The development of childhood internalising problems: A meta-analysis of epigenome-wide-association-studies

BackgroundPre- and postpartum environments and genetic effects influence childhood internalising problems, which increase depression risk. DNA methylation (DNAm) may capture some of these effects. We therefore investigated associations between child blood DNAm and internalising problems. MethodWe meta-analysed probe and region-level epigenome-wide association studies using data from 3 European birth cohorts (ALSPAC, MoBa, Generation R; maximum n = 3,011) from the Pregnancy And Childhood Epigenetics (PACE) Consortium. DNAm was assessed at birth (cord blood) and age 6 years (peripheral blood). Internalising problems (ages 3 and 6) were reported by mothers using the Child Behaviour Checklist or Strengths and Difficulties Questionnaire. Models were adjusted for age at DNAm assessment, 20 surrogate variables, estimated cell proportions, maternal education, age, smoking, and, in secondary analysis maternal anxiety and depression. Public databases were searched for mental health associations with top CpG sites and regions. ResultsNo significant probe-level associations were found between cord or peripheral blood DNAm and internalising problems. In region-level analyses, two differentially methylated regions (DMRs) in cord blood were associated with internalising problems at age 3 (annotated to STK32C, MIR886), and one at age 6 (PFKFB2). At age 6, peripheral blood analyses identified two DMRs (C10orf26 (WBP1L), FAM125A). Several genes showed prior associations with psychiatric phenotypes, including depression. ConclusionThe higher-powered regional-level analyses revealed more associations than probe-level. Amongst others, we identified a region annotated to STK32C that has previously been linked to adolescent depression. Larger samples and refined phenotyping are needed to clarify the role of DNAm in internalising problems. KEY POINTS What is known?O_LIChildhood internalising problems are influenced by genetic, prenatal, and postnatal environments and are risk factors for later depression. C_LIO_LIDNA methylation (DNAm) has been proposed as a potential biological mechanism linking early exposures to mental health outcomes, though evidence remains inconsistent. C_LI What is new?O_LIThis meta-analysis examined associations between child blood DNAm and internalising problems at multiple time points using both probe- and region-level approaches. C_LIO_LIRegion-level analyses, rather than individual CpG sites, revealed associations with internalising problems, identifying regions annotated to genes previously linked to psychiatric phenotypes. C_LI What is significant for clinical practice?O_LIWhile findings are preliminary, they suggest that DNAm signatures in early life may help identify biological pathways relevant to childhood internalising problems. C_LIO_LILarger, longitudinal studies with detailed phenotyping are warranted to confirm these associations before translating DNAm findings into clinical risk markers or interventions. C_LI