Divergent epigenetic responses to perinatal asphyxia in severe mental disorders

Abstract

Epigenetic modifications influenced by environmental exposures are molecular sources of phenotypic heterogeneity found in schizophrenia and bipolar disorder and may contribute to shared etiopathogenetic mechanisms of these two disorders. Newborns who experienced perinatal asphyxia have suffered reduced oxygen delivery to the brain around the time of birth, which increases the risk of later psychiatric diagnosis. This study aimed to investigate DNA methylation in blood cells for associations with a history of perinatal asphyxia, a neurologically harmful condition occurring within the biological environment of birth. We utilized prospective data from the Medical Birth Registry of Norway to identify incidents of perinatal asphyxia in 643 individuals with schizophrenia or bipolar disorder and 676 healthy controls. We performed an epigenome wide association study to distinguish differentially methylated positions associated with perinatal asphyxia. We found an interaction between methylation and exposure to perinatal asphyxia on case-control status, wherein having a history of perinatal asphyxia was associated with an increase of methylation in healthy controls and a decrease of methylation in patients on 4 regions of DNA important for brain development and function. The differentially methylated regions were observed in genes involved in oligodendrocyte survival and axonal myelination and functional recovery (LINGO3); assembly, maturation and maintenance of the brain (BLCAP;NNAT and NANOS2) and axonal transport processes and neural plasticity (SLC2A14). These findings are consistent with the notion that an opposite epigenetic response to perinatal asphyxia, in patients compared with controls, may contribute to molecular mechanisms of risk for schizophrenia and bipolar disorder.

Fig. 1. Overview of the participants included in the sample.

Perinatal asphyxia data from the Medical Birth Registry of Norway (MBRN) is available on births from 1967; therefore, if the participant was not born in Norway or is >50 years, they would not have birth registry information in the MBRN. Quality control (QC); European ancestry (EUR); schizophrenia (SZ); bipolar disorder (BD); major depressive disorder (MDD).

Fig. 2. Differentially methylated regions (DMRs) with a significant perinatal asphyxia × DNAm interaction on case/control status.

Across the four DMRs, methylation patterns differed between groups with perinatal asphyxia exposure. Shaded area represents standard error of the mean (SE). Beta values are for blood methylation status (y-axis).

Fig. 3

Scatterplot demonstrating the correlation between DNA methylation profiles associated with perinatal asphyxia between groups.