DNA methylation as proxy of genetic, prenatal and perinatal psychiatric risk factors

Background. Cord blood DNA methylation profile scores (MPSs) based on genetic and pre-/perinatal risk factors for neurodevelopmental conditions (NDCs) may capture downstream biological effects and help understand how combined exposure signals contribute to NDC risk. Methods. Using data from two longitudinal birth cohorts, Generation R (N-train = 1856, N-test = 476) and ALSPAC (N-validation= 832), we developed cord blood MPSs based on genetic and pre-/perinatal NDC risk factors. We assessed individual and combined predictive performance of risk factors and MPSs for eight childhood psychiatric outcomes (four broad, four specific), measured between ages 5 and 14 years. We also evaluated if the MPSs could be combined into a composite "transmission load" MPS. Results. We validated four novel MPSs: maternal age, birthweight, and genetic liability for ADHD and schizophrenia (r range = 0.08 to 0.29) and included two previously validated MPSs: maternal smoking and gestational age (r range = 0.42 to 0.63). Jointly modeling the six MPSs with their corresponding risk factors explained on average 3.3% of variance in outcomes, higher than that explained by risk factors (1.8%) or MPSs alone (1.6%), indicating complementary sources of risk. The "transmission load" MPS did not replicate due to heterogeneous contributions of the predictors across cohorts. Conclusions. The four novel MPSs based on genetic and pre-/perinatal risk factors can serve as valuable tools for future research. Integrating genetic and prenatal risk factors with DNA methylation at birth can provide insights into their individual and joint contributions to early psychiatric risk and may improve prediction.