Prenatal and early life influences on epigenetic age in children: a study of mother–offspring pairs from two cohort studies

Andrew J Simpkin,Gemma C Sharp,Wendy L Mcardle,Matthew Suderman,Gibran Hemani,Annette Peters,Cavin Ward-Caviness,Tom R Gaunt,Susan M Ring,Caroline L Relton,Melanie Waldenberger,Steve Horvath,Thorkild I A Sørensen,Ellen A Nohr,George Davey Smith,Sonja Kunze,Kate Tilling,Oliver Lyttleton

doi:10.1093/hmg/ddv456

Abstract

DNA methylation-based biomarkers of aging are highly correlated with actual age. Departures of methylation-estimated age from actual age can be used to define epigenetic measures of child development or age acceleration (AA) in adults. Very little is known about genetic or environmental determinants of these epigenetic measures of aging. We obtained DNA methylation profiles using Infinium HumanMethylation450 BeadChips across five time-points in 1018 mother–child pairs from the Avon Longitudinal Study of Parents and Children. Using the Horvath age estimation method, we calculated epigenetic age for these samples. AA was defined as the residuals from regressing epigenetic age on actual age. AA was tested for associations with cross-sectional clinical variables in children. We identified associations between AA and sex, birth weight, birth by caesarean section and several maternal characteristics in pregnancy, namely smoking, weight, BMI, selenium and cholesterol level. Offspring of non-drinkers had higher AA on average but this difference appeared to resolve during childhood. The associations between sex, birth weight and AA found in ARIES were replicated in an independent cohort (GOYA). In children, epigenetic AA measures are associated with several clinically relevant variables, and early life exposures appear to be associated with changes in AA during adolescence. Further research into epigenetic aging, including the use of causal inference methods, is required to better our understanding of aging.

Highlights

There has been considerable recent interest in epigenetic biomarkers of aging [1,2,3,4,5,6], which use an individual’s DNA methylation data to estimate their ‘epigenetic age’, a concept that could be considered a form of biological age
The associations between sex, birth weight and AA found in Accessible Resource for Integrated Epigenomic Studies (ARIES) were replicated in an independent cohort (GOYA)
The GOYA study was used for replication of findings and includes DNA methylation from 981 newborns, along with clinical information on both mothers and children

Summary

Introduction

There has been considerable recent interest in epigenetic biomarkers of aging [1,2,3,4,5,6], which use an individual’s DNA methylation data to estimate their ‘epigenetic age’, a concept that could be considered a form of biological age. The Horvath age estimation method [1] had a correlation of 0.96 between actual and epigenetic age, with individual estimates of epigenetic age within 3 years of actual age, on average. Several recent papers have found that the difference between epigenetic and actual age (known as age acceleration, denoted AA) has biological significance. The epigenetic clock method has been applied to study aging in blood samples from subjects with a severe developmental disorder [12] and to estimate the ages of tissues from centenarians [13]. We could refer to AA as an epigenetic measure of development in children, though for the sake of clarity, we will use AA throughout this article

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Discussion

Conclusion