Differentially Methylated Genomic Regions in Birth‐Weight Discordant Twin Pairs

Abstract

Poor nutrition during critical growth phases may alter the structural and physiologic development of vital organs thus "programming" the susceptibility to adult-onset diseases and disease-related health conditions. Epigenome-wide association studies have been performed in birth-weight discordant twin pairs to find evidence for such "programming" effects, but no significant results emerged. We further investigated this issue using a new computational approach: Instead of probing single genomic sites for significant alterations in epigenetic marks, we scan for differentially methylated genomic regions. Whole genome DNA methylation levels were measured in whole blood from 150 pairs of adult identical twins discordant for birth-weight. Intrapair differential DNA methylation was associated with qualitative (large or small) and quantitative (percentage) birth-weight discordance at each genomic site using regression models adjusting for age and sex. Based on the regression results, genomic regions with consistent alteration patterns of DNA methylation were located and tested for significant robustness using computational permutation tests. This yielded an interesting genomic region on chromosome 1, which is significantly differentially methylated for quantitative birth-weight discordance. The region covers two genes (TYW3 and CRYZ) both reportedly associated with metabolism. We conclude that prenatal conditions for birth-weight discordance may result in persistent epigenetic modifications potentially affecting even adult health.

Impact on birth weight of maternal smoking throughout pregnancy mediated by DNA methylation

“…The genes PIM1 , CNTNAP2 , and ITGB7 were not implicated in previous EWAS of birth weight [ 69 – 71 ]. However, in a gene-based analysis of genetic data obtained from a genome-wide association analysis of birth weight by the EGG Consortium [ 58 ], the present authors found that ITGB7 was strongly associated with birth weight (p=4, 2x10 -7 ).…”

Birth weight discordance, DNA methylation, and cortical morphology of adolescent monozygotic twins

“…However, even with these advantages we could not establish a statistically robust association between BW discordance and DNA methylation. Another study of blood samples from 150 adult MZ twin pairs of various ages (30–74 years) found no association between BW discordance and differences in methylation [Tan et al, ], although using differentially methylated region‐based association analysis, one significantly altered region covering two genes, CRYZ and TYW3 on chromosome 1 was identified [Chen et al, ]. Another study examined human umbilical vein endothelial cells from 22 newborn MZ twin pairs and 12 DZ twin pairs [Gordon et al, ] and found evidence for an association at only one probe at an FDR threshold of Q = 0.07.…”

“…The present study innovated by examining the putative mediating role of DNA methylation on the BW-cortical morphometry relationship. To our knowledge, only a few other studies examining BW related variations in epigenome-wide DNA methylation in MZ twins have been [Chen et al, 2016;Gordon et al, 2012;Souren et al, 2013;Tan et al, 2014]. The most directly comparable work is by Souren et al [Souren et al, 2013], who studied 17 adult twin pairs with methylation data from saliva samples.…”

Lung function discordance in monozygotic twins and associated differences in blood DNA methylation

“…The z -score of lung function can be seen as a relative measure, as it implies the state of the individuals’ lung function, compared to the state expected from the reference population (GLI 2012 [ 68 ]). With that consideration and also due to the distribution of z -scores, which is around 0, we took the intra-pair difference in z -score as a measurement of quantitative discordance, instead of calculating the proportion of discordance between twins as done in previous studies of birth weight discordant MZ twins [ 74 , 75 ].…”