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

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Anna Díez-Villanueva ◽  
Mireia Jordà ◽  
Robert Carreras-Torres ◽  
Henar Alonso ◽  
David Cordero ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Quantitative Trait Loci ◽  
Genetic Variants ◽  
Quantitative Trait ◽  
Regulation Of Gene Expression ◽  
Regulatory Elements ◽  
Colon Tissue ◽  
Tissue Samples ◽  
Trait Loci

Abstract 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.

scholarly journals Mapping methylation quantitative trait loci in cardiac tissues nominates risk loci and biological pathways in congenital heart disease

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Ming Li ◽  
Chen Lyu ◽  
Manyan Huang ◽  
Catherine Do ◽  
Benjamin Tycko ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Quantitative Trait Loci ◽  
Genetic Variants ◽  
Quantitative Trait ◽  
Congenital Heart ◽  
Cardiac Tissues ◽  
Chd Risk ◽  
Trait Loci ◽  
Methylation Quantitative Trait Loci

Abstract Background Most congenital heart defects (CHDs) result from complex interactions among genetic susceptibilities, epigenetic modifications, and maternal environmental exposures. Characterizing the complex relationship between genetic, epigenetic, and transcriptomic variation will enhance our understanding of pathogenesis in this important type of congenital disorder. We investigated cis-acting effects of genetic single nucleotide polymorphisms (SNPs) on local DNA methylation patterns within 83 cardiac tissue samples and prioritized their contributions to CHD risk by leveraging results of CHD genome-wide association studies (GWAS) and their effects on cardiac gene expression. Results We identified 13,901 potential methylation quantitative trait loci (mQTLs) with a false discovery threshold of 5%. Further co-localization analyses and Mendelian randomization indicated that genetic variants near the HLA-DRB6 gene on chromosome 6 may contribute to CHD risk by regulating the methylation status of nearby CpG sites. Additional SNPs in genomic regions on chromosome 10 (TNKS2-AS1 gene) and chromosome 14 (LINC01629 gene) may simultaneously influence epigenetic and transcriptomic variations within cardiac tissues. Conclusions Our results support the hypothesis that genetic variants may influence the risk of CHDs through regulating the changes of DNA methylation and gene expression. Our results can serve as an important source of information that can be integrated with other genetic studies of heart diseases, especially CHDs.

scholarly journals DNMIVD: DNA methylation interactive visualization database

2019 ◽  
Vol 48 (D1) ◽  
pp. D856-D862 ◽  
Author(s):  
Wubin Ding ◽  
Jiwei Chen ◽  
Guoshuang Feng ◽  
Geng Chen ◽  
Jun Wu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Quantitative Trait Loci ◽  
Quantitative Trait ◽  
Interactive Visualization ◽  
The Cancer Genome Atlas ◽  
Prognostic Models ◽  
Differentially Methylated Genes ◽  
Trait Loci ◽  
Methylation Quantitative Trait Loci

Abstract Aberrant DNA methylation plays an important role in cancer progression. However, no resource has been available that comprehensively provides DNA methylation-based diagnostic and prognostic models, expression–methylation quantitative trait loci (emQTL), pathway activity-methylation quantitative trait loci (pathway-meQTL), differentially variable and differentially methylated CpGs, and survival analysis, as well as functional epigenetic modules for different cancers. These provide valuable information for researchers to explore DNA methylation profiles from different aspects in cancer. To this end, we constructed a user-friendly database named DNA Methylation Interactive Visualization Database (DNMIVD), which comprehensively provides the following important resources: (i) diagnostic and prognostic models based on DNA methylation for multiple cancer types of The Cancer Genome Atlas (TCGA); (ii) meQTL, emQTL and pathway-meQTL for diverse cancers; (iii) Functional Epigenetic Modules (FEM) constructed from Protein-Protein Interactions (PPI) and Co-Occurrence and Mutual Exclusive (COME) network by integrating DNA methylation and gene expression data of TCGA cancers; (iv) differentially variable and differentially methylated CpGs and differentially methylated genes as well as related enhancer information; (v) correlations between methylation of gene promoter and corresponding gene expression and (vi) patient survival-associated CpGs and genes with different endpoints. DNMIVD is freely available at http://www.unimd.org/dnmivd/. We believe that DNMIVD can facilitate research of diverse cancers.

