Epigenetic determinants of bone microarchitecture (360G-Wellcome-201222_Z_16_Z)

There is increasing evidence that associations between adverse early life exposures, for example intrauterine vitamin D deficiency, and postnatal skeletal development might be mediated by epigenetic mechanisms. Using a well-established discovery pipeline from genome wide to individual CpG sites and subsequent function, perinatal methylation at two genes (retinoid X receptor alpha gene (RXRA), essential in the action of 1,25(OH)2 vitamin D and other nuclear hormones; and CDKN2A, involved in cell senescence) has been shown to be associated with offspring bone mineral content at four years of age. However, it is unknown whether such associations persist into later childhood, whether they involve bone microarchitecture, and whether supplementation with vitamin D in pregnancy may influence these epigenetic marks. I aim to investigate whether DNA methylation at these two sites is associated with bone mass and microarchitecture at twelve years of age in the offspring of the Southampton Women’s Survey (SWS), and to test whether gestational supplementation with vitamin D, in a completed randomised controlled trial (MAVIDOS), leads to altered DNA methylation at these loci. Finally, I will use SWS data to undertake a genome-wide discovery approach to identify other CpG sites associated with bone mass and microarchitecture.