Multi-omic associations of epigenetic age acceleration are heterogeneously shaped by genetic and environmental influences

Abstract

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, and 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 showed that genetic confounding heterogeneously affected these associations, with six multi-omic factors remaining significantly associated with EAA independent of genetic effects. Replication in older twins showed that some of these associations persist across adult generations.