Deep molecular phenotypes link complex disorders and physiological insult to CpG methylation. (8th January 2018)

• Record Type: Journal Article
• Authors: Zaghlool, Shaza B; Mook-Kanamori, Dennis O; Kader, Sara; Stephan, Nisha; Halama, Anna; Engelke, Rudolf; Sarwath, Hina; Al-Dous, Eman K; Mohamoud, Yasmin A; Roemisch-Margl, Werner; Adamski, Jerzy; Kastenmüller, Gabi; Friedrich, Nele; Visconti, Alessia; Tsai, Pei-Chien; Spector, Tim; Bell, Jordana T; Falchi, Mario; Wahl, Annika; Waldenberger, Melanie; Peters, Annette; Gieger, Christian; Pezer, Marija; Lauc, Gordan; Graumann, Johannes; Malek, Joel A; Suhre, Karsten
• Is Part Of: Human molecular genetics. Volume 27:Number 6(2018:Mar. 15)
• Page Start: 1106
• Page End: 1121
• Publication Date: 2018-01-08
• Subjects: Human molecular genetics -- Periodicals; Human chromosome abnormalities -- Periodicals; 572.8
• DOI: 10.1093/hmg/ddy006
• Languages: English
• ISSNs: 0964-6906

Abstract

Abstract: 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.