Longitudinal epigenetic predictors of amygdala:hippocampus volume ratio

Abstract

Background The ratio between amygdala:hippocampal (AH) volume has been associated with multiple psychiatric problems, including anxiety and aggression. Yet, little is known about its biological underpinnings. Here, we used a methylome-wide approach to test (1) whether DNA methylation in early life (birth, age 7) prospectively associates with total AH volume ratio in early adulthood, and (2) whether significant DNA methylation markers are influenced by prenatal risk factors. Methods Analyses were based on a subsample (n = 109 males) from the Avon Longitudinal Study of Parents and Children (ALSPAC), which included measures of prenatal risk, DNA methylation (Infinium Illumina 450k), T1-weighted brain scans and psychopathology in early adulthood (age 18-21). Amygdala and hippocampus measures were derived using Freesurfer 5.3.0. Methylation markers related to AH volume ratio across time were identified using longitudinal multi-level modeling. Results AH volume ratio correlated positively with age 18 psychosis-like symptoms (p = 0.007). Methylation of a probe in the gene SP6 associated longitudinally with (1) higher AH volume ratio (FDR q-value = 0.01) and (2) higher stressful life events during pregnancy (p = 0.046). SP6 is expressed in the hippocampus and amygdala and has been implicated in cognitive decline in Alzheimer's disease. The association between SP6 DNA methylation, AH volume ratio and psychopathology was replicated in an independent dataset of 101 patients with schizophrenia and 111 healthy controls. Conclusions Our findings suggest that epigenetic alterations in genes implicated in neurodevelopment may contribute to a brain-based biomarker of psychopathology.

A Methylome‐Wide Association Study of Trajectories of Oppositional Defiant Behaviors and Biological Overlap With Attention Deficit Hyperactivity Disorder

“…In living humans, the study of DNA methylation is often limited to peripheral samples, which may not necessarily be a surrogate of CNS activity or be mechanistically involved in a disease. For example, although certain studies with living children/adolescents have attempted to biologically characterize the identified DNA methylation associations by testing whether effects replicate across multiple tissues (Dadds, Schollar‐Root, Lenroot, Moul, & Hawes, ), associate with gene expression (Ruggeri et al., ), or even the structure or function of the brain (Walton et al., ), the mechanistic role of peripheral DNA methylation in the etiology of psychopathology is largely unknown. In fact, it is equally possible that DNA methylation can function as a noncausal biomarker of environmental risk exposure and/or stress‐related disorders.…”

“…Hypothesis-free scans of DNA methylation across the genome (i.e., the methylome) allow for discovery of novel biological correlates, which can aid in the development of more accurate and holistic etiologic knowledge. A recent methylome-wide analysis study by Walton et al (2016), for example, reported a developmental trajectory of high ADHD symptoms (ages 7-15) associated with DNA methylation (at birth) in 13 genetic loci. Of interest, one of the methylome-wide significant loci was linked to ZNF544, previously shown to associate with ADHD (Lasky-Su et al, 2008).…”

“…Of interest, one of the methylome-wide significant loci was linked to ZNF544, previously shown to associate with ADHD (Lasky-Su et al, 2008). Walton et al (2016) did not assess the extent to which DNA methylation loci were influenced by genetic influence and/or prenatal environmental stress exposures or if the ADHD loci associated with ODD-despite research previously described showing genetic and environmental influences on both DNA methylation Rijlaarsdam et al, 2017) and the comorbidity ODD and ADHD .…”

“…Furthermore, recent research suggests that epigenetic effects on the development of psychiatric disorder can be time specific, with DNA methylation at birth indexing early biological vulnerability . Walton et al (2016) utilized the same youth as the present study, and all methylome-wide significant associations were identified at birth, which makes for an optimal framework to compare early biological pathways shared between ODD, the ODD subdimensions, and ADHD. The third aim was to assess genetic influence (i.e., mQTL) on the methylome-wide significant ODD and subdimension DNA methylation loci.…”

Epigenetics applied to psychiatry: Clinical opportunities and future challenges

“…Emerging studies have reported encouraging results concerning the use of methylation changes as diagnostic tools for behavioral and clinical precision phenotyping of patients . A longitudinal study has shown association between SP6 gene DNA methylation, amygdala/hippocampal volume ratio, and psychopathology, supporting the role of DNA methylation as a longitudinal epigenetic predictor. Moreover, blood methylation levels of 5‐HTT and/or BDNF genes have been suggested as promising biomarkers for prediction of pharmacological or psychotherapeutic treatment response in patients suffering from MDD, BD, BPD, PTSD, SCZ and ADHD .…”