Identification of Dynamic Genetic Influences on DNA Methylation from Birth to Adulthood

Li, Y., Staley, J. R., Grossbach, A., Cappadona, C., Lussier, A. A., Dunn, E. C., Felix, J., Cecil, C. A. M., Stein, D. J., Zar, H. J., Walker, V. M., Gaunt, T. R., Tilling, K. R., Mulder, R. H., Simpkin, A. J., Hemani, G., Min, J.

University of Bristol · biorxiv

Paper

Abstract

Whether and how genetic regulation of DNA methylation (DNAm) change across the lifespan remains unclear. Here, we map age dependent methylation quantitative trait loci (longitudinal mQTLs) using linear mixed models applied to repeated blood DNAm measures from birth, childhood, adolescence and adulthood in the Avon Longitudinal Study of Parents and Children. We identify 2,210 longitudinal mQTLs (2,393 SNP-CpG pairs; 7.3% trans) and observe consistent genotype by age effects in two independent cohorts of diverse ancestries (Pearson's r = 0.85 in the Generation R Study; r = 0.56 in the Drakenstein Child Health Study). Longitudinal mQTLs show increasing effects with age at half of loci and associations with multiple phenotypes. CpGs with longitudinal mQTLs are more heritable and enriched in regulatory elements and pathways related to multicellular organism development and cell adhesion. These results chart dynamic genetic influences on the human methylome and provide a novel perspective on epigenetic regulation.

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Research summary

The paper identifies longitudinal mQTLs that influence DNA methylation across the lifespan. This research is relevant as it explores genetic regulation of epigenetic changes over time, which could provide insights into the biological mechanisms of aging and longevity.

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