Pleiotropic Effects of Trait-Associated Genetic Variation on DNA Methylation: Utility for Refining GWAS Loci

Am J Hum Genet. 2017 Jun 1;100(6):954-959. doi: 10.1016/j.ajhg.2017.04.013. Epub 2017 May 18.


Most genetic variants identified in genome-wide association studies (GWASs) of complex traits are thought to act by affecting gene regulation rather than directly altering the protein product. As a consequence, the actual genes involved in disease are not necessarily the most proximal to the associated variants. By integrating data from GWAS analyses with those from genetic studies of regulatory variation, it is possible to identify variants pleiotropically associated with both a complex trait and measures of gene regulation. In this study, we used summary-data-based Mendelian randomization (SMR), a method developed to identify variants pleiotropically associated with both complex traits and gene expression, to identify variants associated with complex traits and DNA methylation. We used large DNA methylation quantitative trait locus (mQTL) datasets generated from two different tissues (blood and fetal brain) to prioritize genes for >40 complex traits with robust GWAS data and found considerable overlap with the results of SMR analyses performed with expression QTL (eQTL) data. We identified multiple examples of variable DNA methylation associated with GWAS variants for a range of complex traits, demonstrating the utility of this approach for refining genetic association signals.

Keywords: DNA methylation; GWAS; blood; brain; complex trait; disease; epigenetics; genetics; genome-wide association study; pleiotropy.

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Brain / embryology
  • Crohn Disease / genetics
  • DNA Methylation / genetics*
  • Fetus / metabolism
  • Genetic Pleiotropy*
  • Genetic Variation*
  • Genome-Wide Association Study*
  • Humans
  • Mendelian Randomization Analysis
  • Migraine Disorders / blood
  • Migraine Disorders / genetics
  • Quantitative Trait Loci / genetics*
  • Quantitative Trait, Heritable*
  • Repressor Proteins / genetics


  • Basic Helix-Loop-Helix Transcription Factors
  • HEY2 protein, human
  • Repressor Proteins