Project description
Human disease phenotypes often manifest differently by sex, including age of onset, disease
incidence, symptoms and response to therapy. DNA methylation is an epigenetic modification
involving the covalent transfer of a methyl group to the 5’ carbon of cytosine residues.
Methylation of DNA plays a key role in determining genomic structure and function, including
regulation of cellular differentiation and gene expression. Population-based studies often use the
Illumina Infinium HumanMethylation450 and MethylationEPIC BeadChip arrays which offer costeffective
measurement of DNA methylation at > 450,000 and > 850,000 loci across all
chromosomes and allow profiling at a large scale. Such research over the last decade has showed
that differential DNA methylation of the autosomes is implicated in a variety of complex
multifactorial diseases. However, X and Y chromosome data have mostly been excluded due to
the analytical complexity associated with sex chromosome dosage differences and the impact of
X-chromosome inactivation. On the autosomes, DNA methylation is quantified as an average of
both alleles, as they typically have similar DNA methylation levels (with the exception of imprinted
loci). However, the inactivation of one X chromosome in females to ensure dosage compensation
leads to the active and inactive X chromosomes having distinct DNA methylation profiles. In this
project, we will develop an analytical pipeline for X and Y chromosome data preprocessing,
including quality control, normalization, and batch correction steps. We aim to explore (1) the
impact of DNA methylation at the X and Y chromosomes on human disease phenotypes e.g. on
sex hormone levels, (2) their interaction with related molecular layers like gene expression,
histone marks or plasma proteins and (3) the impact of environmental factors like tobacco
smoking. To do this, we build on existing DNA methylation data of two large and wellcharacterized
cohort studies (see below) with the ultimate goal of incorporating DNA methylation
at the X and Y chromosomes into population-based cohort research.
Relevant literature
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