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

Mar 13, 2014
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Authors:
Dick KJ, Nelson CP, Tsaprouni L, et al.
Citation:
Lancet 2014;Mar 13:[Epub ahead of print].
Summary By:
Daniel T. Eitzman, MD

Study Questions:

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

Methods:

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.

Results:

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.

Conclusions:

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

Perspective:

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, Biomarkers, Linkage Disequilibrium, Phenotype, Transcription Factors, Gene Expression Regulation, Obesity, Pregnancy


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