The prenatal exposome and genome in predictive modelling of DNA methylation

<jats:p>Introduction: Fetal development represents a critical window during which genetic and environmental influences shape lifelong health. DNA methylation (DNAm) is a candidate underlying mechanism. While individual prenatal exposures have been related to DNAm, no studies have investigated the broader prenatal exposome, nor incorporated genetics with the exposome. Here, we integrated the prenatal exposome and genetics as predictors of DNAm at birth. Methods: We used data from the Dutch Generation R (n=2282) and English Avon Longitudinal Study of Parents and Children (ALSPAC; n=809) cohorts. We performed epigenome-wide elastic net regression, using Generation R for model development/internal validation and ALSPAC for external validation, to predict DNAm at each CpG site. We used three models: Model 1 included 42 prenatal exposures, Model 2 additionally included child sex, gestational age and birth weight, and Model 3 further included meQTLs. Results: In Model 1, the prenatal exposome explained on average 0.7% of DNAm variation across 347 validated CpGs (0.1% of tested CpGs). This increased to 40,044 CpGs (10.2%) with 1.3% of variation explained in Model 2, and 91,305 CpGs (23.2%) with 3.0% of variation explained in Model 3. In Model 1, prenatal smoking was the largest predictor, followed by delivery characteristics, among which meconium-stained amniotic fluid was a novel finding. In Model 3, typically both SNPs and multiple prenatal exposures were selected. Discussion: We find that genomic associations with cord blood DNAm are stronger and more widespread than prenatal exposures, although typically, the prenatal exposome explains additional variation in DNAm beyond genetic influences.</jats:p>