Approximately 1.5 billion people worldwide are overweight or
affected by obesity, and are at risk of developing type 2 diabetes,
cardiovascular disease and related metabolic and inflammatory
disturbances1,2
. Although the mechanisms linking adiposity to
associated clinical conditions are poorly understood, recent studies
suggest that adiposity may influence DNA methylation3–6, a key
regulator of gene expression and molecular phenotype7
. Here we
use epigenome-wide association to show that body mass index
(BMI; a key measure of adiposity) is associated with widespread
changes in DNA methylation (187 genetic loci with P<1×10−7
,
range P=9.2×10−8
to 6.0×10−46; n=10,261 samples). Genetic
association analyses demonstrate that the alterations in DNA
methylation are predominantly the consequence of adiposity,
rather than the cause. We find that methylation loci are enriched
for functional genomic features in multiple tissues (P<0.05), and
show that sentinel methylation markers identify gene expression
signatures at 38 loci (P < 9.0 × 10−6
, range P = 5.5 × 10−6
to
6.1×10−35, n=1,785 samples). The methylation loci identify genes
involved in lipid and lipoprotein metabolism, substrate transport
and inflammatory pathways. Finally, we show that the disturbances
in DNA methylation predict future development of type 2 diabetes
(relative risk per 1 standard deviation increase in methylation risk
score: 2.3 (2.07–2.56); P=1.1×10−54). Our results provide new
insights into the biologic pathways influenced by adiposity, and may
enable development of new strategies for prediction and prevention
of type 2 diabetes and other adverse clinical consequences of obesity