Genome-wide DNA methylation patterns associated with general psychopathology in children

Abstract

Psychiatric symptoms are interrelated and found to be largely captured by a general psychopathology factor (GPF). Although epigenetic mechanisms, such as DNA methylation (DNAm), have been linked to individual psychiatric outcomes, associations with GPF remain unclear. Using data from 440 children aged 10 years participating in the Generation R Study, we examined the associations of DNAm with both general and specific (internalizing, externalizing) factors of psychopathology. Genome-wide DNAm levels, measured in peripheral blood using the Illumina 450K array, were clustered into wider co-methylation networks (‘modules’) using a weighted gene co-expression network analysis. One co-methylated module associated with GPF after multiple testing correction, while none associated with the specific factors. This module comprised of 218 CpG probes, of which 198 mapped onto different genes. The CpG most strongly driving the association with GPF was annotated to FZD1, a gene that has been implicated in schizophrenia and wider neurological processes. Associations between the probes contained in the co-methylated module and GPF were supported in an independent sample of children from the Avon Longitudinal Study of Parents and Children (ALSPAC), as evidenced by significant correlations in effect sizes. These findings might contribute to improving our understanding of dynamic molecular processes underlying complex psychiatric phenotypes.

Epigenome-Wide Associations of Placental DNA Methylation and Behavioral and Emotional Difficulties in Children at 3 Years of Age

“…Epigenome-wide association studies (EWAS) have the potential to uncover other pathways tuning brain wiring, development, and behavior. However, contrary to studies in cord blood [41][42][43][44][45], only one placental EWAS has so far been performed with regard to neonates' neurobehavior [33]. In this study, conducted on 335 participants, the authors found a statistically significant association between two CpGs within FHIT (cg15970800) and ANKRD11 (cg16710656) and neonate attention.…”

DNA methylation and general psychopathology in childhood: an epigenome-wide meta-analysis from the PACE consortium

“…Another important strength is the use of standardized protocols and scripts to fit GPF to the data in a multicohort setting. The GPF scores we analyzed were previously found to associate with a module of co-methylated DNAm probes across the genome [ 23 ], suggesting that it is possible to detect biological correlates of GPF using this study’s measure. Furthermore, the current study showed that GPF consistently negatively correlated with child cognition across the cohorts as expected based on existing evidence [ 7 ], suggesting that it is capturing a similar, valid construct across the cohorts.…”

“…In turn, alterations in DNAm patterns across the genome in peripheral tissues including cord blood, and peripheral blood have been found to associate with a wide range of child and adult mental health outcomes, such as conduct problems, attention deficit hyperactivity disorder (ADHD) symptoms, major depressive disorder (MDD), and schizophrenia [ 19 – 22 ]. Despite a growing body of research implicating an involvement of DNAm in individual mental health outcomes, much less work has focused on the relationship between DNAm and general psychopathology [ 23 ]. To the best of our knowledge, only one study examined the association between genome-wide DNAm patterns and GPF in childhood.…”

“…To the best of our knowledge, only one study examined the association between genome-wide DNAm patterns and GPF in childhood. In this study, data were analyzed cross-sectionally in one cohort, focusing on wider biological networks (so called ‘modules’) of co-methylated DNAm probes across the genome [ 23 ]. As such, we still lack knowledge on how GPF relates to single DNAm probes and the extent to which associations vary across time (i.e., both cross-sectional and prospective associations).…”

“…[19][20][21][22] Despite a growing body of research implicating an involvement of DNAm in individual mental health outcomes, much less work has focused on the relationship between DNAm and general psychopathology. 23 To the best of our knowledge, only one study examined the association between genome-wide DNAm patterns and GPF in childhood. In this study, data were analyzed cross-sectionally in one cohort, focusing on wider biological networks (so called 'modules') of co-methylated DNAm probes across the genome.…”