Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity

Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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 disturbances. Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation, a key regulator of gene expression and molecular phenotype. 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.

Original languageEnglish
Pages (from-to)81-86
Number of pages6
JournalNature
Volume541
Issue number7635
DOIs
Publication statusPublished - 5 Jan 2017

Keywords

  • Adipose Tissue/metabolism
  • Adiposity/genetics
  • Asian Continental Ancestry Group/genetics
  • Blood/metabolism
  • Body Mass Index
  • Cohort Studies
  • DNA Methylation/genetics
  • Diabetes Mellitus, Type 2/complications
  • Epigenesis, Genetic
  • Epigenomics
  • Europe/ethnology
  • European Continental Ancestry Group/genetics
  • Female
  • Genetic Markers
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • India/ethnology
  • Male
  • Obesity/blood
  • Overweight/blood
  • DNA METHYLATION
  • HUMANS
  • MENDELIAN RANDOMIZATION
  • TRENDS
  • GLUCOSE
  • BARIATRIC SURGERY
  • HEALTH
  • TISSUE
  • OBESITY
  • DISEASE

Cite this

Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity (2017). Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity. Nature, 541(7635), 81-86. https://doi.org/10.1038/nature20784