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Identifying causal models between genetically regulated methylation patterns and gene expression in healthy colon tissue

BACKGROUND: DNA methylation is involved in the regulation of gene expression and phenotypic variation, but the inter-relationship between genetic variation, DNA methylation and gene expression remains poorly understood. Here we combine the analysis of genetic variants related to methylation markers...

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Autores principales: Díez-Villanueva, Anna, Jordà, Mireia, Carreras-Torres, Robert, Alonso, Henar, Cordero, David, Guinó, Elisabet, Sanjuan, Xavier, Santos, Cristina, Salazar, Ramón, Sanz-Pamplona, Rebeca, Moreno, Victor
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380335/
https://www.ncbi.nlm.nih.gov/pubmed/34419169
http://dx.doi.org/10.1186/s13148-021-01148-9
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author Díez-Villanueva, Anna
Jordà, Mireia
Carreras-Torres, Robert
Alonso, Henar
Cordero, David
Guinó, Elisabet
Sanjuan, Xavier
Santos, Cristina
Salazar, Ramón
Sanz-Pamplona, Rebeca
Moreno, Victor
author_facet Díez-Villanueva, Anna
Jordà, Mireia
Carreras-Torres, Robert
Alonso, Henar
Cordero, David
Guinó, Elisabet
Sanjuan, Xavier
Santos, Cristina
Salazar, Ramón
Sanz-Pamplona, Rebeca
Moreno, Victor
author_sort Díez-Villanueva, Anna
collection PubMed
description BACKGROUND: DNA methylation is involved in the regulation of gene expression and phenotypic variation, but the inter-relationship between genetic variation, DNA methylation and gene expression remains poorly understood. Here we combine the analysis of genetic variants related to methylation markers (methylation quantitative trait loci: mQTLs) and gene expression (expression quantitative trait loci: eQTLs) with methylation markers related to gene expression (expression quantitative trait methylation: eQTMs), to provide novel insights into the genetic/epigenetic architecture of colocalizing molecular markers. RESULTS: Normal mucosa from 100 patients with colon cancer and 50 healthy donors included in the Colonomics project have been analyzed. Linear models have been used to find mQTLs and eQTMs within 1 Mb of the target gene. From 32,446 eQTLs previously detected, we found a total of 6850 SNPs, 114 CpGs and 52 genes interrelated, generating 13,987 significant combinations of co-occurring associations (meQTLs) after Bonferromi correction. Non-redundant meQTLs were 54, enriched in genes involved in metabolism of glucose and xenobiotics and immune system. SNPs in meQTLs were enriched in regulatory elements (enhancers and promoters) compared to random SNPs within 1 Mb of genes. Three colorectal cancer GWAS SNPs were related to methylation changes, and four SNPs were related to chemerin levels. Bayesian networks have been used to identify putative causal relationships among associated SNPs, CpG and gene expression triads. We identified that most of these combinations showed the canonical pathway of methylation markers causes gene expression variation (60.1%) or non-causal relationship between methylation and gene expression (33.9%); however, in up to 6% of these combinations, gene expression was causing variation in methylation markers. CONCLUSIONS: In this study we provided a characterization of the regulation between genetic variants and inter-dependent methylation markers and gene expression in a set of 150 healthy colon tissue samples. This is an important finding for the understanding of molecular susceptibility on colon-related complex diseases. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13148-021-01148-9.
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spelling pubmed-83803352021-08-23 Identifying causal models between genetically regulated methylation patterns and gene expression in healthy colon tissue Díez-Villanueva, Anna Jordà, Mireia Carreras-Torres, Robert Alonso, Henar Cordero, David Guinó, Elisabet Sanjuan, Xavier Santos, Cristina Salazar, Ramón Sanz-Pamplona, Rebeca Moreno, Victor Clin Epigenetics Research BACKGROUND: DNA methylation is involved in the regulation of gene expression and phenotypic variation, but the inter-relationship between genetic variation, DNA methylation and gene expression remains poorly understood. Here we combine the analysis of genetic variants related to methylation markers (methylation quantitative trait loci: mQTLs) and gene expression (expression quantitative trait loci: eQTLs) with methylation markers related to gene expression (expression quantitative trait methylation: eQTMs), to provide novel insights into the genetic/epigenetic architecture of colocalizing molecular markers. RESULTS: Normal mucosa from 100 patients with colon cancer and 50 healthy donors included in the Colonomics project have been analyzed. Linear models have been used to find mQTLs and eQTMs within 1 Mb of the target gene. From 32,446 eQTLs previously detected, we found a total of 6850 SNPs, 114 CpGs and 52 genes interrelated, generating 13,987 significant combinations of co-occurring associations (meQTLs) after Bonferromi correction. Non-redundant meQTLs were 54, enriched in genes involved in metabolism of glucose and xenobiotics and immune system. SNPs in meQTLs were enriched in regulatory elements (enhancers and promoters) compared to random SNPs within 1 Mb of genes. Three colorectal cancer GWAS SNPs were related to methylation changes, and four SNPs were related to chemerin levels. Bayesian networks have been used to identify putative causal relationships among associated SNPs, CpG and gene expression triads. We identified that most of these combinations showed the canonical pathway of methylation markers causes gene expression variation (60.1%) or non-causal relationship between methylation and gene expression (33.9%); however, in up to 6% of these combinations, gene expression was causing variation in methylation markers. CONCLUSIONS: In this study we provided a characterization of the regulation between genetic variants and inter-dependent methylation markers and gene expression in a set of 150 healthy colon tissue samples. This is an important finding for the understanding of molecular susceptibility on colon-related complex diseases. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13148-021-01148-9. BioMed Central 2021-08-21 /pmc/articles/PMC8380335/ /pubmed/34419169 http://dx.doi.org/10.1186/s13148-021-01148-9 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Díez-Villanueva, Anna
Jordà, Mireia
Carreras-Torres, Robert
Alonso, Henar
Cordero, David
Guinó, Elisabet
Sanjuan, Xavier
Santos, Cristina
Salazar, Ramón
Sanz-Pamplona, Rebeca
Moreno, Victor
Identifying causal models between genetically regulated methylation patterns and gene expression in healthy colon tissue
title Identifying causal models between genetically regulated methylation patterns and gene expression in healthy colon tissue
title_full Identifying causal models between genetically regulated methylation patterns and gene expression in healthy colon tissue
title_fullStr Identifying causal models between genetically regulated methylation patterns and gene expression in healthy colon tissue
title_full_unstemmed Identifying causal models between genetically regulated methylation patterns and gene expression in healthy colon tissue
title_short Identifying causal models between genetically regulated methylation patterns and gene expression in healthy colon tissue
title_sort identifying causal models between genetically regulated methylation patterns and gene expression in healthy colon tissue
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380335/
https://www.ncbi.nlm.nih.gov/pubmed/34419169
http://dx.doi.org/10.1186/s13148-021-01148-9
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