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

Shaza B. Zaghlool, Dennis O. Mook-Kanamori, Sara Kader, Nisha Stephan, Anna Halama, Rudolf Engelke, Hina Sarwath, Eman Aldous, Yasmin A. Mohamoud, Werner Roemisch-Margl, Jerzy Adamski, Gabi Kastenmüller, Nele Friedrich, Alessia Visconti, Pei Chien Tsai, Tim Spector, Jordana T. Bell, Mario Falchi, Annika Wahl, Melanie WaldenbergerAnnette Peters, Christian Gieger, Marija Pezer, Gordan Lauc, Johannes Graumann, Joel A. Malek, Karsten Suhre

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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 bodys 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 NMRbased 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.

Original languageEnglish
Pages (from-to)1066-1121
Number of pages56
JournalHuman Molecular Genetics
Issue number6
Publication statusPublished - 15 Mar 2018


ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Zaghlool, S. B., Mook-Kanamori, D. O., Kader, S., Stephan, N., Halama, A., Engelke, R., Sarwath, H., Aldous, E., Mohamoud, Y. A., Roemisch-Margl, W., Adamski, J., Kastenmüller, G., Friedrich, N., Visconti, A., Tsai, P. C., Spector, T., Bell, J. T., Falchi, M., Wahl, A., ... Suhre, K. (2018). Deep molecular phenotypes link complex disorders and physiological insult to CpG methylation. Human Molecular Genetics, 27(6), 1066-1121.