An epigenome-wide study of body mass index and DNA methylation in blood using participants from the Sister Study cohort

Abstract

Background/Objectives The relationship between obesity and chronic disease risk is well-established; the underlying biological mechanisms driving this risk increase may include obesity-related epigenetic modifications. To explore this hypothesis, we conducted a genome-wide analysis of DNA methylation and body mass index (BMI) using data from a subset of women in the Sister Study. Subjects/Methods The Sister Study is a cohort of 50,884 U.S. women who had a sister with breast cancer but were free of breast cancer themselves at enrollment. Study participants completed examinations which included measurements of height and weight, and provided blood samples. Blood DNA methylation data generated with the Illumina Infinium HumanMethylation27 BeadChip array covering 27,589 CpG sites was available for 871 women from a prior study of breast cancer and DNA methylation. To identify differentially methylated CpG sites associated with body mass index, we analyzed this methylation data using robust linear regression with adjustment for age and case status. For those CpGs passing the false discovery rate significance level, we examined the association in a replication set comprised of a non-overlapping group of 187 women from the Sister Study who had DNA methylation data generated using the Infinium HumanMethylation450 BeadChip array. Analysis of this expanded 450K array identified additional BMI-associated sites which were investigated with targeted pyrosequencing. Results Four CpG sites reached genome-wide significance (FDR q<0.05) in the discovery set and associations for all four were significant at strict Bonferroni correction in the replication set. An additional 23 sites passed FDR in the replication set and 5 were replicated by pyrosequencing in the discovery set. Several of the genes identified including ANGPT4, RORC, SOCS3, FSD2, XYLT1, ABCG1, STK39, ASB2, and CRHR2 have been linked to obesity and obesity-related chronic diseases. Conclusions Our findings support the hypothesis that obesity-related epigenetic differences are detectable in blood and may be related to risk of chronic disease.

Novel DNA methylation sites of glucose and insulin homeostasis: an integrative cross-omics analysis

“…We further validated 13 previous reported CpG 244 sites in 11 independent loci. Based on the cross-omics analyses, our report complements earlier studies 12,13,17-245 25,34 for multiple DNA methylation sites related to the pathology early in the development of T2D through 246 genetics and/or gene expression. We also present in silico evidence supporting the potential involvement of 247 the nine new methylation sites.…”

“…resistance (HOMA-IR) and BMI 12,13,[17][18][19][20][21][22][23][24][25] (Supplementary Table 2). Of the known CpG sites, three located in 155 SLC7A11, CPT1A, and SREBF1 associated with both glucose and insulin.…”

Histone deacetylase 9 promoter hypomethylation associated with adipocyte dysfunction is a statin-related metabolic effect

“…Elevated ABCG1 expression is associated with increased fat mass from obese individuals, suggesting that ABCG1 is also involved in human adipogenesis (25). Although genome-wide association studies have not found any single nucleotide polymorphisms (SNPs) within or nearby ABCG1 associated with increased T2D risk, several EWAS have found that hypermethylation in the ABCG1 gene was associated with fasting glucose, HbA1C levels, lipid metabolism, fasting insulin, T2D risk and BMI (15,16,22,35–38). Additional observations in mouse models have shown that Abcg1 −/− mice were protected from high fat diet-induced glucose intolerance (39).…”

“…Adipogenesis occurs as a result of metabolic cues that trigger the induction of key differentiation regulators, such as ADIPOQ, FASN, PPARg, ABCG1 and GLUT4 (9–12). Epigenome wide association studies (EWAS) have found that hypermethylation within one of these genes involved in adipogenesis, ABCG1 , was associated with increased body mass index (BMI), insulin resistance and T2D risk (13–16), opening avenues in the elucidation of the links between adipogenesis and metabolic diseases.…”

Multifaceted genome-wide study identifies novel regulatory loci for body mass index in Indians

“…Additionally, DNA methylation marks in blood at four CpG sites residing in LGALS3BP, RORC, SOCS3 and ANGPT4 retained robust association with BMI levels in American Women [47]. 2 5 Identification of BAI3 variant rs6913677 as cis-meth-QTL demonstrates that variant may fine-tune adiposity via affecting BAI3 gene expression.…”