A peripheral epigenetic signature of immune system genes is linked to neocortical thickness and memory

Abstract

Increasing age is tightly linked to decreased thickness of the human neocortex. The biological mechanisms that mediate this effect are hitherto unknown. The DNA methylome, as part of the epigenome, contributes significantly to age-related phenotypic changes. Here, we identify an epigenetic signature that is associated with cortical thickness (P=3.86 × 10−8) and memory performance in 533 healthy young adults. The epigenetic effect on cortical thickness was replicated in a sample comprising 596 participants with major depressive disorder and healthy controls. The epigenetic signature mediates partially the effect of age on cortical thickness (P<0.001). A multilocus genetic score reflecting genetic variability of this signature is associated with memory performance (P=0.0003) in 3,346 young and elderly healthy adults. The genomic location of the contributing methylation sites points to the involvement of specific immune system genes. The decomposition of blood methylome-wide patterns bears considerable potential for the study of brain-related traits.

Cross Talk: The Microbiota and Neurodevelopmental Disorders

“…A bidirectional communication system exists between the immune system and the CNS. Neuroimmune signaling during the prenatal or early post-natal developmental stages can have long lasting effects on the brain, and is an important determinant of cognitive function and emotional behavior (Dantzer et al, 2008 ; Bilbo et al, 2012 ; Filiano et al, 2017 ; Freytag et al, 2017 ). Peripheral cytokine signaling can modulate astrocytes, microglia and neurons in the CNS (Kohman and Rhodes, 2013 ).…”

Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group

“…Crucially, while initial reports have demonstrated that although DNA methylation patterns are largely tissue-specific, often differing between blood and brain [20,21], there are also similarities [22] and blood DNA methylation shows promise as a biomarker for brain-related traits, including neuropsychiatric disorders [23][24][25][26][27], cognitive ability [28,29] and future psychopathology [26]. However, only a few studies of small sample sizes have reported associations between blood DNA methylation and brain phenotypes [26,[30][31][32].…”

A systematic review of neuroimaging epigenetic research: Calling for an increased focus on development

“…5 No association was found between either EAA measure and cortical thickness. 16 The heterogeneity in these findings reflect the current uncertainty in the field of epigenetic ageing overall. 22 Studies that followed a candidate gene approach focused primarily on SERT (n=13), followed by OXT/R (n=8), FKBP5 (n=7), NR3C1 (n=4), and BDNF (n=4).…”

“…Six studies included a replication step in an independent cohort and none performed a meta-analysis of multiple cohorts. For instance, Freytag et al 16 performed independent component analysis on 450k DNAm data in blood in a sample of 514 healthy young adults. One of these DNAm components, enriched for processes related to immune function and inflammation, was associated with cortical thickness after correcting for age.…”

“…EAA (in all studies residualized or controlled for chronological age) was investigated predominantly in studies interested in stress or age-related cognitive decline. 5,16,[18][19][20][21] Most studies reported a negative association between Horvath's EAA and brain morphology, such as global white matter tract integrity 20 and left hippocampal volume. 19 Negative associations were also reported between Hannum's EAA and integrity of the corpus callosum measures via diffusion MRI.…”