Adiposity associated DNA methylation signatures in adolescents are related to leptin and perinatal factors

R.C Huang,P.E Melton,M.A Burton,L.J Beilin,R Clarke-Harris,E Cook,K.M Godfrey,G.C Burdge,T.A Mori,D Anderson,S Rauschert,J M Craig,M.S Kobor,J.L Macisaac,A.M Morin,W.H Oddy,C.E Pennell,J.D Holbrook,K.A Lillycrop

doi:10.1080/15592294.2021.1876297

Abstract

ABSTRACT Epigenetics links perinatal influences with later obesity. We identifed differentially methylated CpG (dmCpG) loci measured at 17 years associated with concurrent adiposity measures and examined whether these were associated with hsCRP, adipokines, and early life environmental factors. Genome-wide DNA methylation from 1192 Raine Study participants at 17 years, identified 29 dmCpGs (Bonferroni corrected p < 1.06E-07) associated with body mass index (BMI), 10 with waist circumference (WC) and 9 with subcutaneous fat thickness. DmCpGs within Ras Association (RalGDS/AF-6), Pleckstrin Homology Domains 1 (RAPH1), Musashi RNA-Binding Protein 2 (MSI2), and solute carrier family 25 member 10 (SLC25A10) are associated with both BMI and WC. Validation by pyrosequencing confirmed these associations and showed that MSI2 , SLC25A10 , and RAPH1 methylation was positively associated with serum leptin. These were also associated with the early environment; MSI2 methylation (β = 0.81, p = 0.0004) was associated with pregnancy maternal smoking, SLC25A10 (CpG2 β = 0.12, p = 0.002) with pre- and early pregnancy BMI, and RAPH1 (β = −1.49, p = 0.036) with gestational weight gain. Adjusting for perinatal factors, methylation of the dmCpGs within MSI2, RAPH1, and SLC25A10 independently predicted BMI, accounting for 24% of variance. MSI2 methylation was additionally associated with BMI over time (17 years old β = 0.026, p = 0.0025; 20 years old β = 0.027, p = 0.0029) and between generations (mother β = 0.044, p = 7.5e-04). Overall findings suggest that DNA methylation in MSI2, RAPH1, and SLC25A10 in blood may be robust markers, mediating through early life factors.

Highlights

Studies suggest that susceptibility to obesity in later life may be influenced by the early life envir onment
Our Epigenome-wide DNA methylation association studies (EWAS) identified novel differentially methylated CpG (dmCpG) in peripheral blood associated with measures of adiposity in adolescents, with a considerable overlap in the dmCpGs associated with body mass index (BMI), waist circumference (WC), and subcutaneous fat (SC) fat thickness
DNA methylation at three novel dmCpG loci related to the genes Musashi RNA-Binding Protein 2 (MSI2), SLCA25A10, and RAPH1 was associated with a wide range of adiposity/body composition mea sures in adolescents, and with a number of antena tal factors including gestational weight gain (GWG), maternal BMI, and maternal smoking

Summary

Introduction

Studies suggest that susceptibility to obesity in later life may be influenced by the early life envir onment. Variations in maternal body composition and diet can induce persistent changes in metabolism and body composition in the offspring [1], while in humans, higher mater nal BMI and excessive gestational weight gain (GWG) independently increase obesity risk in the offspring [2]. Mechanisms by which the environment influences adiposity are suggested to involve the epigenetic reg ulation of genes. Variations in maternal diet induced changes in the methylation of key metabolic genes, which often persist through the lifecourse, accompanied by changes in gene expres sion and the metabolic proceses they control [3]. Human studies suggest a role for epigenetics in mediating the effects of the early life environment on later disease risk. Maternal carbohydrate intake and offspring adiposity have been associated with differential methylation of the promoter of the RXRA gene in the umbilical cord [4], while perinatal methylation of CpGs within the promoter of the long non-coding RNA ANRIL is associated with antenatal growth faltering and higher adiposity at age 6 years

Methods

Results

Conclusion