scholarly journals Identification of tissue-specific and common methylation quantitative trait loci in healthy individuals using MAGAR

2021 ◽  
Author(s):  
Michael Scherer ◽  
Gilles Gasparoni ◽  
Souad Rahmouni ◽  
Tatiana Shashkova ◽  
Marion Arnoux ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Quantitative Trait Loci ◽  
Genetic Variants ◽  
Quantitative Trait ◽  
Healthy Individuals ◽  
Cell Type ◽  
Systematic Analysis ◽  
Trait Loci ◽  
Cell Type Specific ◽  
Methylation Quantitative Trait Loci

Background: Understanding the influence of genetic variants on DNA methylation is fundamental for the interpretation of epigenomic data in the context of disease. There is a need for systematic approaches not only for determining methylation quantitative trait loci (methQTL) but also for discriminating general from cell-type-specific effects. Results: Here, we present a two-step computational framework MAGAR, which fully supports identification of methQTLs from matched genotyping and DNA methylation data, and additionally the identification of quantitative cell-type-specific methQTL effects. In a pilot analysis, we apply MAGAR on data in four tissues (ileum, rectum, T-cells, B-cells) from healthy individuals and demonstrate the discrimination of common from cell-type-specific methQTLs. We experimentally validate both types of methQTLs in an independent dataset comprising additional cell types and tissues. Finally, we validate selected methQTLs (PON1, ZNF155, NRG2) by ultra-deep local sequencing. In line with previous reports, we find cell-type-specific methQTLs to be preferentially located in enhancer elements. Conclusions: Our analysis demonstrates that a systematic analysis of methQTLs provides important new insights on the influences of genetic variants to cell-type-specific epigenomic variation.

scholarly journals Identification of tissue-specific and common methylation quantitative trait loci in healthy individuals using MAGAR

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Michael Scherer ◽  
Gilles Gasparoni ◽  
Souad Rahmouni ◽  
Tatiana Shashkova ◽  
Marion Arnoux ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Quantitative Trait Loci ◽  
Genetic Variants ◽  
Quantitative Trait ◽  
Healthy Individuals ◽  
Cell Type ◽  
Data Set ◽  
Trait Loci ◽  
Cell Type Specific ◽  
Methylation Quantitative Trait Loci

Abstract Background Understanding the influence of genetic variants on DNA methylation is fundamental for the interpretation of epigenomic data in the context of disease. There is a need for systematic approaches not only for determining methylation quantitative trait loci (methQTL), but also for discriminating general from cell type-specific effects. Results Here, we present a two-step computational framework MAGAR (https://bioconductor.org/packages/MAGAR), which fully supports the identification of methQTLs from matched genotyping and DNA methylation data, and additionally allows for illuminating cell type-specific methQTL effects. In a pilot analysis, we apply MAGAR on data in four tissues (ileum, rectum, T cells, B cells) from healthy individuals and demonstrate the discrimination of common from cell type-specific methQTLs. We experimentally validate both types of methQTLs in an independent data set comprising additional cell types and tissues. Finally, we validate selected methQTLs located in the PON1, ZNF155, and NRG2 genes by ultra-deep local sequencing. In line with previous reports, we find cell type-specific methQTLs to be preferentially located in enhancer elements. Conclusions Our analysis demonstrates that a systematic analysis of methQTLs provides important new insights on the influences of genetic variants to cell type-specific epigenomic variation.

scholarly journals Systematic Mendelian randomization framework elucidates hundreds of genetic loci which may influence disease through changes in DNA methylation levels

2017 ◽  
Author(s):  
Tom G. Richardson ◽  
Philip C. Haycock ◽  
Jie Zheng ◽  
Nicholas J. Timpson ◽  
Tom R. Gaunt ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Quantitative Trait Loci ◽  
Genetic Variants ◽  
Quantitative Trait ◽  
Complex Traits ◽  
Complex Disease ◽  
Mendelian Randomization ◽  
High Rate ◽  
Trait Variation ◽  
Trait Loci

