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Deep molecular phenotypes link complex disorders and physiological insult to CpG methylation.
- Source :
-
Human molecular genetics [Hum Mol Genet] 2018 Mar 15; Vol. 27 (6), pp. 1106-1121. - Publication Year :
- 2018
-
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.
- Subjects :
- Basic Helix-Loop-Helix Transcription Factors genetics
Carrier Proteins genetics
Computational Biology methods
Epigenesis, Genetic
Female
Genetic Association Studies methods
Genome, Human
Genome-Wide Association Study methods
Humans
Lipids blood
Male
Metabolome
Repressor Proteins genetics
CpG Islands
DNA Methylation
Glucose Metabolism Disorders genetics
Obesity genetics
Tobacco Smoking genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2083
- Volume :
- 27
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Human molecular genetics
- Publication Type :
- Academic Journal
- Accession number :
- 29325019
- Full Text :
- https://doi.org/10.1093/hmg/ddy006