Methylation profile scores (MPSs) aggregate the effects of many DNA methylation (DNAm) sites across the genome into a single continuous value per individual. These scores are rapidly gaining traction in health research, as they translate DNAm patterns into summary measures that can be used to address many clinical and epidemiological questions. Most current research, however, is focused on adults, with little consideration given to transferability to children and adolescents. In this Review, we aim to provide a practical guide introducing MPSs and to discuss the current status of MPSs in child and adolescent populations. First, we introduce the diverse applications of MPSs, including the following: (1) use as exposure proxies to estimate exposures that are missing, under-reported, or hard to measure (eg, an MPS for exposure to maternal prenatal smoking); (2) use as biological proxies to summarise physiological processes such as inflammation (eg, an MPS for C-reactive protein); (3) use in risk stratification, where MPS variation is associated with risk of a future health outcome (eg, cardiometabolic disease); (4) use in diagnostics, where MPSs are used to detect disease states (currently most established for rare Mendelian syndromes and paediatric brain tumours); and (5) use in pharmacoepigenetics and treatment monitoring, an emerging area where MPSs are used to predict treatment response or track symptom change over time. Second, we outline specific considerations that apply to the developmental context, which explain why child and adolescent MPSs often differ from their later-life counterparts. Third, we provide recommendations on how to critically judge paediatric MPS studies. Finally, we conclude that, at present, with a few notable exceptions, most MPSs are better characterised as research tools at an early stage of development rather than clinical tools, and we highlight future directions for the field.
Isabel K. Schuurmans, S. Defina, A. Hermans et al.· The Lancet Child & Adolescen...· 0 citations
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.
Elena Isaevska, Rosa H. Mulder, Isabel K. Schuurmans et al.· medRxiv· 0 citations
It is found 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.
Rosa H. Mulder, Elena Isaevska, C. Cappadona et al.· bioRxiv· 0 citations