Genetic and environmental influences on DNA methylation

Abstract

Epigenetic mechanisms respond to both genetic and environmental factors, but these underlying effects are not yet fully characterized or completely understood. In this thesis I used twins as a tool for evaluating the effect of genetic and environmental impacts on DNA methylation, a well-known epigenetic mechanism. DNA methylation was studied on a genome-wide scale in human blood samples with a combination of bioinformatics, computational, and statistical approaches. First, genetic influences on DNA methylation profiles were assessed by estimation of the heritability of DNA methylation and identification of methylation-quantitative trait loci in identical and non-identical twins profiled with the commonly used Infinium HumanMethylation450 BeadChip and the new enhancer-enriched Infinium MethylationEPIC Beadchip. Strong genetic effects (heritability > 0.4) were detected for 10% of sites and common genetic variants were identified to affect methylation levels at 22% of sites, from the 771,169 interrogated CpG sites across the genome. Second, I explored influences on the early-life methylome by comparing genome-wide DNA methylation profiles in naturally-conceived twins and twins conceived by in vitro fertilisation. Analysis of epigenetic profiles obtained by methylated DNA immunoprecipitation coupled with deep sequencing detected small changes at a gene previously associated with infertility, TNP1. Finally, I explored the effect of intrinsic factors on adult DNA methylation profiles, performing epigenome-wide studies of menopause and related phenotypes such as the use of hormone replacement therapy, which have metabolic consequences in middle-aged women. Epigenetic changes at seven CpG sites were associated with hormone replacement therapy. In summary, the results presented in this thesis give insights into genetic and specific environmental influences on the human epigenome.

Date of Award	2018
Original language	English
Awarding Institution	King's College London
Supervisor	Jordana Bell (Supervisor) & Tim Spector (Supervisor)