A novel approach to risk exposure and epigenetics-the use of multidimensional context to gain insights into the early origins of cardiometabolic and neurocognitive health.

Background: Each mother-child dyad represents a unique combination of genetic and environmental factors. This constellation of variables impacts the expression of countless genes. Numerous studies have uncovered changes in DNA methylation (DNAm), a form of epigenetic regulation, in offspring related to maternal risk factors. How these changes work together to link maternal-child risks to childhood cardiometabolic and neurocognitive traits remains unknown. This question is a key research priority as such traits predispose to future non-communicable diseases (NCDs). We propose viewing risk and the genome through a multidimensional lens to identify common DNAm patterns shared among diverse risk profiles.

Methods: We identified multifactorial Maternal Risk Profiles (MRPs) generated from population-based data (n = 15,454, Avon Longitudinal Study of Parents and Children (ALSPAC)). Using cord blood HumanMethylation450 BeadChip data, we identified genome-wide patterns of DNAm that co-vary with these MRPs. We tested the prospective relation of these DNAm patterns (n = 914) to future outcomes using decision tree analysis. We then tested the reproducibility of these patterns in (1) DNAm data at age 7 and 17 years within the same cohort (n = 973 and 974, respectively) and (2) cord DNAm in an independent cohort, the Generation R Study (n = 686).

Results: We identified twenty MRP-related DNAm patterns at birth in ALSPAC. Four were prospectively related to cardiometabolic and/or neurocognitive childhood outcomes. These patterns were replicated in DNAm data from blood collected at later ages. Three of these patterns were externally validated in cord DNAm data in Generation R. Compared to previous literature, DNAm patterns exhibited novel spatial distribution across the genome that intersects with chromatin functional and tissue-specific signatures.

Conclusions: To our knowledge, we are the first to leverage multifactorial population-wide data to detect patterns of variability in DNAm. This context-based approach decreases biases stemming from overreliance on specific samples or variables. We discovered molecular patterns demonstrating prospective and replicable relations to complex traits. Moreover, results suggest that patterns harbour a genome-wide organisation specific to chromatin regulation and target tissues. These preliminary findings warrant further investigation to better reflect the reality of human context in molecular studies of NCDs.