DNA Methylation and Body-Mass Index: A Genome-Wide Analysis

Study Questions:

Is body mass index (BMI) affected by DNA methylation?


Whole-blood DNA was analyzed from 479 subjects with a methylation array. Methylation levels were tested for association with BMI. Positive associations were tested in a replication cohort of 339 subjects and persistent significant associations, then tested in a second replication cohort of 1,789 subjects. Association of methylation at BMI-associated sites with genetic variants and gene expression was also analyzed.


An association between methylation and BMI was confirmed in all cohorts with three probes residing in intron 1 of HIF3A. Two single-nucleotide polymorphisms (SNPs) showed independent associations with one of these methylation sites, but these SNPs were not associated with BMI.


The authors concluded that increased BMI is associated with increased methylation at the HIF3A locus in blood cells and in adipose tissue.


Obesity is a complex phenotype affected by environmental and genetic factors. Genome-wide analysis studies have identified numerous SNPs associated with obesity, but effects are controversial and small, probably accounting for <1.5% of variation between individuals. Transcriptional regulation of genes also occurs via DNA methylation, which may be affected by both genetic and environmental factors. Using a newly developed array accounting for about 485,000 methylation sites spanning 99% of genes, these authors identified a novel association between BMI and a locus that regulates responses to hypoxia (a hypoxia-inducible transcription factor). As SNPs associated with methylation at this site were not associated with BMI, it may be that these findings are a result rather than a cause of obesity. The role of this methylation site in mediating downstream effects of obesity in humans will require further study.

Keywords: DNA Replication, DNA Methylation, Body Mass Index, Polymorphism, Single Nucleotide, Biological Markers, Linkage Disequilibrium, Phenotype, Transcription Factors, Gene Expression Regulation, Obesity, Pregnancy

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