Quantifying the role of transcript levels in mediating DNA methylation effects on complex traits and diseases.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 36477627.
- Also identified by DOI 10.1038/s41467-022-35196-3 and PMC identifier 9729239.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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.
Medical subject headings
- Multifactorial Inheritance
- DNA Methylation