DNA methylation at birth and lateral ventricular volume in childhood: a neuroimaging epigenetics study

Abstract

BackgroundLateral ventricular volume (LVV) enlargement has been repeatedly linked to schizophrenia; yet, what biological factors shape LVV during early development remain unclear. DNA methylation (DNAm), an essential process for neurodevelopment that is altered in schizophrenia, is a key molecular system of interest.MethodsIn this study, we conducted the first epigenome‐wide association study of neonatal DNAm in cord blood with LVV in childhood (measured using T1‐weighted brain scans at 10 years), based on data from a large population‐based birth cohort, the Generation R Study (N = 840). Employing both probe‐level and methylation profile score (MPS) approaches, we further examined whether epigenetic modifications identified at birth in cord blood are: (a) also observed cross‐sectionally in childhood using peripheral blood DNAm at age of 10 years (Generation R, N = 370) and (b) prospectively associated with LVV measured in young adulthood in an all‐male sample from the Avon Longitudinal Study of Parents and Children (ALSPAC, N = 114).ResultsAt birth, DNAm levels at four CpGs (annotated to potassium channel tetramerization domain containing 3, KCTD3; SHH signaling and ciliogenesis regulator, SDCCAG8; glutaredoxin, GLRX) prospectively associated with childhood LVV after genome‐wide correction; these genes have been implicated in brain development and psychiatric traits including schizophrenia. An MPS capturing a broader epigenetic profile of LVV – but not individual top hits – showed significant cross‐sectional associations with LVV in childhood in Generation R and prospectively associated with LVV in early adulthood within ALSPAC.ConclusionsThis study finds suggestive evidence that DNAm at birth prospectively associates with LVV at different life stages, albeit with small effect sizes. The prediction of MPS on LVV in a childhood sample and an independent male adult sample further underscores the stability and reproducibility of DNAm as a potential marker for LVV. Future studies with larger samples and comparable time points across development are needed to further elucidate how DNAm associates with this clinically relevant brain structure and risk for neuropsychiatric disorders, and what factors explain the identified DNAm profile of LVV at birth.

Epigenome Defines Aberrant Brain Laterality in Major Mental Illnesses

“…More evidence in support of the epigenetic regulation/determination of language and handedness comes from a meta-analysis of the whole-blood DNA methylation of almost 4000 adults, reporting that the DNA methylation of CpG sites closed to the genetic variants associated with handedness were significantly linked to left-handedness compared to other CpG sites [ 124 ]. A more recent genome-wide DNA methylation analysis of neonate’s cord blood revealed that the methylation of KCTD , SDCCAG8 , and GLRX genes which are involved in brain functions are prospectively associated with the left ventricle volume at age 10 years [ 125 ], with an enlargement in SCZ (see Table 1 ).…”

Consortium Profile: The Methylation, Imaging and NeuroDevelopment (MIND) Consortium

“…An alternative approach to address developmental timing in multi-cohort studies involves strategic pooling of summary data at specific age ranges, as opposed to pooling all cohorts together regardless of age. This approach is commonly used in the PACE consortium (e.g., [6,37]), prioritize one epigenetic time point of interest (e.g., birth, because it is generally the time point with the largest sample size, or because of a focus on pregnancy exposures) and then query later DNAm assessments by (i) adopting a follow-forward approach, where significant CpG sites are selected for further analysis and tested at subsequent time points (e.g., [7,9,47]) or by (ii) conducting a completely new set of analyses at later developmental stages (e.g., running separate epigenome-wide analyses using DNAm at birth and DNAm in childhood in relation to the same child outcome [6,37]). While this strategy helps to partition analyses according to more developmentally-specific age groups, it does not directly quantify temporal changes in DNAm-brain associations, nor does it account for the potential non-linearity of this relationship over time.…”

“…DNA methylation (DNAm) is an epigenetic process that can regulate gene activity in response to both genetic and environmental influences [1,2], beginning in utero. While DNAm plays a key role in healthy development and function [3], alterations in DNAm have also been linked to the emergence of disease states, including brain-based disorders such as neurodevelopmental, psychiatric, and neurological conditions [4][5][6][7][8][9][10]. In addition, peripheral markers of DNAm are often more accessible to measure than several brain-based phenotypes.…”