Deep molecular phenotypes link complex disorders and physiological insult to CpG methylation

Hum Mol Genet. 2018 Mar 15;27(6):1106-1121. doi: 10.1093/hmg/ddy006.


Epigenetic regulation of cellular function provides a mechanism for rapid organismal adaptation to changes in health, lifestyle and environment. Associations of cytosine-guanine di-nucleotide (CpG) methylation with clinical endpoints that overlap with metabolic phenotypes suggest a regulatory role for these CpG sites in the body's response to disease or environmental stress. We previously identified 20 CpG sites in an epigenome-wide association study (EWAS) with metabolomics that were also associated in recent EWASs with diabetes-, obesity-, and smoking-related endpoints. To elucidate the molecular pathways that connect these potentially regulatory CpG sites to the associated disease or lifestyle factors, we conducted a multi-omics association study including 2474 mass-spectrometry-based metabolites in plasma, urine and saliva, 225 NMR-based lipid and metabolite measures in blood, 1124 blood-circulating proteins using aptamer technology, 113 plasma protein N-glycans and 60 IgG-glyans, using 359 samples from the multi-ethnic Qatar Metabolomics Study on Diabetes (QMDiab). We report 138 multi-omics associations at these CpG sites, including diabetes biomarkers at the diabetes-associated TXNIP locus, and smoking-specific metabolites and proteins at multiple smoking-associated loci, including AHRR. Mendelian randomization suggests a causal effect of metabolite levels on methylation of obesity-associated CpG sites, i.e. of glycerophospholipid PC(O-36: 5), glycine and a very low-density lipoprotein (VLDL-A) on the methylation of the obesity-associated CpG loci DHCR24, MYO5C and CPT1A, respectively. Taken together, our study suggests that multi-omics-associated CpG methylation can provide functional read-outs for the underlying regulatory response mechanisms to disease or environmental insults.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Carrier Proteins / genetics
  • Computational Biology / methods
  • CpG Islands*
  • DNA Methylation*
  • Epigenesis, Genetic
  • Female
  • Genetic Association Studies / methods
  • Genome, Human
  • Genome-Wide Association Study / methods
  • Glucose Metabolism Disorders / genetics*
  • Humans
  • Lipids / blood
  • Male
  • Metabolome
  • Obesity / genetics*
  • Repressor Proteins / genetics
  • Tobacco Smoking / genetics*


  • AHRR protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • Carrier Proteins
  • Lipids
  • Repressor Proteins
  • TXNIP protein, human