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

Yueying Li; James R Staley; Anna Großbach; Claudio Cappadona; Alexandre A. Lussier; Erin C. Dunn; Janine F. Felix; Charlotte A. M. Cecil; Dan J. Stein; Heather Joy Zar; Venexia M. Walker; Tom R. Gaunt; Kate M. Tilling; Rosa H. Mulder; Andrew J. Simpkin; Gibran Hemani; Josine L. Min

doi:10.64898/2026.03.09.710470

GenomicsbioRxivMar 10, 2026

Preprint

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

Yueying Li iD, James R Staley iD, Anna Großbach iD, Claudio Cappadona iD, Alexandre A. Lussier iD, Erin C. Dunn iD, Janine F. Felix iD, Charlotte A. M. Cecil iD, Dan J. Stein iD, Heather Joy Zar iD, Venexia M. Walker iD, Tom R. Gaunt iD, Kate M. Tilling iD, Rosa H. Mulder iD, Andrew J. Simpkin iD, Gibran Hemani iD, Josine L. Min iD

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 (Pearsons 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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