Integrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes
Nature Communications · 33 authors, 25 centres
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This study used integrative genomics on human adipocytes to find DNA methylation differences between obese and lean individuals. The researchers found that many of these methylation changes are likely a consequence of obesity, but Mendelian randomisation suggests a causal role for a significant fraction in obesity and its metabolic consequences.
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The study conducted an epigenome-wide association study (EWAS) on DNA methylation in human subcutaneous and visceral adipocytes from extreme obesity case-control samples. It integrated methylation data with adipocyte-specific transcriptomics and chromatin interaction datasets to link obesity-associated methylation sites to gene expression changes in pathways related to development, metabolism, and inflammation. Mendelian randomisation analyses were used to assess causality. The results showed extensive, depot-specific methylation changes associated with obesity. Integration with genomic data connected these changes to over 500 genes, including a microRNA cluster linked to insulin resistance. Mendelian randomisation implicated up to 26% of obesity-associated methylation sites as having a causal effect on obesity and related metabolic traits. Functional validation in cellular models suggested roles in adipogenesis and lipid handling. Limitations include the focus on extreme traits and the need for experimental validation of specific causal mechanisms.
