Longitudinal epigenetic predictors of amygdala:hippocampus volume ratio

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), and 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 101patients 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.