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Limited Association between Schizophrenia Genetic Risk Factors and Transcriptomic Features

Schizophrenia is a polygenic disorder with many genomic regions contributing to schizophrenia risk. The majority of genetic variants associated with schizophrenia lie in the non-coding genome and are thought to contribute to transcriptional regulation. Extensive transcriptomic dysregulation has been...

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Autores principales: Yu, Alice W., Peery, J. David, Won, Hyejung
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304922/
https://www.ncbi.nlm.nih.gov/pubmed/34356078
http://dx.doi.org/10.3390/genes12071062
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author Yu, Alice W.
Peery, J. David
Won, Hyejung
author_facet Yu, Alice W.
Peery, J. David
Won, Hyejung
author_sort Yu, Alice W.
collection PubMed
description Schizophrenia is a polygenic disorder with many genomic regions contributing to schizophrenia risk. The majority of genetic variants associated with schizophrenia lie in the non-coding genome and are thought to contribute to transcriptional regulation. Extensive transcriptomic dysregulation has been detected from postmortem brain samples of schizophrenia-affected individuals. However, the relationship between schizophrenia genetic risk factors and transcriptomic features has yet to be explored. Herein, we examined whether varying gene expression features, including differentially expressed genes (DEGs), co-expression networks, and central hubness of genes, contribute to the heritability of schizophrenia. We leveraged quantitative trait loci and chromatin interaction profiles to identify schizophrenia risk variants assigned to the genes that represent different transcriptomic features. We then performed stratified linkage disequilibrium score regression analysis on these variants to estimate schizophrenia heritability enrichment for different gene expression features. Notably, DEGs and co-expression networks showed nominal heritability enrichment. This nominal association can be partly explained by cellular heterogeneity, as DEGs were associated with the genetic risk of schizophrenia in a cell type-specific manner. Moreover, DEGs were enriched for target genes of schizophrenia-associated transcription factors, suggesting that the transcriptomic signatures of schizophrenia are the result of transcriptional regulatory cascades elicited by genetic risk factors.
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spelling pubmed-83049222021-07-25 Limited Association between Schizophrenia Genetic Risk Factors and Transcriptomic Features Yu, Alice W. Peery, J. David Won, Hyejung Genes (Basel) Article Schizophrenia is a polygenic disorder with many genomic regions contributing to schizophrenia risk. The majority of genetic variants associated with schizophrenia lie in the non-coding genome and are thought to contribute to transcriptional regulation. Extensive transcriptomic dysregulation has been detected from postmortem brain samples of schizophrenia-affected individuals. However, the relationship between schizophrenia genetic risk factors and transcriptomic features has yet to be explored. Herein, we examined whether varying gene expression features, including differentially expressed genes (DEGs), co-expression networks, and central hubness of genes, contribute to the heritability of schizophrenia. We leveraged quantitative trait loci and chromatin interaction profiles to identify schizophrenia risk variants assigned to the genes that represent different transcriptomic features. We then performed stratified linkage disequilibrium score regression analysis on these variants to estimate schizophrenia heritability enrichment for different gene expression features. Notably, DEGs and co-expression networks showed nominal heritability enrichment. This nominal association can be partly explained by cellular heterogeneity, as DEGs were associated with the genetic risk of schizophrenia in a cell type-specific manner. Moreover, DEGs were enriched for target genes of schizophrenia-associated transcription factors, suggesting that the transcriptomic signatures of schizophrenia are the result of transcriptional regulatory cascades elicited by genetic risk factors. MDPI 2021-07-12 /pmc/articles/PMC8304922/ /pubmed/34356078 http://dx.doi.org/10.3390/genes12071062 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Yu, Alice W.
Peery, J. David
Won, Hyejung
Limited Association between Schizophrenia Genetic Risk Factors and Transcriptomic Features
title Limited Association between Schizophrenia Genetic Risk Factors and Transcriptomic Features
title_full Limited Association between Schizophrenia Genetic Risk Factors and Transcriptomic Features
title_fullStr Limited Association between Schizophrenia Genetic Risk Factors and Transcriptomic Features
title_full_unstemmed Limited Association between Schizophrenia Genetic Risk Factors and Transcriptomic Features
title_short Limited Association between Schizophrenia Genetic Risk Factors and Transcriptomic Features
title_sort limited association between schizophrenia genetic risk factors and transcriptomic features
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304922/
https://www.ncbi.nlm.nih.gov/pubmed/34356078
http://dx.doi.org/10.3390/genes12071062
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