Early life affects late-life health through determining DNA methylation across the lifespan: A twin study

Abstract

Background: Previous findings for the genetic and environmental contributions to DNA methylation variation were for limited age ranges only. We investigated the lifespan contributions and their implications for human health for the first time.

Methods: 1,720 monozygotic twin (MZ) pairs and 1,107 dizygotic twin (DZ) pairs aged 0-92 years were included. Familial correlations (i.e., correlations between twins) for 353,681 methylation sites were estimated and modelled as a function of twin pair cohabitation history.

Findings: The methylome average familial correlation was around zero at birth (MZ pair: -0.01; DZ pair: -0.04), increased with the time of twins living together during childhood at rates of 0.16 (95%CI: 0.12-0.20) for MZ pairs and 0.13 (95%CI: 0.07-0.20) for DZ pairs per decade, and decreased with the time of living apart during adulthood at rates of 0.026 (95%CI: 0.019-0.033) for MZ pairs and 0.027 (95%CI: 0.011-0.043) for DZ pairs per decade. Neither the increasing nor decreasing rate differed by zygosity (both P>0.1), consistent with cohabitation environment shared by twins, rather than genetic factors, influencing the methylation familial correlation changes. Familial correlations for 6.6% (23,386/353,681) sites changed with twin pair cohabitation history. These sites were enriched for high heritability, proximal promoters, and epigenetic/genetic associations with various early-life factors and late-life health conditions.

Interpretation: Early life strongly influences DNA methylation variation across the lifespan, and the effects are stronger for heritable sites and sites biologically relevant to the regulation of gene expression. Early life could affect late-life health through influencing DNA methylation.

Funding: Victorian Cancer Agency, Cancer Australia, Cure Cancer Foundation.

Keywords: DNA methylation; DOHaD hypothesis; Heritability; Twin study.

Figure 1

DNA methylation familial correlation across the lifespan for the 1,720 monozygotic twin pairs and 1,107 dizygotic twin pairs a) Pattern of the overall twin pair correlation changed with age. Study-, zygosity- and site-specific twin pair correlation across the 353,681 investigated sites are showed as boxplots. The dashed curves are the zygosity-specific Locally Weighted Scatterplot Smoothing curves fitted across all studies. The plot is cropped along Y axis to better present the pattern. The full plot is in Figure S3. PETS – Peri/postnatal Epigenetic Twins Study; BSGS – Brisbane System Genetics Study; E-Risk – Environmental Risk Longitudinal Twin Study; DTR – Danish Twin Registry, with participants of two age groups: younger and older adults; NTR – Netherlands Twin Register; AMDTSS – Australian Mammographic Density Twins and Sisters Study; MuTHER – Multiple Tissue Human Expression Resource Study; OATS – Older Australian Twins Study; LSADT – Longitudinal Study of Aging Danish Twins, with samples collected in years 1997 and 2007, respectively. b) The overall twin pair correlation as a function of cohabitation history. The dashed lines are the zygosity-specific fitted lines from modelling the overall twin pair correlation of the 353,681 investigated sites as a function twin pair cohabitation history, with confidence intervals showed as ribbons.

Figure 2

Epigenetic association enrichment of the 23,386 cohabitation-dependent sites a) QQ plot for the enrichment analysis of the 40 investigated human traits/exposures. b) P-values for the 40 investigated human traits/exposures from the enrichment analysis. The P-values (Fisher's exact test) are shown as -log₁₀(P). Red bars are the significant human traits/exposures with a false discovery rate <5%.

Figure 3

Genetic association enrichment of the 23,386 cohabitation-dependent sites a) QQ plot for the enrichment analysis of the 3,292 investigated human traits/exposures. b) P-values for the 59 significant human traits/exposures from the enrichment analysis. The P-values (Fisher's exact test) are showed as -log₁₀(P). Red bars are the significant human traits/exposures with a false discovery rate <5%. Only significant traits/exposures are showed in the plot. The results for all the traits/exposures are in Table S3.