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DNA methylation is influenced by genetic and non-genetic factors. Here, we chart quantitative trait loci (QTLs) that modulate levels of methylation at highly conserved CpGs using liver methylome data from mouse strains belonging to the BXD family. A regulatory hotspot on chromosome 5 had the highest density of trans-acting methylation QTLs (trans-meQTLs) associated with multiple distant CpGs. We refer to this locus as meQTL.5a. Trans-modulated CpGs showed age-dependent changes and were enriched in developmental genes, including several members of the MODY pathway (maturity onset diabetes of the young). The joint modulation by genotype and ageing resulted in a more ‘aged methylome’ for BXD strains that inherited the DBA/2J parental allele at meQTL.5a. Further, several gene expression traits, body weight, and lipid levels mapped to meQTL.5a, and there was a modest linkage with lifespan. DNA binding motif and protein–protein interaction enrichment analyses identified the hepatic nuclear factor,  Hnf1a  (MODY3 gene in humans), as a strong candidate. The pleiotropic effects of meQTL.5a could contribute to variations in body size and metabolic traits, and influence CpG methylation and epigenetic ageing that could have an impact on lifespan.

Pleiotropic influence of DNA methylation QTLs on physiological and ageing traits