Reay, William R. Atkins, Joshua R. Quidé, Yann Carr, Vaughan J. Green, Melissa J. Cairns, Murray J. Mol Psychiatry Article Retinoid metabolites of vitamin A are intrinsically linked to neural development, connectivity and plasticity, and have been implicated in the pathophysiology of schizophrenia. We hypothesised that a greater burden of common and rare genomic variation in genes involved with retinoid biogenesis and signalling could be associated with schizophrenia and its cognitive symptoms. Common variants associated with schizophrenia in the largest genome-wide association study were aggregated in retinoid genes and used to formulate a polygenic risk score (PRS(Ret)) for each participant in the Australian Schizophrenia Research Bank. In support of our hypothesis, we found PRS(Ret) to be significantly associated with the disorder. Cases with severe cognitive deficits, while not further differentiated by PRS(Ret), were enriched with rare variation in the retinoic acid receptor beta gene RARB, detected through whole-genome sequencing. RARB rare variant burden was also associated with reduced cerebellar volume in the cases with marked cognitive deficit, and with covariation in grey matter throughout the brain. An excess of rare variation was further observed in schizophrenia in retinoic acid response elements proximal to target genes, which we show are differentially expressed in the disorder in two RNA sequencing datasets. Our results suggest that genomic variation may disrupt retinoid signalling in schizophrenia, with particular significance for cases with severe cognitive impairment. Nature Publishing Group UK 2018-12-07 2020 /pmc/articles/PMC7156344/ /pubmed/30532020 http://dx.doi.org/10.1038/s41380-018-0305-0 Text en © The Author(s) 2018 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Reay, William R.
Atkins, Joshua R.
Quidé, Yann
Carr, Vaughan J.
Green, Melissa J.
Cairns, Murray J.
Polygenic disruption of retinoid signalling in schizophrenia and a severe cognitive deficit subtype
title Polygenic disruption of retinoid signalling in schizophrenia and a severe cognitive deficit subtype
title_full Polygenic disruption of retinoid signalling in schizophrenia and a severe cognitive deficit subtype
title_fullStr Polygenic disruption of retinoid signalling in schizophrenia and a severe cognitive deficit subtype
title_full_unstemmed Polygenic disruption of retinoid signalling in schizophrenia and a severe cognitive deficit subtype
title_short Polygenic disruption of retinoid signalling in schizophrenia and a severe cognitive deficit subtype
title_sort polygenic disruption of retinoid signalling in schizophrenia and a severe cognitive deficit subtype
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156344/
https://www.ncbi.nlm.nih.gov/pubmed/30532020
http://dx.doi.org/10.1038/s41380-018-0305-0
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