Multi‐Omic Associations of Epigenetic Age Acceleration Are Heterogeneously Shaped by Genetic and Environmental Influences

Connections between the multi-ome and epigenetic age acceleration (EAA), and especially whether these are influenced by genetic or environmental factors, remain underexplored. We therefore quantified associations between the multi-ome comprising four layers-the proteome, metabolome, external exposome (here, sociodemographic factors), and specific exposome (here, lifestyle)-with six different EAA estimates. Two twin cohorts were used in a discovery-replication scheme, comprising, respectively, young (N = 642; mean age = 22.3) and older (N = 354; mean age = 62.3) twins. Within-pair twin designs were used to assess genetic and environmental effects on associations. We identified 40 multi-omic factors, of which 28 were proteins, associated with EAA in the young twins while adjusting for sex, smoking, and body mass index. Within-pair analyses revealed that genetic confounding influenced these associations heterogeneously, with six multi-omic factors -matrix metalloproteinase 9, complement component C6, histidine, glycoprotein acetyls, lactate, and neighborhood percentage of nonagenarians- remaining significantly associated with EAA, independent of genetic effects. Replication analyses showed that some associations assessed in young twins were consistent in older twins. Our study highlights the differential influence of genetic effects on the associations between the multi-ome and EAA and shows that some, but not all, of the associations persist into adulthood.