DNA Methylation Changes in theIGF1RGene in Birth Weight Discordant Adult Monozygotic Twins

Abstract

Low birth weight (LBW) can have an impact on health outcomes in later life, especially in relation to predisposition to metabolic disease. Several studies suggest that LBW resulting from restricted intrauterine growth leaves a footprint on DNA methylation in utero, and this influence likely persists into adulthood. To investigate this further, we performed epigenome-wide association analyses of blood DNA methylation using Infinium HumanMethylation450 BeadChip profiles in 71 adult monozygotic (MZ) twin pairs who were extremely discordant for birth weight. A signal mapping to the IGF1R gene (cg12562232, p = 2.62 × 10 −8 ), was significantly associated with birth weight discordance at a genome-wide false-discovery rate (FDR) of 0.05. We pursued replication in three additional independent datasets of birth weight discordant MZ pairs and observed the same direction of association, but the results were not significant. However, a meta-analysis across the four independent samples, in total 216 birth-weight discordant MZ twin pairs, showed a significant positive association between birth weight and DNA methylation differences at IGF1R (random-effects meta-analysis p = .04), and the effect was particularly pronounced in older twins (randomeffects meta-analysis p = .008, 98 older birth-weight discordant MZ twin pairs). The results suggest that severe intra-uterine growth differences (birth weight discordance >20%) are associated with methylation changes in the IGF1R gene in adulthood, independent of genetic effects.

Copy Number Variants and Exome Sequencing Analysis in Six Pairs of Chinese Monozygotic Twins Discordant for Congenital Heart Disease

“…These epigenetic differences may account for phenotypic discordance in MZ twins. Multiple studies have explored the epigenetic changes in twins discordant for a range of congenital diseases, including autism spectrum disorder (Nguyen et al, 2010 ; Wong et al, 2014 ), birth weight (Souren et al, 2013 ; Tsai et al, 2015 ), congenital renal agenesis (Jin et al, 2014 ), and congenital cataracts (Wei et al, 2015 ). Recently, epigenetic aberrations have been sought in CHDs (Serra-Juhé et al, 2015 ; Vecoli et al, 2015 ) but not in CHD-discordant twins.…”

Metabolomics profiling reveals novel markers for leukocyte telomere length

“…DNA was extracted from whole blood, bisulfite converted and subsequently analyzed using the Infinium 450K kit as previously described [ 50 ]. The beta mixture quantile dilation (BMIQ) method was performed to correct for technical variation [ 51 ].…”

Epigenome-wide Association of DNA Methylation in Whole Blood With Bone Mineral Density

“…One of the most stable epigenetic processes is DNA methylation, or the addition of a CH 3 methyl group to cytosine, typically in the context of cytosine paired sequentially to a guanine nucleotide, separated by a phosphate group (CpG). DNA methylation is known to play a role in gene expression and cell differentiation, and differential DNA methylation has been linked to multiple human complex traits and disease phenotypes . Studies performed using bone samples have identified epigenetic alterations that influence bone cell function .…”

“…DNA methylation is known to play a role in gene expression and cell differentiation, (7,8) and differential DNA methylation has been linked to multiple human complex traits and disease phenotypes. (5,(9)(10)(11)(12) Studies performed using bone samples have identified epigenetic alterations that influence bone cell function. (13,14) We studied epigenetic variation in whole blood, as a proxy for difficult-to-acquire samples such as bone, in relation to BMD because epigenetic markers are often stable across multiple tissues, and immune cells within blood are known to influence bone homeostasis.…”