AbstractWe have undertaken an extensive Mendelian randomization (MR) study using methylation quantitative trait loci (mQTL) as genetic instruments to assess the potential causal relationship between genetic variation, DNA methylation and 139 complex traits. Using two-sample MR, we observed 1,191 effects across 62 traits where genetic variants were associated with both proximal DNA methylation (i.e. cis-mQTL) and complex trait variation (P<1.39x10−08). Joint likelihood mapping provided evidence that the causal mQTL for 364 of these effects across 58 traits was also likely the causal variant for trait variation. These effects showed a high rate of replication in the UK Biobank dataset for 14 selected traits, as 121 of the attempted 129 effects replicated. Integrating expression quantitative trait loci (eQTL) data suggested that genetic variants responsible for 319 of the 364 mQTL effects also influence gene expression, which indicates a coordinated system of effects that are consistent with causality. CpG sites were enriched for histone mark peaks in tissue types relevant to their associated trait and implicated genes were enriched across relevant biological pathways. Though we are unable to distinguish mediation from horizontal pleiotropy in these analyses, our findings should prove valuable in identifying candidate loci for further evaluation and help develop mechanistic insight into the aetiology of complex disease.

scholarly journals Epigenomes of Human Hearts Reveal New Genetic Variants Relevant for Cardiac Disease and Phenotype

2020 ◽  
Vol 127 (6) ◽  
pp. 761-777 ◽  
Author(s):  
Wilson Lek Wen Tan ◽  
Chukwuemeka George Anene-Nzelu ◽  
Eleanor Wong ◽  
Chang Jie Mick Lee ◽  
Hui San Tan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Quantitative Trait Loci ◽  
Genetic Variants ◽  
Quantitative Trait ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Trait Loci

Rationale: Identifying genetic markers for heterogeneous complex diseases such as heart failure is challenging and requires prohibitively large cohort sizes in genome-wide association studies to meet the stringent threshold of genome-wide statistical significance. On the other hand, chromatin quantitative trait loci, elucidated by direct epigenetic profiling of specific human tissues, may contribute toward prioritizing subthreshold variants for disease association. Objective: Here, we captured noncoding genetic variants by performing epigenetic profiling for enhancer H3K27ac chromatin immunoprecipitation followed by sequencing in 70 human control and end-stage failing hearts. Methods and Results: We have mapped a comprehensive catalog of 47 321 putative human heart enhancers and promoters. Three thousand eight hundred ninety-seven differential acetylation peaks (FDR [false discovery rate], 5%) pointed to pathways altered in heart failure. To identify cardiac histone acetylation quantitative trait loci (haQTLs), we regressed out confounding factors including heart failure disease status and used the G-SCI (Genotype-independent Signal Correlation and Imbalance) test 1 to call out 1680 haQTLs (FDR, 10%). RNA sequencing performed on the same heart samples proved a subset of haQTLs to have significant association also to gene expression (expression quantitative trait loci), either in cis (180) or through long-range interactions (81), identified by Hi-C (high-throughput chromatin conformation assay) and HiChIP (high-throughput protein centric chromatin) performed on a subset of hearts. Furthermore, a concordant relationship between the gain or disruption of TF (transcription factor)-binding motifs, inferred from alternative alleles at the haQTLs, implied a surprising direct association between these specific TF and local histone acetylation in human hearts. Finally, 62 unique loci were identified by colocalization of haQTLs with the subthreshold loci of heart-related genome-wide association studies datasets. Conclusions: Disease and phenotype association for 62 unique loci are now implicated. These loci may indeed mediate their effect through modification of enhancer H3K27 acetylation enrichment and their corresponding gene expression differences (bioRxiv: https://doi.org/10.1101/536763 ). Graphical Abstract: A graphical abstract is available for this article.

scholarly journals Abundant Quantitative Trait Loci Exist for DNA Methylation and Gene Expression in Human Brain

PLoS Genetics ◽  
2010 ◽  
Vol 6 (5) ◽  
pp. e1000952 ◽  
Author(s):  
J. Raphael Gibbs ◽  
Marcel P. van der Brug ◽  
Dena G. Hernandez ◽  
Bryan J. Traynor ◽  
Michael A. Nalls ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Quantitative Trait Loci ◽  
Human Brain ◽  
Quantitative Trait ◽  
Trait Loci
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