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Genetics of DNA Methylation and Its Role in Disease Susecptibility (2015–2018)

Abstract:
DNA methylation is crucial in regulating cellular processes including the silencing of gene expression, cellular differentiation and maintaining genomic stability. Thus it is not surprising that there is increasing evidence for a major role of epigenetic mechanisms in the development of disease. Despite the importance of DNA methylation, there are currently fundamental gaps in our knowledge of the genetic and environmental control of its variation. Understanding the genetic regulation of DNA methylation is particularly important as the majority of genome-wide association hits for complex disease are recognised to be regulatory in nature and DNA methylation provides a potential target for therapeutic intervention. My research aims to elucidate the genetic control of DNA methylation, to understand how this affects disease susceptibility, and to define the molecular mechanisms underlying its effect on gene-expression. I will perform genome-wide association studies on DNA methylation levels at over 400,000 sites using three locally available cohorts and combine these in a large international consortium meta-analysis. The role of genetic variation in DNA methylation in disease susceptibility will be quantified by testing the proportion of genetic variation explained by the combined total of all identified mQTL for a range of diseases and endophenotyes. Finally, the direction of biological causation between genotype and differences in DNA methylation and gene-expression will be elucidated. This will result in the identification of the functional mechanism for many of the genetic associations for DNA methylation and gene expression levels, providing knowledge to target them for future therapeutic intervention.
Grant type:
NHMRC Career Development Fellowship
Researchers:

  • Dr Allan McRae

    Principal Research Fellow, ARC Fund
    Institute for Molecular Bioscience
    Interim Director, GIH
    Pro-Vice-Chancellor (Research Infrastructure)
Funded by:
National Health and Medical Research Council