A Genome-Wide mQTL Analysis in Human Adipose Tissue Identifies Genetic Variants Associated with DNA Methylation, Gene Expression and Metabolic Traits

PLoS One. 2016 Jun 20;11(6):e0157776. doi: 10.1371/journal.pone.0157776. eCollection 2016.


Little is known about the extent to which interactions between genetics and epigenetics may affect the risk of complex metabolic diseases and/or their intermediary phenotypes. We performed a genome-wide DNA methylation quantitative trait locus (mQTL) analysis in human adipose tissue of 119 men, where 592,794 single nucleotide polymorphisms (SNPs) were related to DNA methylation of 477,891 CpG sites, covering 99% of RefSeq genes. SNPs in significant mQTLs were further related to gene expression in adipose tissue and obesity related traits. We found 101,911 SNP-CpG pairs (mQTLs) in cis and 5,342 SNP-CpG pairs in trans showing significant associations between genotype and DNA methylation in adipose tissue after correction for multiple testing, where cis is defined as distance less than 500 kb between a SNP and CpG site. These mQTLs include reported obesity, lipid and type 2 diabetes loci, e.g. ADCY3/POMC, APOA5, CETP, FADS2, GCKR, SORT1 and LEPR. Significant mQTLs were overrepresented in intergenic regions meanwhile underrepresented in promoter regions and CpG islands. We further identified 635 SNPs in significant cis-mQTLs associated with expression of 86 genes in adipose tissue including CHRNA5, G6PC2, GPX7, RPL27A, THNSL2 and ZFP57. SNPs in significant mQTLs were also associated with body mass index (BMI), lipid traits and glucose and insulin levels in our study cohort and public available consortia data. Importantly, the Causal Inference Test (CIT) demonstrates how genetic variants mediate their effects on metabolic traits (e.g. BMI, cholesterol, high-density lipoprotein (HDL), hemoglobin A1c (HbA1c) and homeostatic model assessment of insulin resistance (HOMA-IR)) via altered DNA methylation in human adipose tissue. This study identifies genome-wide interactions between genetic and epigenetic variation in both cis and trans positions influencing gene expression in adipose tissue and in vivo (dys)metabolic traits associated with the development of obesity and diabetes.

MeSH terms

  • Adipose Tissue / metabolism*
  • Adult
  • Body Mass Index
  • Cohort Studies
  • CpG Islands / genetics
  • DNA Methylation / genetics*
  • Diabetes Mellitus, Type 2 / genetics
  • Gene Expression Regulation*
  • Genetic Association Studies
  • Genetic Variation*
  • Genome, Human*
  • Glycated Hemoglobin A / metabolism
  • Humans
  • Male
  • Obesity / genetics
  • Phenotype
  • Polymorphism, Single Nucleotide / genetics
  • Quantitative Trait Loci / genetics*
  • Quantitative Trait, Heritable*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reproducibility of Results
  • Scandinavian and Nordic Countries


  • Glycated Hemoglobin A
  • RNA, Messenger

Grant support

This work was supported by grants from the Swedish Research Council (2013/3018, http://www.vr.se/, CL; 523-2010-1062, http://www.vr.se/, CL), Region Skåne (ALF), Knut and Alice Wallenberg Foundation, Novo Nordisk Foundation, EFSD/Lilly Fellowship, Söderberg Foundation, The Swedish Diabetes foundation, Påhlsson Foundation, EXODIAB, Linné grant (B31 5631/2006), The Danish Strategic Research Council, The Danish Council for Independent Research, Rigshospitalet, University of Copenhagen, Steno Diabetes Center, and Danish Diabetes Academy. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.