B4401 - Making sense of the varying methylome and varying disease patterns - 11/09/2023

B number: 
Principal applicant name: 
Josine Min | MRC IEU
Gibran Hemani, Johann Hawe, Yueying Li
Title of project: 
Making sense of the varying methylome and varying disease patterns
Proposal summary: 

DNA methylation (DNAm) plays a central role in gene regulation. However, it is unknown how DNAm patterns change. For example, through genetic factors or physiological states.
Longitudinal birth cohort studies such as ALSPAC provide an unique opportunity to study DNAm patterns over time and to link it to varying physiological states. Quantitative traits comprising your physiological state (such as BMI, glucose and inflammation levels) have varying patterns over time. Similarly eczema and asthma have varying disease patterns over time. Identifying changes in DNAm preceding a change in physiological state or a disease status may lead to identification of a marker that predicts disease outcome.(1)
Multiple studies have identified genetic variants associated with DNAm (mQTL: methylation quantitative trait locus) by combining genome wide genotype information with DNAm levels.(2) The Genetics of DNA methylation Consortium brought together a large number of cohorts to identify mQTLs in blood and investigated whether the mQTLs play a role in disease etiology.(3) Modelling DNAm trajectories with genetic variation could improve our understanding of biological mechanisms.

1. Chen R, Xia L, Tu K, Duan M, Kukurba K, Li-Pook-Than J, et al. Longitudinal personal DNA methylome dynamics in a human with a chronic condition. Nat Med. 2018;24(12):1930-9.
2. Gaunt TR, Shihab HA, Hemani G, Min JL, Woodward G, Lyttleton O, et al. Systematic identification of genetic influences on methylation across the human life course. Genome Biol. 2016;17:61.
3. Min JL, Hemani G, Hannon E, Dekkers KF, Castillo-Fernandez J, Luijk R, et al. Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation. Nat Genet. 2021;53(9):1311-21.

Impact of research: 
Date proposal received: 
Wednesday, 23 August, 2023
Date proposal approved: 
Monday, 4 September, 2023
Molecular genetics and genomics, eczema, asthma, glucose, BMI, inflammation markers, GWAS of DNA methylation, mendelian randomization, colocalization, longitudinal modelling, machine learning, Epigenetics