Longitudinal Epigenetic Predictors of Amygdala:hippocampus Volume Ratio

J Child Psychol Psychiatry. 2017 Dec;58(12):1341-1350. doi: 10.1111/jcpp.12740. Epub 2017 May 8.

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 (a) whether DNA methylation in early life (birth, age 7) prospectively associates with total AH volume ratio in early adulthood, and (b) 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, 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 multilevel modeling.

Results: Amygdala:hippocampal volume ratio correlated positively with age 18 psychosis-like symptoms (p = .007). Methylation of a probe in the gene SP6 associated longitudinally with (a) higher AH volume ratio (FDR q-value = .01) and (b) higher stressful life events during pregnancy (p = .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.

Keywords: Avon Longitudinal Study of Parents and Children; DNA methylation; amygdala; hippocampus; longitudinal; methylome-wide.

MeSH terms

  • Adolescent
  • Adult
  • Amygdala / anatomy & histology*
  • Amygdala / diagnostic imaging
  • Amygdala / metabolism
  • Amygdala / pathology
  • Child
  • DNA Methylation*
  • Epigenesis, Genetic
  • Female
  • Hippocampus / anatomy & histology*
  • Hippocampus / diagnostic imaging
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Humans
  • Infant, Newborn
  • Kruppel-Like Transcription Factors / metabolism
  • Longitudinal Studies
  • Magnetic Resonance Imaging
  • Male
  • Pregnancy
  • Prenatal Exposure Delayed Effects*
  • Psychotic Disorders / diagnostic imaging
  • Psychotic Disorders / metabolism*
  • Psychotic Disorders / pathology*
  • Risk
  • Stress, Psychological / complications*
  • Young Adult

Substances

  • Kruppel-Like Transcription Factors