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Zaghlool, S.B.* ; Mook-Kanamori, D.O.* ; Kader, S.* ; Stephan, N.* ; Halama, A.* ; Engelke, R.* ; Sarwath, H.* ; Al-Dous, E.K.* ; Mohamoud, Y.A.* ; Römisch-Margl, W. ; Adamski, J. ; Kastenmüller, G. ; Friedrich, N.* ; Visconti, A.* ; Tsai, P.C.* ; Spector, T.* ; Bell, J.* ; Falchi, M.* ; Wahl, A. ; Waldenberger, M. ; Peters, A. ; Gieger, C. ; Pezer, M.* ; Lauc, G.* ; Graumann, J.* ; Malek, J.A.* ; Suhre, K.*

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

Hum. Mol. Genet. 27, 1106-1121 (2018)
Publ. Version/Full Text Postprint Research data DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Mendelian Randomization ; Glycomics ; Lipidomics ; Metabolomics ; Methylation ; Multi-omics ; Proteomics; Epigenome-wide Association; Body-mass Index; Differential Dna Methylation; Self-reported Smoking; Mendelian Randomization; Biomarker Discovery; Tobacco-smoking; Down-regulation; Serum Cotinine; Human Plasma
ISSN (print) / ISBN 0964-6906
e-ISSN 1460-2083
Journal Human Molecular Genetics
Quellenangaben Volume: 27, Issue: 6, Pages: 1106-1121 Article Number: , Supplement: ,
Publisher Oxford University Press
Publishing Place Oxford
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Bioinformatics and Systems Biology (IBIS)
Institute of Experimental Genetics (IEG)
Institute of Epidemiology II (EPI2)