Abstract
Childhood adversity is an early life stressor associated with increased risk of several psychiatric disorders such as depression. Epigenetic changes, primarily DNA methylation, can be affected by early life stress, which in turn might contribute to altered disease susceptibility later in life. One plausible biomarker of early life stress is methylation of the ionotropic glutamate receptor NMDA type subunit 2B (GRIN2B) gene, which has been previously shown to be epigenetically affected by prenatal environmental stressors. Here, we set out to investigate if stress-inducing adversity during childhood is associated with changes in methylation of GRIN2B in adulthood. We studied 186 individuals from a Swedish naturalistic population-based cohort who had provided saliva samples (DNA) as well as information regarding both childhood adversity (CA) and depressive symptoms (dep) (nCA,dep = 41, nCA,no-dep = 56, nno-CA,dep = 40, Nno-CA,no-dep = 49). Methylation at four CpG sites in a regulatory region of GRIN2B was analysed using bisulfite pyrosequencing. Associations for methylation status to childhood adversity and to depression status were investigated using linear regression models. Our study shows that childhood adversity is associated with increased methylation levels of GRIN2B in adulthood, for three of the measured CpGs (p = 0.007, 0.006 and 5 × 10−14). This indicates that GRIN2B methylation is susceptible to early life stress, and that methylation at this gene is persistent over time. No association was found between GRIN2B methylation and depression status. Yet, this does not rule out a role for alterations in GRIN2B methylation for other neuropsychological outcomes not studied here.
Highlights
On top of the genetic information, environmental factors, especially early in life, shape an organism’s phenotype and disease susceptibility later in life (Gluckman and Hanson, 2004; Suzuki, 2018)
Childhood adversity (CA), such as parental death, neglect, sexual, physical or emotional abuse, and friction within the family, is an early life stressor that has been associated with an increased risk of psychiatric disorders like depression (Collishaw et al, 2007; Widom et al, 2007; Liu, 2017), psychosis (Varese et al, 2012) and schizophrenia (Wells et al, 2020), and with cognitive impairments (Pechtel and Pizza galli, 2011; Martins et al, 2019; Wells et al, 2020)
We have previously shown that methylation in a GRIN2B regulatory region is affected by chemical exposure during development (Alavian- Ghavanini et al, 2018), and others have shown that GRIN2B methyl ation is altered in schizophrenia patients (Fachim et al, 2019)
Summary
On top of the genetic information, environmental factors, especially early in life, shape an organism’s phenotype and disease susceptibility later in life (Gluckman and Hanson, 2004; Suzuki, 2018). Changes in epigenetic patterns, such as DNA methylation, induced during development can be stable throughout life and are thought to be one link between early life expo sures and health outcomes later in life (Marsit, 2015; Provencal and Binder, 2015; Tran and Miyake, 2017; Burns et al, 2018; Goyal et al, 2019; Park et al, 2019). Methylation of genes with other cellular functions such as cellular/neuronal plasticity has been reported to be affected by CA (Labonte et al, 2012; Yang et al, 2013; Checknita et al, 2018), indicating that several molecular mechanisms may underlie associations between CA and mental and cognitive health outcomes later in life
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