Abstract
BackgroundEven if genetics play an important role, individual variation in stature remains unexplained at the molecular level. Indeed, genome-wide association study (GWAS) have revealed hundreds of variants that contribute to the variability of height but could explain only a limited part of it, and no single variant accounts for more than 0.3% of height variance. At the interface of genetics and environment, epigenetics contributes to phenotypic diversity. Quantifying the impact of epigenetic variation on quantitative traits, an emerging challenge in humans, has not been attempted for height. Since insulin-like growth factor 1 (IGF1) controls postnatal growth, we tested whether the CG methylation of the two promoters (P1 and P2) of the IGF1 gene is a potential epigenetic contributor to the individual variation in circulating IGF1 and stature in growing children.ResultsChild height was closely correlated with serum IGF1. The methylation of a cluster of six CGs located within the proximal part of the IGF1 P2 promoter showed a strong negative association with serum IGF1 and growth. The highest association was for CG-137 methylation, which contributed 13% to the variance of height and 10% to serum IGF1. CG methylation (studied in children undergoing surgery) was approximately 50% lower in liver and growth plates, indicating that the IGF1 promoters are tissue-differentially methylated regions (t-DMR). CG methylation was inversely correlated with the transcriptional activity of the P2 promoter in mononuclear blood cells and in transfection experiments, suggesting that the observed association of methylation with the studied traits reflects true biological causality.ConclusionsOur observations introduce epigenetics among the individual determinants of child growth and serum IGF1. The P2 promoter of the IGF1 gene is the first epigenetic quantitative trait locus (QTLepi) reported in humans. The CG methylation of the P2 promoter takes place among the multifactorial factors explaining the variation in human stature.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-015-0062-8) contains supplementary material, which is available to authorized users.
Highlights
Even if genetics play an important role, individual variation in stature remains unexplained at the molecular level
Methylation levels were comparable in white blood cells (WBC), peripheral blood mononuclear cells (PBMC), and CD4+ T lymphocytes (Figure 2)
The insulin-like growth factor 1 (IGF1) promoters can be considered as tissue differentially methylated regions (t-DMR)
Summary
Even if genetics play an important role, individual variation in stature remains unexplained at the molecular level. Quantifying the impact of epigenetic variation on quantitative traits, an emerging challenge in humans, has not been attempted for height. Genetics seems to explain a major but limited part of height variability across individuals. Quantitative geneticists envision DNA sequence variants as the only source of heritable phenotypes. This view should be revised in light of accumulating evidence for widespread epigenetic variation in natural populations [12,13]. While epigenetics is a considerable source of inherited and acquired variability among humans [14], its contribution to height variability has not been studied
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