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

Tianye Jia, Jenny van Dongen, Nicola J Armstrong, Anouk den Braber, Rick Jansen, Rachel Brouwer, Dorret I Boomsma, Dennis van t Ent, Sylvane Desrivières, ENIGMA Epigenetics Working Group

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)-three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.

Original languageEnglish
Pages (from-to)3884-3895
JournalMolecular Psychiatry
Volume26
Issue number8
Early online date6 Dec 2019
DOIs
Publication statusPublished - Aug 2021

Funding

FundersFunder number
National Institutes of HealthU54 EB020403
National Institute on AgingR56AG058854
Horizon 2020 Framework Programme695313
Sixth Framework ProgrammeLSHM-CT- 2007-037286
FP7 Joint Technology Initiatives115300-2
FP7 Health603016
National Outstanding Youth Science Fund Project of National Natural Science Foundation of ChinaB18015
Medical Research CouncilMR/N027558/1, MR/N000390/1
Svenska Forskningsrådet Formas259-2012-23
Science and Technology Commission of Shanghai Municipality16JC1420402, 2018SHZDZX01, 18PJ1400900
Medical Research FoundationMR/R00465X/1
National Natural Science Foundation of China-Yunnan Joint Fund81801773

    Cohort Studies

    • Netherlands Twin Register (NTR)

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