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

Autori
Zaghlool, S.B. ; Mook-Kanamori, D.O. ; Kader, S. ; Stephan, N. ; Halama, A. ; Engelke, R. ; Sarwath, H. ; Al-Dous, E.K. ; Mohamoud, Y.A. ; Roemisch-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, Marija ; Lauc, Gordan ; Graumann, J. ; Malek, J.A. ; Suhre, K.

Izvornik
Human molecular genetics (0964-6906) 27 (2018), 6; 1106-1121

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
Mendelian randomization ; glycomics ; lipidomics ; metabolomics ; methylation ; multi-omics ; proteomics

Sažetak
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 2, 474 mass- spectrometry based metabolites in plasma, urine, and saliva, 225 NMR based lipid and metabolite measures in blood, 1, 124 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.

Izvorni jezik
Engleski

Znanstvena područja
Biologija, Temeljne medicinske znanosti

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