Epigenome-Wide Study Identified Methylation Sites Associated with the Risk of Obesity

Nutrients. 2021 Jun 9;13(6):1984. doi: 10.3390/nu13061984.


Here, we performed a genome-wide search for methylation sites that contribute to the risk of obesity. We integrated methylation quantitative trait locus (mQTL) data with BMI GWAS information through a SNP-based multiomics approach to identify genomic regions where mQTLs for a methylation site co-localize with obesity risk SNPs. We then tested whether the identified site contributed to BMI through Mendelian randomization. We identified multiple methylation sites causally contributing to the risk of obesity. We validated these findings through a replication stage. By integrating expression quantitative trait locus (eQTL) data, we noted that lower methylation at cg21178254 site upstream of CCNL1 contributes to obesity by increasing the expression of this gene. Higher methylation at cg02814054 increases the risk of obesity by lowering the expression of MAST3, whereas lower methylation at cg06028605 contributes to obesity by decreasing the expression of SLC5A11. Finally, we noted that rare variants within 2p23.3 impact obesity by making the cg01884057 site more susceptible to methylation, which consequently lowers the expression of POMC, ADCY3 and DNAJC27. In this study, we identify methylation sites associated with the risk of obesity and reveal the mechanism whereby a number of these sites exert their effects. This study provides a framework to perform an omics-wide association study for a phenotype and to understand the mechanism whereby a rare variant causes a disease.

Keywords: EWAS; Mendelian randomization; epigenetics; multiomics; obesity.

MeSH terms

  • Adenylyl Cyclases / genetics
  • Body Mass Index
  • Cyclins / genetics
  • DNA Methylation / genetics*
  • Epigenome / genetics*
  • Epigenomics / methods
  • Genetic Predisposition to Disease / genetics*
  • Genome-Wide Association Study
  • HSP40 Heat-Shock Proteins / genetics
  • Humans
  • Mendelian Randomization Analysis
  • Microtubule-Associated Proteins / genetics
  • Obesity / genetics*
  • Phenotype
  • Polymorphism, Single Nucleotide / genetics
  • Pro-Opiomelanocortin / genetics
  • Protein Serine-Threonine Kinases / genetics
  • Quantitative Trait Loci
  • Risk Factors
  • Sodium-Glucose Transport Proteins / genetics
  • rab GTP-Binding Proteins / genetics


  • CCNL1 protein, human
  • Cyclins
  • HSP40 Heat-Shock Proteins
  • Microtubule-Associated Proteins
  • SLC5A11 protein, human
  • Sodium-Glucose Transport Proteins
  • Pro-Opiomelanocortin
  • MAST3 protein, human
  • Protein Serine-Threonine Kinases
  • DNAJC27 protein, human
  • rab GTP-Binding Proteins
  • Adenylyl Cyclases
  • adenylate cyclase 3