DNA methylation QTL mapping across diverse human tissues provides molecular links between genetic variation and complex traits

Nat Genet. 2023 Jan;55(1):112-122. doi: 10.1038/s41588-022-01248-z. Epub 2022 Dec 12.

Abstract

Studies of DNA methylation (DNAm) in solid human tissues are relatively scarce; tissue-specific characterization of DNAm is needed to understand its role in gene regulation and its relevance to complex traits. We generated array-based DNAm profiles for 987 human samples from the Genotype-Tissue Expression (GTEx) project, representing 9 tissue types and 424 subjects. We characterized methylome and transcriptome correlations (eQTMs), genetic regulation in cis (mQTLs and eQTLs) across tissues and e/mQTLs links to complex traits. We identified mQTLs for 286,152 CpG sites, many of which (>5%) show tissue specificity, and mQTL colocalizations with 2,254 distinct GWAS hits across 83 traits. For 91% of these loci, a candidate gene link was identified by integration of functional maps, including eQTMs, and/or eQTL colocalization, but only 33% of loci involved an eQTL and mQTL present in the same tissue type. With this DNAm-focused integrative analysis, we contribute to the understanding of molecular regulatory mechanisms in human tissues and their impact on complex traits.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Chromosome Mapping
  • DNA Methylation* / genetics
  • Genetic Variation / genetics
  • Genome-Wide Association Study
  • Humans
  • Multifactorial Inheritance
  • Quantitative Trait Loci* / genetics