Genetics
Identification of Dynamic Genetic influences on DNA methylation From Birth to Adulthood Yueying Li* Yueying Li Josine Min Gibran Hemani James Staley Kate Tilling Tom Gaunt Venexia Walker Anna Grossbach Andrew Simpkin Rosa Mulder Claudio Cappadona
Background: DNA methylation (DNAm) is a key epigenetic mechanism underlying human trait diversity and exhibits time trajectories. While methylation quantitative trait locus (mQTL) studies have elucidated genetic factors associated with interindividual DNAm differences, it remains unclear whether genetic influences vary across developmental stages. This study aims to identify dynamic genetic associations with DNAm from birth to early adulthood (longitudinal mQTLs).
Methods: In the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort, we used data from child participants with DNAm measurements available at ≥ 2 time points. Our analysis targeted 236,298 previously reported mQTL-CpG pairs from the Genetics of DNA methylation Consortium that were also associated in ALSPAC. Linear mixed models were used to evaluate interactions between mQTLs and age. The identified longitudinal mQTLs were tested for replication in the Generation R cohort and the Drakenstein Child Health Study.
Results: 2,210 longitudinal mQTLs (1.1% of tested mQTLs) associated with 2,329 CpG sites were identified, forming 2,393 mQTL-CpG pairs, of which 176 pairs involved long-range (trans) associations. The most pronounced changes in both mQTL-CpG associations and DNAm levels occurred between birth and age 7. The identified longitudinal mQTLs overlapped with 589 GWAS loci, where no single phenotype showed significant enrichment across the entire mQTL set. Compared to other CpGs, longitudinal mQTL CpGs were enriched in regulatory elements of gene expression across tissues and exhibited a greater proportion of variability attributable to genetic effects.
Conclusion: A minority of genetic variants are associated with DNAm in a dynamic manner, particularly during early developmental stages. Our findings provide insights into the discrepancies observed across mQTL studies in different age groups and underscore the need for research into biological mechanisms specific to childhood.
