Immune pathways and prenatal/perinatal environmental exposures contribute to epigenetic gestational age prediction and acceleration

DNA methylation (DNAm), capturing chronological gestational age (GA) and epigenetic gestational age acceleration (EGAA), can be modified by environmental exposures. The Asthma&Allergy array is a new DNAm array developed with content focused on asthma and allergy loci. The association between content on the Asthma&Allergy array and chronological GA and EGAA has not been evaluated alone or in the context of prenatal/perinatal exposures. We performed an epigenome wide association study (EWAS) chronological GA at single CpG sites and regions in cord blood from 391 newborn children from a Detroit-based birth cohort. We further constructed a multi-CpG site methylation model to predict chronological GA. Also, associations between prenatal/perinatal environmental factors with GA, epigenetic gestational age (EGA), and EGAA were assessed. We identified 2,435 CpG sites associated with chronological GA, and CpGs within the HLA class II locus (<i>HLA-DRB1, HLA-DQB1, HLA-DRB6</i>) were among the most significantly associated with chronological GA. Our multi-CpG site model attained higher predictive accuracy (R² = 0.88) comparable to other published methods. Using genes implicated in region-based analyses (<i>n</i> = 395 regions), the pathways most significantly enriched with chronological GA-associated CpGs included T helper 1(Th1) and 2(Th2) activation, B-cell development, and IL-10 signaling, which were also enriched in at least one of the other published epigenetic GA clocks. In multi-exposure models, infant's first-born status and maternal parity were associated with EGAA. Our findings highlight enrichment for T cell modulated pathways and antigen presentation as biological processes associated with chronological GA, as well as prenatal/perinatal factors that may affect EGAA.