Quantifying the role of transcript levels in mediating DNA methylation effects on complex traits and diseases.

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Etat: Public
Version: Final published version
Licence: CC BY 4.0
ID Serval
serval:BIB_8C3AFBD3E3D3
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Quantifying the role of transcript levels in mediating DNA methylation effects on complex traits and diseases.
Périodique
Nature communications
Auteur⸱e⸱s
Sadler M.C., Auwerx C., Lepik K., Porcu E., Kutalik Z.
ISSN
2041-1723 (Electronic)
ISSN-L
2041-1723
Statut éditorial
Publié
Date de publication
07/12/2022
Peer-reviewed
Oui
Volume
13
Numéro
1
Pages
7559
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Résumé
High-dimensional omics datasets provide valuable resources to determine the causal role of molecular traits in mediating the path from genotype to phenotype. Making use of molecular quantitative trait loci (QTL) and genome-wide association study (GWAS) summary statistics, we propose a multivariable Mendelian randomization (MVMR) framework to quantify the proportion of the impact of the DNA methylome (DNAm) on complex traits that is propagated through the assayed transcriptome. Evaluating 50 complex traits, we find that on average at least 28.3% (95% CI: [26.9%-29.8%]) of DNAm-to-trait effects are mediated through (typically multiple) transcripts in the cis-region. Several regulatory mechanisms are hypothesized, including methylation of the promoter probe cg10385390 (chr1:8'022'505) increasing the risk for inflammatory bowel disease by reducing PARK7 expression. The proposed integrative framework can be extended to other omics layers to identify causal molecular chains, providing a powerful tool to map and interpret GWAS signals.
Mots-clé
Multifactorial Inheritance, DNA Methylation/genetics, Genome-Wide Association Study
Pubmed
Web of science
Open Access
Oui
Création de la notice
15/12/2022 12:32
Dernière modification de la notice
19/07/2023 5:55
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