Deep molecular phenotypes link complex disorders and physiological insult to CpG methylation
Year: 2018
Type: article
Study design: Observational Study
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.
Source: Human Molecular Genetics
DOI: 10.1093/hmg/ddy006
Authors: Shaza B Zaghlool, Dennis O Mook-Kanamori, Sara Kader, Nisha Stephan, Anna Halama, Rudolf Engelke, Hina Sarwath, Eman K Al-Dous, 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 Waldenberger, Annette Peters, Christian Gieger, Marija Pezer, Gordan Lauc, Johannes Graumann, Joel A Malek, Karsten Suhre
Institutions: Weill Cornell Medical College in Qatar, Weill Cornell Medicine, Virginia Tech, Leiden University, Leiden University Medical Center, Helmholtz Munich, Institute of Bioinformatics and Systems Biology, German Center for Diabetes Research, Universitätsmedizin Greifswald, Universität Greifswald, King's College London, German Centre for Cardiovascular Research, Genos (Croatia), Max Planck Institute for Heart and Lung Research
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2783170744